Christine Kilgore

WASHINGTON – Dietary fiber impacts not only the composition of the gut microbiome, but the production of a broad spectrum of microbiota-produced metabolites – including amino acid metabolites – that may modify health, said Gary D. Wu, MD, of the University of Pennsylvania, Philadelphia.

During the 2022 Gut Microbiota for Health World Summit, organized by the American Gastroenterological Association and the European Society of Neurogastroenterology and Motility, Dr. Wu led a plenary session in which the impact of diet on the microbiome was characterized as important, rapid, personalized, likely modest relative to other contributing ecological factors, influenced by the process of cooking, and exceedingly difficult to tease apart and characterize in human studies.

In a human study published in 2021, Dr. Wu and coinvestigators performed a controlled feeding experiment with 30 healthy volunteers, randomizing them to several weeks of a vegan diet, an omnivore diet (a typical American diet), and an exclusive enteral nutrition diet (EEN) devoid of dietary fiber.

They compared the composition and metabolic function of the gut microbiome during three phases: an initial dietary phase (days 1-5), a purge phase in which antibiotics and polyethylene glycol were administered to transiently reduce bacterial load in the gut (days 6-8), and a recovery phase (days 9-15).

Diversity of the gut microbiota recovered from the purge phase in both vegans and omnivores, but not in those receiving EEN. “The EEN diet was having a profound effect on the [short-term] recovery of microbiota,” said Dr. Wu, the Ferdinand G. Weisbrod Professor in Gastroenterology, in describing the Food And Resulting Microbial Metabolites study.

Using genetic sequencing, microbial culturing, and bioinformatics processing, the researchers also determined that EEN subsequently led to metabolites that were distinct from omnivores and vegans. Unexpectedly, bacterial metabolites of amino acid origin – not only carbohydrate origin – were altered in the EEN group, suggesting a broad impact of dietary fiber on the bacterial metabolome. EEN-induced alterations in the microbiome and metabolome resolved after the study period, he noted.

In other words, “depriving or supplying the gut microbiome with one dietary component (i.e., fiber) can directly impact metabolites of an unrelated portion of the diet (i.e., amino acids) via the induction of specific gut bacterial taxa,” Dr. Wu and colleagues wrote.

Clinically, the results as a whole suggest that the combination of antibiotics with EEN may be less effective in patients with Crohn’s disease than EEN alone, and can be potentially harmful, they said.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Wu said that, for patients in the ICU on EEN treatment and antibiotics, “we do need to think carefully about microbiota reconstitution because it could have a very significant effect not only on short-chain fatty acid metabolites but on amino acid metabolites that may be good or bad in the setting of disease.”

The scientific rationale for the effectiveness of EEN for IBD is still not well understood, he noted. “All I can say is that EEN works in IBD, but there are aspects about the microbiota and diet and IBD that we don’t understand.”


 

Dietary impact through the immigration lens

In another presentation, Dan Knights, PhD, of the University of Minnesota, Minneapolis, described his lab’s findings on the association of U.S. immigration with loss of gut microbiome diversity, and the role of diet.

As part of the Immigration Microbiome Project reported several years ago, his team collected stool, dietary recalls, and anthropometrics from 550 Hmong and Karen individuals living in Thailand and the United States, including first- and second-generation immigrants, as well as some U.S.-born European American individuals. They found that the gut microbiome of immigrants changed within months of arriving in the United States, and that immigration status had a stronger effect on the microbiome than obesity status.

“By the time people were in their second generation, their microbiomes were roughly on the same order of diversity as U.S. controls,” said Dr. Knights, associate professor in the Biotechnology Institute and the department of computer science and engineering.

Dietary changes only partly explained microbiome variation, however. “By the second generation, the microbiome tended to be fully Westernized, but the diet was only partly Westernized,” he said. “Diet is only part of the story.”

Other research from his lab, including one study that performed daily fecal shotgun sequencing on 34 people, has found that effects of diet on the microbiome are likely to be observable within days, and that microbial responses to food are highly personalized. Diet appears to explain about 6% of the daily microbiome variation within an individual, and “an average diet explains about 4% of microbiome variation between people,” Dr. Knights said.
 

The impact of cooking

“The gut microbiota responds to food and to its form,” said Rachel N. Carmody, PhD, of the department of human evolutionary biology at Harvard University, Cambridge, during the plenary session. Her research has shown that, in mice, a plant diet served raw versus cooked quickly reshaped the gut microbiome and disrupted gut microbial physiology. Notably, shifts in gut microbiota modulated host energy status – one of the many areas that begs further research.

The effects of cooking have also been detectable in human pilot studies. “We saw different changes in the microbiome when [study participants] were eating the same plant items either raw or cooked,” she said. “Some microbes were affected only on the raw diet, other were affected only on the cooked diet.”

Other research in animal models and humans has demonstrated a significant amount of plasticity in the microbiome in response to diet. “In mice you get the microbiome signatures to shift within 24 hours by feeding them a new diet,” Dr. Carmody said.

In an interview about the plenary session, Eugene B. Chang, MD, the Martin Boyer Distinguished Professor of Medicine at the University of Chicago, said that he was struck both by the resiliency of individual gut microbiomes overall and by findings that, “in animal models where conditions and diets can be carefully controlled, diet and environment are major drivers of gut microbial membership and function.”

Dr. Chang coled a separate workshop on “defining a healthy gut microbiome” – a task that he said remains “a challenge [and is not yet] resolved, at least with general consensus.”

Dr. Chang, Dr. Wu, and Dr. Carmody reported no relevant disclosures. Dr. Knights disclosed that he is a paid adviser to Diversigen, a company involved with the commercialization of microbiome analysis.

The 2022 Gut Microbiota for Health World Summit was supported by sponsorships from Danone, Ferring Pharmaceuticals, Aimmune Therapeutics and Seres Therapeutics, Sanofi, and Intrinsic Medicine Inc. with additional support from educational grants provided by Ferring Pharmaceuticals and Salix Pharmaceuticals.

Through the AGA Center for Gut Microbiome Research and Education, AGA is committed to keeping you up-to-speed on the latest news, research and policy updates related to the gut microbiome: www.gastro.org/microbiome.

WASHINGTON – Dietary fiber impacts not only the composition of the gut microbiome, but the production of a broad spectrum of microbiota-produced metabolites – including amino acid metabolites – that may modify health, said Gary D. Wu, MD, of the University of Pennsylvania, Philadelphia.

During the 2022 Gut Microbiota for Health World Summit, organized by the American Gastroenterological Association and the European Society of Neurogastroenterology and Motility, Dr. Wu led a plenary session in which the impact of diet on the microbiome was characterized as important, rapid, personalized, likely modest relative to other contributing ecological factors, influenced by the process of cooking, and exceedingly difficult to tease apart and characterize in human studies.

In a human study published in 2021, Dr. Wu and coinvestigators performed a controlled feeding experiment with 30 healthy volunteers, randomizing them to several weeks of a vegan diet, an omnivore diet (a typical American diet), and an exclusive enteral nutrition diet (EEN) devoid of dietary fiber.

They compared the composition and metabolic function of the gut microbiome during three phases: an initial dietary phase (days 1-5), a purge phase in which antibiotics and polyethylene glycol were administered to transiently reduce bacterial load in the gut (days 6-8), and a recovery phase (days 9-15).

Diversity of the gut microbiota recovered from the purge phase in both vegans and omnivores, but not in those receiving EEN. “The EEN diet was having a profound effect on the [short-term] recovery of microbiota,” said Dr. Wu, the Ferdinand G. Weisbrod Professor in Gastroenterology, in describing the Food And Resulting Microbial Metabolites study.

Using genetic sequencing, microbial culturing, and bioinformatics processing, the researchers also determined that EEN subsequently led to metabolites that were distinct from omnivores and vegans. Unexpectedly, bacterial metabolites of amino acid origin – not only carbohydrate origin – were altered in the EEN group, suggesting a broad impact of dietary fiber on the bacterial metabolome. EEN-induced alterations in the microbiome and metabolome resolved after the study period, he noted.

In other words, “depriving or supplying the gut microbiome with one dietary component (i.e., fiber) can directly impact metabolites of an unrelated portion of the diet (i.e., amino acids) via the induction of specific gut bacterial taxa,” Dr. Wu and colleagues wrote.

Clinically, the results as a whole suggest that the combination of antibiotics with EEN may be less effective in patients with Crohn’s disease than EEN alone, and can be potentially harmful, they said.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Wu said that, for patients in the ICU on EEN treatment and antibiotics, “we do need to think carefully about microbiota reconstitution because it could have a very significant effect not only on short-chain fatty acid metabolites but on amino acid metabolites that may be good or bad in the setting of disease.”

The scientific rationale for the effectiveness of EEN for IBD is still not well understood, he noted. “All I can say is that EEN works in IBD, but there are aspects about the microbiota and diet and IBD that we don’t understand.”


 

Dietary impact through the immigration lens

In another presentation, Dan Knights, PhD, of the University of Minnesota, Minneapolis, described his lab’s findings on the association of U.S. immigration with loss of gut microbiome diversity, and the role of diet.

As part of the Immigration Microbiome Project reported several years ago, his team collected stool, dietary recalls, and anthropometrics from 550 Hmong and Karen individuals living in Thailand and the United States, including first- and second-generation immigrants, as well as some U.S.-born European American individuals. They found that the gut microbiome of immigrants changed within months of arriving in the United States, and that immigration status had a stronger effect on the microbiome than obesity status.

“By the time people were in their second generation, their microbiomes were roughly on the same order of diversity as U.S. controls,” said Dr. Knights, associate professor in the Biotechnology Institute and the department of computer science and engineering.

Dietary changes only partly explained microbiome variation, however. “By the second generation, the microbiome tended to be fully Westernized, but the diet was only partly Westernized,” he said. “Diet is only part of the story.”

Other research from his lab, including one study that performed daily fecal shotgun sequencing on 34 people, has found that effects of diet on the microbiome are likely to be observable within days, and that microbial responses to food are highly personalized. Diet appears to explain about 6% of the daily microbiome variation within an individual, and “an average diet explains about 4% of microbiome variation between people,” Dr. Knights said.
 

The impact of cooking

“The gut microbiota responds to food and to its form,” said Rachel N. Carmody, PhD, of the department of human evolutionary biology at Harvard University, Cambridge, during the plenary session. Her research has shown that, in mice, a plant diet served raw versus cooked quickly reshaped the gut microbiome and disrupted gut microbial physiology. Notably, shifts in gut microbiota modulated host energy status – one of the many areas that begs further research.

The effects of cooking have also been detectable in human pilot studies. “We saw different changes in the microbiome when [study participants] were eating the same plant items either raw or cooked,” she said. “Some microbes were affected only on the raw diet, other were affected only on the cooked diet.”

Other research in animal models and humans has demonstrated a significant amount of plasticity in the microbiome in response to diet. “In mice you get the microbiome signatures to shift within 24 hours by feeding them a new diet,” Dr. Carmody said.

In an interview about the plenary session, Eugene B. Chang, MD, the Martin Boyer Distinguished Professor of Medicine at the University of Chicago, said that he was struck both by the resiliency of individual gut microbiomes overall and by findings that, “in animal models where conditions and diets can be carefully controlled, diet and environment are major drivers of gut microbial membership and function.”

Dr. Chang coled a separate workshop on “defining a healthy gut microbiome” – a task that he said remains “a challenge [and is not yet] resolved, at least with general consensus.”

Dr. Chang, Dr. Wu, and Dr. Carmody reported no relevant disclosures. Dr. Knights disclosed that he is a paid adviser to Diversigen, a company involved with the commercialization of microbiome analysis.

The 2022 Gut Microbiota for Health World Summit was supported by sponsorships from Danone, Ferring Pharmaceuticals, Aimmune Therapeutics and Seres Therapeutics, Sanofi, and Intrinsic Medicine Inc. with additional support from educational grants provided by Ferring Pharmaceuticals and Salix Pharmaceuticals.

Through the AGA Center for Gut Microbiome Research and Education, AGA is committed to keeping you up-to-speed on the latest news, research and policy updates related to the gut microbiome: www.gastro.org/microbiome.

WASHINGTON – Dietary fiber impacts not only the composition of the gut microbiome, but the production of a broad spectrum of microbiota-produced metabolites – including amino acid metabolites – that may modify health, said Gary D. Wu, MD, of the University of Pennsylvania, Philadelphia.

During the 2022 Gut Microbiota for Health World Summit, organized by the American Gastroenterological Association and the European Society of Neurogastroenterology and Motility, Dr. Wu led a plenary session in which the impact of diet on the microbiome was characterized as important, rapid, personalized, likely modest relative to other contributing ecological factors, influenced by the process of cooking, and exceedingly difficult to tease apart and characterize in human studies.

In a human study published in 2021, Dr. Wu and coinvestigators performed a controlled feeding experiment with 30 healthy volunteers, randomizing them to several weeks of a vegan diet, an omnivore diet (a typical American diet), and an exclusive enteral nutrition diet (EEN) devoid of dietary fiber.

They compared the composition and metabolic function of the gut microbiome during three phases: an initial dietary phase (days 1-5), a purge phase in which antibiotics and polyethylene glycol were administered to transiently reduce bacterial load in the gut (days 6-8), and a recovery phase (days 9-15).

Diversity of the gut microbiota recovered from the purge phase in both vegans and omnivores, but not in those receiving EEN. “The EEN diet was having a profound effect on the [short-term] recovery of microbiota,” said Dr. Wu, the Ferdinand G. Weisbrod Professor in Gastroenterology, in describing the Food And Resulting Microbial Metabolites study.

Using genetic sequencing, microbial culturing, and bioinformatics processing, the researchers also determined that EEN subsequently led to metabolites that were distinct from omnivores and vegans. Unexpectedly, bacterial metabolites of amino acid origin – not only carbohydrate origin – were altered in the EEN group, suggesting a broad impact of dietary fiber on the bacterial metabolome. EEN-induced alterations in the microbiome and metabolome resolved after the study period, he noted.

In other words, “depriving or supplying the gut microbiome with one dietary component (i.e., fiber) can directly impact metabolites of an unrelated portion of the diet (i.e., amino acids) via the induction of specific gut bacterial taxa,” Dr. Wu and colleagues wrote.

Clinically, the results as a whole suggest that the combination of antibiotics with EEN may be less effective in patients with Crohn’s disease than EEN alone, and can be potentially harmful, they said.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Wu said that, for patients in the ICU on EEN treatment and antibiotics, “we do need to think carefully about microbiota reconstitution because it could have a very significant effect not only on short-chain fatty acid metabolites but on amino acid metabolites that may be good or bad in the setting of disease.”

The scientific rationale for the effectiveness of EEN for IBD is still not well understood, he noted. “All I can say is that EEN works in IBD, but there are aspects about the microbiota and diet and IBD that we don’t understand.”


 

Dietary impact through the immigration lens

In another presentation, Dan Knights, PhD, of the University of Minnesota, Minneapolis, described his lab’s findings on the association of U.S. immigration with loss of gut microbiome diversity, and the role of diet.

As part of the Immigration Microbiome Project reported several years ago, his team collected stool, dietary recalls, and anthropometrics from 550 Hmong and Karen individuals living in Thailand and the United States, including first- and second-generation immigrants, as well as some U.S.-born European American individuals. They found that the gut microbiome of immigrants changed within months of arriving in the United States, and that immigration status had a stronger effect on the microbiome than obesity status.

“By the time people were in their second generation, their microbiomes were roughly on the same order of diversity as U.S. controls,” said Dr. Knights, associate professor in the Biotechnology Institute and the department of computer science and engineering.

Dietary changes only partly explained microbiome variation, however. “By the second generation, the microbiome tended to be fully Westernized, but the diet was only partly Westernized,” he said. “Diet is only part of the story.”

Other research from his lab, including one study that performed daily fecal shotgun sequencing on 34 people, has found that effects of diet on the microbiome are likely to be observable within days, and that microbial responses to food are highly personalized. Diet appears to explain about 6% of the daily microbiome variation within an individual, and “an average diet explains about 4% of microbiome variation between people,” Dr. Knights said.
 

The impact of cooking

“The gut microbiota responds to food and to its form,” said Rachel N. Carmody, PhD, of the department of human evolutionary biology at Harvard University, Cambridge, during the plenary session. Her research has shown that, in mice, a plant diet served raw versus cooked quickly reshaped the gut microbiome and disrupted gut microbial physiology. Notably, shifts in gut microbiota modulated host energy status – one of the many areas that begs further research.

The effects of cooking have also been detectable in human pilot studies. “We saw different changes in the microbiome when [study participants] were eating the same plant items either raw or cooked,” she said. “Some microbes were affected only on the raw diet, other were affected only on the cooked diet.”

Other research in animal models and humans has demonstrated a significant amount of plasticity in the microbiome in response to diet. “In mice you get the microbiome signatures to shift within 24 hours by feeding them a new diet,” Dr. Carmody said.

In an interview about the plenary session, Eugene B. Chang, MD, the Martin Boyer Distinguished Professor of Medicine at the University of Chicago, said that he was struck both by the resiliency of individual gut microbiomes overall and by findings that, “in animal models where conditions and diets can be carefully controlled, diet and environment are major drivers of gut microbial membership and function.”

Dr. Chang coled a separate workshop on “defining a healthy gut microbiome” – a task that he said remains “a challenge [and is not yet] resolved, at least with general consensus.”

Dr. Chang, Dr. Wu, and Dr. Carmody reported no relevant disclosures. Dr. Knights disclosed that he is a paid adviser to Diversigen, a company involved with the commercialization of microbiome analysis.

The 2022 Gut Microbiota for Health World Summit was supported by sponsorships from Danone, Ferring Pharmaceuticals, Aimmune Therapeutics and Seres Therapeutics, Sanofi, and Intrinsic Medicine Inc. with additional support from educational grants provided by Ferring Pharmaceuticals and Salix Pharmaceuticals.

Through the AGA Center for Gut Microbiome Research and Education, AGA is committed to keeping you up-to-speed on the latest news, research and policy updates related to the gut microbiome: www.gastro.org/microbiome.

Intravenous gentamicin therapy was associated with new laminin 332 – a major component of anchoring filaments in the dermal-epidermal junction – in the skin of five pediatric patients with intermediate or severe junctional epidermolysis bullosa (JEB) caused by nonsense variants.

The newly generated structural protein persisted during the 3-month randomized clinical trial and was associated with significant wound closure – with no signs of ototoxic effects, nephrotoxic effects, or anti–laminin 332 autoantibody induction, investigators recently reported in JAMA Dermatology.

JEB is a rare, autosomal recessive disorder caused mainly by nonsense variants (i.e., mutations) in the LAMA3, LAMB3, or LAMC2 genes that encode laminin, resulting in widespread blisters and erosions of the skin. Current treatment is limited to supportive management and palliative care, and children with its severe subtype are likely to die within the first year of life.

“With data indicating a robust response to short-term gentamicin treatment and the marked stability of laminin 332, we envision that gentamicin could be delivered as a short-term pulse therapy every 2-3 months for patients with JEB caused by nonsense variants,” the researchers wrote.

Of the five patients, ages 3 months to 10 years, three received 7.5 mg/kg IV gentamicin daily for 14 days, and two received 10 mg/kg daily for 24 days at the University of Southern California, Los Angeles.

All had confirmed nonsense variants in LAMA3 or LAMB3 in one or two alleles, and all had minimal laminin 332 expression at baseline as determined by immunofluorescence. After treatment, each of the children had increased, sustained expression of laminin 332.

The researchers monitored three open wounds in each patient. By 1 month, seven of nine wounds in those receiving the lower-dose therapy and all of the wounds in those receiving the higher-dose therapy showed at least 50% closure. By 3 months, eight of nine wounds in the lower-dose group, and all wounds in the higher-dose group showed greater than 85% closure.

In an interview, senior investigators Mei Chen, PhD, professor of dermatology, and David T. Woodley, MD, professor and chair of dermatology, both at USC, emphasized laminin’s long half-life.“Once these skin structural proteins are generated at the dermal-epidermal junction, they are long-lasting structures, which means the therapy can be pulsed rather than continuously delivered, which can obviate some of the known side effects of the medication,” Dr. Woodley said.

Gentamicin, an aminoglycoside, works as a “read-through therapy,” inducing ribosomal read-through of premature termination codons (PTCs) caused by nonsense mutations. The read-through allows translation to proceed and full-length proteins to be generated.

Gentamicin read-through therapy is also being investigated for recessive dystrophic epidermolysis bullosa (RDEB) attributable to nonsense mutations. The culprit mutations in this form of EB occur in a gene that encodes collagen type VII alpha 1, which, like laminin, is responsible for dermal-epidermal adherence. A clinical trial of intravenous gentamicin for RDEB is ongoing at USC, Dr. Chen said.


 

EBS-MD case report

It may also have a role in treating epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), according to investigators in Madrid. Their case report, published in JAMA Dermatology, details how two 14-day courses of infused gentamicin therapy were followed by re-expression of plectin in the skin for 4-5 months and mild improvement in symptoms in one patient, a woman in her 30s, with a homozygous nonsense variant in PLEC1.

In an editorial accompanying the two reports, Anna L. Bruckner, MD, MSCS, professor of dermatology, University of Colorado at Denver, Aurora, and colleagues expressed cautious optimism and said that additional research on the feasibility, possible cumulative toxic effects, risk of microbial resistance, and overall clinical relevance is needed.

Still, the “investigators should be applauded for taking advantage of a readily available systemic treatment to target cutaneous and extracutaneous symptoms of patients who have very limited treatment options at this time,” they wrote. While all forms of EB are considered orphan disorders, JEB and EBS-MD have received less research attention than RDEB.

The JEB study evaluated patients with clinical assessments/quality of life surveys and with a validated clinical score that considers skin and mucosae – the Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI). There were small positive changes in EBDASI scores, but data were incomplete and therefore difficult to interpret.

A “noteworthy” finding, the authors wrote, were improvements in emotions and functioning in two of the children who were eligible given their older ages for assessment with the Skindex-16 quality-of-life survey. The improvements suggest “potential psychosocial benefits” of the gentamicin therapy.

The JEB study was supported in part by grants from the EB Research Partnership and EB Medical Research Foundation and an award from the Congressionally Directed Medical Research Program. In addition to the grants, Dr. Woodley and Dr. Chen reported receiving personal fees from Phoenix Tissue Repair outside of the submitted work. For the EBS-MD case report, the authors reported no disclosures. Dr. Bruckner, corresponding author of the editorial, reported grants from several companies outside the submitted work.

Intravenous gentamicin therapy was associated with new laminin 332 – a major component of anchoring filaments in the dermal-epidermal junction – in the skin of five pediatric patients with intermediate or severe junctional epidermolysis bullosa (JEB) caused by nonsense variants.

The newly generated structural protein persisted during the 3-month randomized clinical trial and was associated with significant wound closure – with no signs of ototoxic effects, nephrotoxic effects, or anti–laminin 332 autoantibody induction, investigators recently reported in JAMA Dermatology.

JEB is a rare, autosomal recessive disorder caused mainly by nonsense variants (i.e., mutations) in the LAMA3, LAMB3, or LAMC2 genes that encode laminin, resulting in widespread blisters and erosions of the skin. Current treatment is limited to supportive management and palliative care, and children with its severe subtype are likely to die within the first year of life.

“With data indicating a robust response to short-term gentamicin treatment and the marked stability of laminin 332, we envision that gentamicin could be delivered as a short-term pulse therapy every 2-3 months for patients with JEB caused by nonsense variants,” the researchers wrote.

Of the five patients, ages 3 months to 10 years, three received 7.5 mg/kg IV gentamicin daily for 14 days, and two received 10 mg/kg daily for 24 days at the University of Southern California, Los Angeles.

All had confirmed nonsense variants in LAMA3 or LAMB3 in one or two alleles, and all had minimal laminin 332 expression at baseline as determined by immunofluorescence. After treatment, each of the children had increased, sustained expression of laminin 332.

The researchers monitored three open wounds in each patient. By 1 month, seven of nine wounds in those receiving the lower-dose therapy and all of the wounds in those receiving the higher-dose therapy showed at least 50% closure. By 3 months, eight of nine wounds in the lower-dose group, and all wounds in the higher-dose group showed greater than 85% closure.

In an interview, senior investigators Mei Chen, PhD, professor of dermatology, and David T. Woodley, MD, professor and chair of dermatology, both at USC, emphasized laminin’s long half-life.“Once these skin structural proteins are generated at the dermal-epidermal junction, they are long-lasting structures, which means the therapy can be pulsed rather than continuously delivered, which can obviate some of the known side effects of the medication,” Dr. Woodley said.

Gentamicin, an aminoglycoside, works as a “read-through therapy,” inducing ribosomal read-through of premature termination codons (PTCs) caused by nonsense mutations. The read-through allows translation to proceed and full-length proteins to be generated.

Gentamicin read-through therapy is also being investigated for recessive dystrophic epidermolysis bullosa (RDEB) attributable to nonsense mutations. The culprit mutations in this form of EB occur in a gene that encodes collagen type VII alpha 1, which, like laminin, is responsible for dermal-epidermal adherence. A clinical trial of intravenous gentamicin for RDEB is ongoing at USC, Dr. Chen said.


 

EBS-MD case report

It may also have a role in treating epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), according to investigators in Madrid. Their case report, published in JAMA Dermatology, details how two 14-day courses of infused gentamicin therapy were followed by re-expression of plectin in the skin for 4-5 months and mild improvement in symptoms in one patient, a woman in her 30s, with a homozygous nonsense variant in PLEC1.

In an editorial accompanying the two reports, Anna L. Bruckner, MD, MSCS, professor of dermatology, University of Colorado at Denver, Aurora, and colleagues expressed cautious optimism and said that additional research on the feasibility, possible cumulative toxic effects, risk of microbial resistance, and overall clinical relevance is needed.

Still, the “investigators should be applauded for taking advantage of a readily available systemic treatment to target cutaneous and extracutaneous symptoms of patients who have very limited treatment options at this time,” they wrote. While all forms of EB are considered orphan disorders, JEB and EBS-MD have received less research attention than RDEB.

The JEB study evaluated patients with clinical assessments/quality of life surveys and with a validated clinical score that considers skin and mucosae – the Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI). There were small positive changes in EBDASI scores, but data were incomplete and therefore difficult to interpret.

A “noteworthy” finding, the authors wrote, were improvements in emotions and functioning in two of the children who were eligible given their older ages for assessment with the Skindex-16 quality-of-life survey. The improvements suggest “potential psychosocial benefits” of the gentamicin therapy.

The JEB study was supported in part by grants from the EB Research Partnership and EB Medical Research Foundation and an award from the Congressionally Directed Medical Research Program. In addition to the grants, Dr. Woodley and Dr. Chen reported receiving personal fees from Phoenix Tissue Repair outside of the submitted work. For the EBS-MD case report, the authors reported no disclosures. Dr. Bruckner, corresponding author of the editorial, reported grants from several companies outside the submitted work.

Intravenous gentamicin therapy was associated with new laminin 332 – a major component of anchoring filaments in the dermal-epidermal junction – in the skin of five pediatric patients with intermediate or severe junctional epidermolysis bullosa (JEB) caused by nonsense variants.

The newly generated structural protein persisted during the 3-month randomized clinical trial and was associated with significant wound closure – with no signs of ototoxic effects, nephrotoxic effects, or anti–laminin 332 autoantibody induction, investigators recently reported in JAMA Dermatology.

JEB is a rare, autosomal recessive disorder caused mainly by nonsense variants (i.e., mutations) in the LAMA3, LAMB3, or LAMC2 genes that encode laminin, resulting in widespread blisters and erosions of the skin. Current treatment is limited to supportive management and palliative care, and children with its severe subtype are likely to die within the first year of life.

“With data indicating a robust response to short-term gentamicin treatment and the marked stability of laminin 332, we envision that gentamicin could be delivered as a short-term pulse therapy every 2-3 months for patients with JEB caused by nonsense variants,” the researchers wrote.

Of the five patients, ages 3 months to 10 years, three received 7.5 mg/kg IV gentamicin daily for 14 days, and two received 10 mg/kg daily for 24 days at the University of Southern California, Los Angeles.

All had confirmed nonsense variants in LAMA3 or LAMB3 in one or two alleles, and all had minimal laminin 332 expression at baseline as determined by immunofluorescence. After treatment, each of the children had increased, sustained expression of laminin 332.

The researchers monitored three open wounds in each patient. By 1 month, seven of nine wounds in those receiving the lower-dose therapy and all of the wounds in those receiving the higher-dose therapy showed at least 50% closure. By 3 months, eight of nine wounds in the lower-dose group, and all wounds in the higher-dose group showed greater than 85% closure.

In an interview, senior investigators Mei Chen, PhD, professor of dermatology, and David T. Woodley, MD, professor and chair of dermatology, both at USC, emphasized laminin’s long half-life.“Once these skin structural proteins are generated at the dermal-epidermal junction, they are long-lasting structures, which means the therapy can be pulsed rather than continuously delivered, which can obviate some of the known side effects of the medication,” Dr. Woodley said.

Gentamicin, an aminoglycoside, works as a “read-through therapy,” inducing ribosomal read-through of premature termination codons (PTCs) caused by nonsense mutations. The read-through allows translation to proceed and full-length proteins to be generated.

Gentamicin read-through therapy is also being investigated for recessive dystrophic epidermolysis bullosa (RDEB) attributable to nonsense mutations. The culprit mutations in this form of EB occur in a gene that encodes collagen type VII alpha 1, which, like laminin, is responsible for dermal-epidermal adherence. A clinical trial of intravenous gentamicin for RDEB is ongoing at USC, Dr. Chen said.


 

EBS-MD case report

It may also have a role in treating epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), according to investigators in Madrid. Their case report, published in JAMA Dermatology, details how two 14-day courses of infused gentamicin therapy were followed by re-expression of plectin in the skin for 4-5 months and mild improvement in symptoms in one patient, a woman in her 30s, with a homozygous nonsense variant in PLEC1.

In an editorial accompanying the two reports, Anna L. Bruckner, MD, MSCS, professor of dermatology, University of Colorado at Denver, Aurora, and colleagues expressed cautious optimism and said that additional research on the feasibility, possible cumulative toxic effects, risk of microbial resistance, and overall clinical relevance is needed.

Still, the “investigators should be applauded for taking advantage of a readily available systemic treatment to target cutaneous and extracutaneous symptoms of patients who have very limited treatment options at this time,” they wrote. While all forms of EB are considered orphan disorders, JEB and EBS-MD have received less research attention than RDEB.

The JEB study evaluated patients with clinical assessments/quality of life surveys and with a validated clinical score that considers skin and mucosae – the Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI). There were small positive changes in EBDASI scores, but data were incomplete and therefore difficult to interpret.

A “noteworthy” finding, the authors wrote, were improvements in emotions and functioning in two of the children who were eligible given their older ages for assessment with the Skindex-16 quality-of-life survey. The improvements suggest “potential psychosocial benefits” of the gentamicin therapy.

The JEB study was supported in part by grants from the EB Research Partnership and EB Medical Research Foundation and an award from the Congressionally Directed Medical Research Program. In addition to the grants, Dr. Woodley and Dr. Chen reported receiving personal fees from Phoenix Tissue Repair outside of the submitted work. For the EBS-MD case report, the authors reported no disclosures. Dr. Bruckner, corresponding author of the editorial, reported grants from several companies outside the submitted work.

WASHINGTON – Dietary fiber impacts not only the composition of the gut microbiome, but the production of a broad spectrum of microbiota-produced metabolites – including amino acid metabolites – that may modify health, said Gary D. Wu, MD, of the University of Pennsylvania, Philadelphia.

During the 2022 Gut Microbiota for Health World Summit, organized by the American Gastroenterological Association and the European Society of Neurogastroenterology and Motility, Dr. Wu led a plenary session in which the impact of diet on the microbiome was characterized as important, rapid, personalized, likely modest relative to other contributing ecological factors, influenced by the process of cooking, and exceedingly difficult to tease apart and characterize in human studies.

In a human study published in 2021, Dr. Wu and coinvestigators performed a controlled feeding experiment with 30 healthy volunteers, randomizing them to several weeks of a vegan diet, an omnivore diet (a typical American diet), and an exclusive enteral nutrition diet (EEN) devoid of dietary fiber.

They compared the composition and metabolic function of the gut microbiome during three phases: an initial dietary phase (days 1-5), a purge phase in which antibiotics and polyethylene glycol were administered to transiently reduce bacterial load in the gut (days 6-8), and a recovery phase (days 9-15).

Diversity of the gut microbiota recovered from the purge phase in both vegans and omnivores, but not in those receiving EEN. “The EEN diet was having a profound effect on the [short-term] recovery of microbiota,” said Dr. Wu, the Ferdinand G. Weisbrod Professor in Gastroenterology, in describing the Food And Resulting Microbial Metabolites study.

Using genetic sequencing, microbial culturing, and bioinformatics processing, the researchers also determined that EEN subsequently led to metabolites that were distinct from omnivores and vegans. Unexpectedly, bacterial metabolites of amino acid origin – not only carbohydrate origin – were altered in the EEN group, suggesting a broad impact of dietary fiber on the bacterial metabolome. EEN-induced alterations in the microbiome and metabolome resolved after the study period, he noted.

In other words, “depriving or supplying the gut microbiome with one dietary component (i.e., fiber) can directly impact metabolites of an unrelated portion of the diet (i.e., amino acids) via the induction of specific gut bacterial taxa,” Dr. Wu and colleagues wrote.

Clinically, the results as a whole suggest that the combination of antibiotics with EEN may be less effective in patients with Crohn’s disease than EEN alone, and can be potentially harmful, they said.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Wu said that, for patients in the ICU on EEN treatment and antibiotics, “we do need to think carefully about microbiota reconstitution because it could have a very significant effect not only on short-chain fatty acid metabolites but on amino acid metabolites that may be good or bad in the setting of disease.”

The scientific rationale for the effectiveness of EEN for IBD is still not well understood, he noted. “All I can say is that EEN works in IBD, but there are aspects about the microbiota and diet and IBD that we don’t understand.”


 

Dietary impact through the immigration lens

In another presentation, Dan Knights, PhD, of the University of Minnesota, Minneapolis, described his lab’s findings on the association of U.S. immigration with loss of gut microbiome diversity, and the role of diet.

As part of the Immigration Microbiome Project reported several years ago, his team collected stool, dietary recalls, and anthropometrics from 550 Hmong and Karen individuals living in Thailand and the United States, including first- and second-generation immigrants, as well as some U.S.-born European American individuals. They found that the gut microbiome of immigrants changed within months of arriving in the United States, and that immigration status had a stronger effect on the microbiome than obesity status.

“By the time people were in their second generation, their microbiomes were roughly on the same order of diversity as U.S. controls,” said Dr. Knights, associate professor in the Biotechnology Institute and the department of computer science and engineering.

Dietary changes only partly explained microbiome variation, however. “By the second generation, the microbiome tended to be fully Westernized, but the diet was only partly Westernized,” he said. “Diet is only part of the story.”

Other research from his lab, including one study that performed daily fecal shotgun sequencing on 34 people, has found that effects of diet on the microbiome are likely to be observable within days, and that microbial responses to food are highly personalized. Diet appears to explain about 6% of the daily microbiome variation within an individual, and “an average diet explains about 4% of microbiome variation between people,” Dr. Knights said.
 

The impact of cooking

“The gut microbiota responds to food and to its form,” said Rachel N. Carmody, PhD, of the department of human evolutionary biology at Harvard University, Cambridge, during the plenary session. Her research has shown that, in mice, a plant diet served raw versus cooked quickly reshaped the gut microbiome and disrupted gut microbial physiology. Notably, shifts in gut microbiota modulated host energy status – one of the many areas that begs further research.

The effects of cooking have also been detectable in human pilot studies. “We saw different changes in the microbiome when [study participants] were eating the same plant items either raw or cooked,” she said. “Some microbes were affected only on the raw diet, other were affected only on the cooked diet.”

Other research in animal models and humans has demonstrated a significant amount of plasticity in the microbiome in response to diet. “In mice you get the microbiome signatures to shift within 24 hours by feeding them a new diet,” Dr. Carmody said.

In an interview about the plenary session, Eugene B. Chang, MD, the Martin Boyer Distinguished Professor of Medicine at the University of Chicago, said that he was struck both by the resiliency of individual gut microbiomes overall and by findings that, “in animal models where conditions and diets can be carefully controlled, diet and environment are major drivers of gut microbial membership and function.”

Dr. Chang co-led a separate workshop on “defining a healthy gut microbiome” – a task that he said remains “a challenge [and is not yet] resolved, at least with general consensus.”

Dr. Chang, Dr. Wu, and Dr. Carmody reported no relevant disclosures. Dr. Knights disclosed that he is a paid adviser to Diversigen, a company involved with the commercialization of microbiome analysis.

The 2022 Gut Microbiota for Health World Summit was supported by sponsorships from Danone, Ferring Pharmaceuticals, Aimmune Therapeutics and Seres Therapeutics, Sanofi, and Intrinsic Medicine Inc. with additional support from educational grants provided by Ferring Pharmaceuticals and Salix Pharmaceuticals.

This article was updated 4/5/22.

WASHINGTON – Dietary fiber impacts not only the composition of the gut microbiome, but the production of a broad spectrum of microbiota-produced metabolites – including amino acid metabolites – that may modify health, said Gary D. Wu, MD, of the University of Pennsylvania, Philadelphia.

During the 2022 Gut Microbiota for Health World Summit, organized by the American Gastroenterological Association and the European Society of Neurogastroenterology and Motility, Dr. Wu led a plenary session in which the impact of diet on the microbiome was characterized as important, rapid, personalized, likely modest relative to other contributing ecological factors, influenced by the process of cooking, and exceedingly difficult to tease apart and characterize in human studies.

In a human study published in 2021, Dr. Wu and coinvestigators performed a controlled feeding experiment with 30 healthy volunteers, randomizing them to several weeks of a vegan diet, an omnivore diet (a typical American diet), and an exclusive enteral nutrition diet (EEN) devoid of dietary fiber.

They compared the composition and metabolic function of the gut microbiome during three phases: an initial dietary phase (days 1-5), a purge phase in which antibiotics and polyethylene glycol were administered to transiently reduce bacterial load in the gut (days 6-8), and a recovery phase (days 9-15).

Diversity of the gut microbiota recovered from the purge phase in both vegans and omnivores, but not in those receiving EEN. “The EEN diet was having a profound effect on the [short-term] recovery of microbiota,” said Dr. Wu, the Ferdinand G. Weisbrod Professor in Gastroenterology, in describing the Food And Resulting Microbial Metabolites study.

Using genetic sequencing, microbial culturing, and bioinformatics processing, the researchers also determined that EEN subsequently led to metabolites that were distinct from omnivores and vegans. Unexpectedly, bacterial metabolites of amino acid origin – not only carbohydrate origin – were altered in the EEN group, suggesting a broad impact of dietary fiber on the bacterial metabolome. EEN-induced alterations in the microbiome and metabolome resolved after the study period, he noted.

In other words, “depriving or supplying the gut microbiome with one dietary component (i.e., fiber) can directly impact metabolites of an unrelated portion of the diet (i.e., amino acids) via the induction of specific gut bacterial taxa,” Dr. Wu and colleagues wrote.

Clinically, the results as a whole suggest that the combination of antibiotics with EEN may be less effective in patients with Crohn’s disease than EEN alone, and can be potentially harmful, they said.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Wu said that, for patients in the ICU on EEN treatment and antibiotics, “we do need to think carefully about microbiota reconstitution because it could have a very significant effect not only on short-chain fatty acid metabolites but on amino acid metabolites that may be good or bad in the setting of disease.”

The scientific rationale for the effectiveness of EEN for IBD is still not well understood, he noted. “All I can say is that EEN works in IBD, but there are aspects about the microbiota and diet and IBD that we don’t understand.”


 

Dietary impact through the immigration lens

In another presentation, Dan Knights, PhD, of the University of Minnesota, Minneapolis, described his lab’s findings on the association of U.S. immigration with loss of gut microbiome diversity, and the role of diet.

As part of the Immigration Microbiome Project reported several years ago, his team collected stool, dietary recalls, and anthropometrics from 550 Hmong and Karen individuals living in Thailand and the United States, including first- and second-generation immigrants, as well as some U.S.-born European American individuals. They found that the gut microbiome of immigrants changed within months of arriving in the United States, and that immigration status had a stronger effect on the microbiome than obesity status.

“By the time people were in their second generation, their microbiomes were roughly on the same order of diversity as U.S. controls,” said Dr. Knights, associate professor in the Biotechnology Institute and the department of computer science and engineering.

Dietary changes only partly explained microbiome variation, however. “By the second generation, the microbiome tended to be fully Westernized, but the diet was only partly Westernized,” he said. “Diet is only part of the story.”

Other research from his lab, including one study that performed daily fecal shotgun sequencing on 34 people, has found that effects of diet on the microbiome are likely to be observable within days, and that microbial responses to food are highly personalized. Diet appears to explain about 6% of the daily microbiome variation within an individual, and “an average diet explains about 4% of microbiome variation between people,” Dr. Knights said.
 

The impact of cooking

“The gut microbiota responds to food and to its form,” said Rachel N. Carmody, PhD, of the department of human evolutionary biology at Harvard University, Cambridge, during the plenary session. Her research has shown that, in mice, a plant diet served raw versus cooked quickly reshaped the gut microbiome and disrupted gut microbial physiology. Notably, shifts in gut microbiota modulated host energy status – one of the many areas that begs further research.

The effects of cooking have also been detectable in human pilot studies. “We saw different changes in the microbiome when [study participants] were eating the same plant items either raw or cooked,” she said. “Some microbes were affected only on the raw diet, other were affected only on the cooked diet.”

Other research in animal models and humans has demonstrated a significant amount of plasticity in the microbiome in response to diet. “In mice you get the microbiome signatures to shift within 24 hours by feeding them a new diet,” Dr. Carmody said.

In an interview about the plenary session, Eugene B. Chang, MD, the Martin Boyer Distinguished Professor of Medicine at the University of Chicago, said that he was struck both by the resiliency of individual gut microbiomes overall and by findings that, “in animal models where conditions and diets can be carefully controlled, diet and environment are major drivers of gut microbial membership and function.”

Dr. Chang co-led a separate workshop on “defining a healthy gut microbiome” – a task that he said remains “a challenge [and is not yet] resolved, at least with general consensus.”

Dr. Chang, Dr. Wu, and Dr. Carmody reported no relevant disclosures. Dr. Knights disclosed that he is a paid adviser to Diversigen, a company involved with the commercialization of microbiome analysis.

The 2022 Gut Microbiota for Health World Summit was supported by sponsorships from Danone, Ferring Pharmaceuticals, Aimmune Therapeutics and Seres Therapeutics, Sanofi, and Intrinsic Medicine Inc. with additional support from educational grants provided by Ferring Pharmaceuticals and Salix Pharmaceuticals.

This article was updated 4/5/22.

WASHINGTON – Dietary fiber impacts not only the composition of the gut microbiome, but the production of a broad spectrum of microbiota-produced metabolites – including amino acid metabolites – that may modify health, said Gary D. Wu, MD, of the University of Pennsylvania, Philadelphia.

During the 2022 Gut Microbiota for Health World Summit, organized by the American Gastroenterological Association and the European Society of Neurogastroenterology and Motility, Dr. Wu led a plenary session in which the impact of diet on the microbiome was characterized as important, rapid, personalized, likely modest relative to other contributing ecological factors, influenced by the process of cooking, and exceedingly difficult to tease apart and characterize in human studies.

In a human study published in 2021, Dr. Wu and coinvestigators performed a controlled feeding experiment with 30 healthy volunteers, randomizing them to several weeks of a vegan diet, an omnivore diet (a typical American diet), and an exclusive enteral nutrition diet (EEN) devoid of dietary fiber.

They compared the composition and metabolic function of the gut microbiome during three phases: an initial dietary phase (days 1-5), a purge phase in which antibiotics and polyethylene glycol were administered to transiently reduce bacterial load in the gut (days 6-8), and a recovery phase (days 9-15).

Diversity of the gut microbiota recovered from the purge phase in both vegans and omnivores, but not in those receiving EEN. “The EEN diet was having a profound effect on the [short-term] recovery of microbiota,” said Dr. Wu, the Ferdinand G. Weisbrod Professor in Gastroenterology, in describing the Food And Resulting Microbial Metabolites study.

Using genetic sequencing, microbial culturing, and bioinformatics processing, the researchers also determined that EEN subsequently led to metabolites that were distinct from omnivores and vegans. Unexpectedly, bacterial metabolites of amino acid origin – not only carbohydrate origin – were altered in the EEN group, suggesting a broad impact of dietary fiber on the bacterial metabolome. EEN-induced alterations in the microbiome and metabolome resolved after the study period, he noted.

In other words, “depriving or supplying the gut microbiome with one dietary component (i.e., fiber) can directly impact metabolites of an unrelated portion of the diet (i.e., amino acids) via the induction of specific gut bacterial taxa,” Dr. Wu and colleagues wrote.

Clinically, the results as a whole suggest that the combination of antibiotics with EEN may be less effective in patients with Crohn’s disease than EEN alone, and can be potentially harmful, they said.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Wu said that, for patients in the ICU on EEN treatment and antibiotics, “we do need to think carefully about microbiota reconstitution because it could have a very significant effect not only on short-chain fatty acid metabolites but on amino acid metabolites that may be good or bad in the setting of disease.”

The scientific rationale for the effectiveness of EEN for IBD is still not well understood, he noted. “All I can say is that EEN works in IBD, but there are aspects about the microbiota and diet and IBD that we don’t understand.”


 

Dietary impact through the immigration lens

In another presentation, Dan Knights, PhD, of the University of Minnesota, Minneapolis, described his lab’s findings on the association of U.S. immigration with loss of gut microbiome diversity, and the role of diet.

As part of the Immigration Microbiome Project reported several years ago, his team collected stool, dietary recalls, and anthropometrics from 550 Hmong and Karen individuals living in Thailand and the United States, including first- and second-generation immigrants, as well as some U.S.-born European American individuals. They found that the gut microbiome of immigrants changed within months of arriving in the United States, and that immigration status had a stronger effect on the microbiome than obesity status.

“By the time people were in their second generation, their microbiomes were roughly on the same order of diversity as U.S. controls,” said Dr. Knights, associate professor in the Biotechnology Institute and the department of computer science and engineering.

Dietary changes only partly explained microbiome variation, however. “By the second generation, the microbiome tended to be fully Westernized, but the diet was only partly Westernized,” he said. “Diet is only part of the story.”

Other research from his lab, including one study that performed daily fecal shotgun sequencing on 34 people, has found that effects of diet on the microbiome are likely to be observable within days, and that microbial responses to food are highly personalized. Diet appears to explain about 6% of the daily microbiome variation within an individual, and “an average diet explains about 4% of microbiome variation between people,” Dr. Knights said.
 

The impact of cooking

“The gut microbiota responds to food and to its form,” said Rachel N. Carmody, PhD, of the department of human evolutionary biology at Harvard University, Cambridge, during the plenary session. Her research has shown that, in mice, a plant diet served raw versus cooked quickly reshaped the gut microbiome and disrupted gut microbial physiology. Notably, shifts in gut microbiota modulated host energy status – one of the many areas that begs further research.

The effects of cooking have also been detectable in human pilot studies. “We saw different changes in the microbiome when [study participants] were eating the same plant items either raw or cooked,” she said. “Some microbes were affected only on the raw diet, other were affected only on the cooked diet.”

Other research in animal models and humans has demonstrated a significant amount of plasticity in the microbiome in response to diet. “In mice you get the microbiome signatures to shift within 24 hours by feeding them a new diet,” Dr. Carmody said.

In an interview about the plenary session, Eugene B. Chang, MD, the Martin Boyer Distinguished Professor of Medicine at the University of Chicago, said that he was struck both by the resiliency of individual gut microbiomes overall and by findings that, “in animal models where conditions and diets can be carefully controlled, diet and environment are major drivers of gut microbial membership and function.”

Dr. Chang co-led a separate workshop on “defining a healthy gut microbiome” – a task that he said remains “a challenge [and is not yet] resolved, at least with general consensus.”

Dr. Chang, Dr. Wu, and Dr. Carmody reported no relevant disclosures. Dr. Knights disclosed that he is a paid adviser to Diversigen, a company involved with the commercialization of microbiome analysis.

The 2022 Gut Microbiota for Health World Summit was supported by sponsorships from Danone, Ferring Pharmaceuticals, Aimmune Therapeutics and Seres Therapeutics, Sanofi, and Intrinsic Medicine Inc. with additional support from educational grants provided by Ferring Pharmaceuticals and Salix Pharmaceuticals.

This article was updated 4/5/22.

The view of irritable bowel syndrome (IBS) as a disorder of altered interactions within the brain-gut-microbiome system is supported today by “extensive clinical, brain and microbiome-derived evidence,” Emeran A. Mayer, MD, of the University of California, Los Angeles, said at the annual Gut Microbiota for Health World Summit.

A recently published genome-wide analysis from the United Kingdom of more than 53,000 people with IBS found shared genetic pathways with mood and anxiety disorders and “is one of the most convincing studies to date [showing] that we’re not dealing with separate disorders, but that we’re dealing with the brain-gut-microbiome system,” said Dr. Mayer, director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience, and codirector of the Cure: Digestive Diseases Research Center at UCLA.

©Artem_Furman/Thinkstockphotos.com

Meanwhile, multi-omics analyses from his team have established significant differences in the composition and function of the gut microbiome between IBS and healthy controls and, significantly, between IBS subgroups, he reported.

The genome analysis, published in Nature Genetics, utilized the UK Biobank, which contains genome-wide SNP genotyping data and health data for a half a million individuals. People with IBS were identified with a digestive health questionnaire that included Rome III symptom criteria.

In their cohort of 53,400 IBS cases and 433,201 healthy controls, the researchers identified 6 genetic susceptibility loci for IBS, 3 of which have previously been shown to be associated with depression, neuroticism, and other psychiatric disorders. (Significant associations were replicated in a 23andMe panel.) “The study emphasizes that GI symptoms [of IBS] and mood and anxiety disorders are two sides of the same coin,” Dr. Mayer said.
 

Differences in IBS subtypes

The team’s multi-omics profiles of the intestinal microbiota in IBS and its subtypes, based on bowel habits, have shown that IBS is characterized by “altered abundances of certain bacterial taxa, transcripts, and metabolites,” he said.

The research, awaiting publication, has also shown that IBS metabolites, transcripts, and transcript/gene ratios differentiate IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C) with high accuracy. In addition, the IBS-D subtype is differentiated from IBS-C by “diverse functional shifts including increased polyamines, bile acids, glutamate synthesis, and ethanolamine utilization,” Dr. Mayer said.

In related multi-omics research incorporating brain imaging data, Dr. Mayer’s team has identified greater alterations in measures of brain connectivity in the IBS-D group, “just as we saw for the microbiome parameters as well,” he said at the meeting, which was sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology & Motility.

These “are all associations,” he noted. The microbiome is an established integral player in gut-brain communication, but “a casual role between the gut microbiome and IBS remains to be established.”

Although mechanistic studies are still in earlier stages, it’s clear that the microbiome is a potentially important site for therapeutic interventions. “Microbiome-targeted therapies are likely to be effective in subsets of IBS patients, based on their bowel habits, and on microbiome features,” said Dr. Mayer.

Impact of probiotics

In reviewing key research, Dr. Mayer also pointed to interventional studies that support bidirectional relationships between the brain and the gut microbiome.

Studies of gut microbiome-targeted therapies in patients with IBS have shown mixed results – both positive and negative findings – and have been of variable quality. However, a couple of well-done small studies “have shown that probiotics can modulate brain activity and affect psychiatric symptoms,” Dr. Mayer said.

One of these studies, a randomized, double-blind placebo-controlled study of 44 adults with IBS, found reductions in depression scores and changes in brain activation patterns in those who took the probiotic Bifidobacterium longum.

Studies in healthy women are also telling. One of his team’s studies looked at the impact of 4 weeks of a fermented milk product with a 5-strain probiotic consortium on brain intrinsic connectivity and responses to emotional attention tasks.

“We saw significant changes in the connectivity of multiple brain regions ... networks related to emotional regulation circuits within the brain,” he said. “We have to assume that the perturbation happened at the gut-microbiome level.”

A study from Germany demonstrated that the probiotic Bifidobacterium longum modulated brain activity of healthy individuals during social stress.
 

Impact of cognitive-behavioral therapy

Emanating from the brain, nonpharmaceutical brain-targeted therapies have been shown to reduce IBS symptom severity, he said. In one randomized controlled trial of more than 400 patients with refractory IBS, a primarily home-based version of cognitive behavioral therapy (CBT) produced significant and sustained improvement in symptoms compared with education.

And a study published last year by Dr. Mayer and coinvestigators demonstrated that a positive clinical response to CBT was associated with changes in both the brain (changes in functional and structural connectivity) and the gut microbiota.

Eighty-four IBS patients underwent multimodal brain imaging and psychological assessments before and after CBT, and 34 of the participants underwent microbiome assessments with 16S rRNA A gene sequencing, untargeted metabolomics, and measurement of short-chain fatty acid from fecal samples collected at baseline and post treatment.

In comparing responders (58) and nonresponders (26), the researchers found that response to CBT could be predicted from baseline microbiota composition (including increased Clostridiales and decreased Bacteroides), and that responders had microbial shifts after therapy – including expansion of Bacteroides – in addition to distinct brain changes. “We know which brain networks [in patients with IBS] are sensitive to CBT,” said Dr. Mayer.

Eugene B. Chang, MD, the Martin Boyer Distinguished Professor of Medicine at the University of Chicago and director of the university’s Microbiome Medicine Program, said in an interview after the meeting that the brain-gut-microbiome system “is a very important area for investigation” not only for IBS but for hepatic encephalopathy and other problems and disorders such as neurodegenerative disorders (e.g., Alzheimer’s and Parkinson’s) and circadian disruption, “where gut dysbiosis has been implicated as causative or contributory.”

The specialty still has very little understanding of IBS, and “clinical practice remains largely empirical,” he said, noting that his program is embarking on studies of the brain-gut microbiome system.

Dr. Mayer reported that he serves on the advisory board of Axial Biotherapeutics, Pendulum, Bloom Science, and several other companies. Dr. Chang reported that he has no relevant disclosures.

The view of irritable bowel syndrome (IBS) as a disorder of altered interactions within the brain-gut-microbiome system is supported today by “extensive clinical, brain and microbiome-derived evidence,” Emeran A. Mayer, MD, of the University of California, Los Angeles, said at the annual Gut Microbiota for Health World Summit.

A recently published genome-wide analysis from the United Kingdom of more than 53,000 people with IBS found shared genetic pathways with mood and anxiety disorders and “is one of the most convincing studies to date [showing] that we’re not dealing with separate disorders, but that we’re dealing with the brain-gut-microbiome system,” said Dr. Mayer, director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience, and codirector of the Cure: Digestive Diseases Research Center at UCLA.

©Artem_Furman/Thinkstockphotos.com

Meanwhile, multi-omics analyses from his team have established significant differences in the composition and function of the gut microbiome between IBS and healthy controls and, significantly, between IBS subgroups, he reported.

The genome analysis, published in Nature Genetics, utilized the UK Biobank, which contains genome-wide SNP genotyping data and health data for a half a million individuals. People with IBS were identified with a digestive health questionnaire that included Rome III symptom criteria.

In their cohort of 53,400 IBS cases and 433,201 healthy controls, the researchers identified 6 genetic susceptibility loci for IBS, 3 of which have previously been shown to be associated with depression, neuroticism, and other psychiatric disorders. (Significant associations were replicated in a 23andMe panel.) “The study emphasizes that GI symptoms [of IBS] and mood and anxiety disorders are two sides of the same coin,” Dr. Mayer said.
 

Differences in IBS subtypes

The team’s multi-omics profiles of the intestinal microbiota in IBS and its subtypes, based on bowel habits, have shown that IBS is characterized by “altered abundances of certain bacterial taxa, transcripts, and metabolites,” he said.

The research, awaiting publication, has also shown that IBS metabolites, transcripts, and transcript/gene ratios differentiate IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C) with high accuracy. In addition, the IBS-D subtype is differentiated from IBS-C by “diverse functional shifts including increased polyamines, bile acids, glutamate synthesis, and ethanolamine utilization,” Dr. Mayer said.

In related multi-omics research incorporating brain imaging data, Dr. Mayer’s team has identified greater alterations in measures of brain connectivity in the IBS-D group, “just as we saw for the microbiome parameters as well,” he said at the meeting, which was sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology & Motility.

These “are all associations,” he noted. The microbiome is an established integral player in gut-brain communication, but “a casual role between the gut microbiome and IBS remains to be established.”

Although mechanistic studies are still in earlier stages, it’s clear that the microbiome is a potentially important site for therapeutic interventions. “Microbiome-targeted therapies are likely to be effective in subsets of IBS patients, based on their bowel habits, and on microbiome features,” said Dr. Mayer.

Impact of probiotics

In reviewing key research, Dr. Mayer also pointed to interventional studies that support bidirectional relationships between the brain and the gut microbiome.

Studies of gut microbiome-targeted therapies in patients with IBS have shown mixed results – both positive and negative findings – and have been of variable quality. However, a couple of well-done small studies “have shown that probiotics can modulate brain activity and affect psychiatric symptoms,” Dr. Mayer said.

One of these studies, a randomized, double-blind placebo-controlled study of 44 adults with IBS, found reductions in depression scores and changes in brain activation patterns in those who took the probiotic Bifidobacterium longum.

Studies in healthy women are also telling. One of his team’s studies looked at the impact of 4 weeks of a fermented milk product with a 5-strain probiotic consortium on brain intrinsic connectivity and responses to emotional attention tasks.

“We saw significant changes in the connectivity of multiple brain regions ... networks related to emotional regulation circuits within the brain,” he said. “We have to assume that the perturbation happened at the gut-microbiome level.”

A study from Germany demonstrated that the probiotic Bifidobacterium longum modulated brain activity of healthy individuals during social stress.
 

Impact of cognitive-behavioral therapy

Emanating from the brain, nonpharmaceutical brain-targeted therapies have been shown to reduce IBS symptom severity, he said. In one randomized controlled trial of more than 400 patients with refractory IBS, a primarily home-based version of cognitive behavioral therapy (CBT) produced significant and sustained improvement in symptoms compared with education.

And a study published last year by Dr. Mayer and coinvestigators demonstrated that a positive clinical response to CBT was associated with changes in both the brain (changes in functional and structural connectivity) and the gut microbiota.

Eighty-four IBS patients underwent multimodal brain imaging and psychological assessments before and after CBT, and 34 of the participants underwent microbiome assessments with 16S rRNA A gene sequencing, untargeted metabolomics, and measurement of short-chain fatty acid from fecal samples collected at baseline and post treatment.

In comparing responders (58) and nonresponders (26), the researchers found that response to CBT could be predicted from baseline microbiota composition (including increased Clostridiales and decreased Bacteroides), and that responders had microbial shifts after therapy – including expansion of Bacteroides – in addition to distinct brain changes. “We know which brain networks [in patients with IBS] are sensitive to CBT,” said Dr. Mayer.

Eugene B. Chang, MD, the Martin Boyer Distinguished Professor of Medicine at the University of Chicago and director of the university’s Microbiome Medicine Program, said in an interview after the meeting that the brain-gut-microbiome system “is a very important area for investigation” not only for IBS but for hepatic encephalopathy and other problems and disorders such as neurodegenerative disorders (e.g., Alzheimer’s and Parkinson’s) and circadian disruption, “where gut dysbiosis has been implicated as causative or contributory.”

The specialty still has very little understanding of IBS, and “clinical practice remains largely empirical,” he said, noting that his program is embarking on studies of the brain-gut microbiome system.

Dr. Mayer reported that he serves on the advisory board of Axial Biotherapeutics, Pendulum, Bloom Science, and several other companies. Dr. Chang reported that he has no relevant disclosures.

The view of irritable bowel syndrome (IBS) as a disorder of altered interactions within the brain-gut-microbiome system is supported today by “extensive clinical, brain and microbiome-derived evidence,” Emeran A. Mayer, MD, of the University of California, Los Angeles, said at the annual Gut Microbiota for Health World Summit.

A recently published genome-wide analysis from the United Kingdom of more than 53,000 people with IBS found shared genetic pathways with mood and anxiety disorders and “is one of the most convincing studies to date [showing] that we’re not dealing with separate disorders, but that we’re dealing with the brain-gut-microbiome system,” said Dr. Mayer, director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience, and codirector of the Cure: Digestive Diseases Research Center at UCLA.

©Artem_Furman/Thinkstockphotos.com

Meanwhile, multi-omics analyses from his team have established significant differences in the composition and function of the gut microbiome between IBS and healthy controls and, significantly, between IBS subgroups, he reported.

The genome analysis, published in Nature Genetics, utilized the UK Biobank, which contains genome-wide SNP genotyping data and health data for a half a million individuals. People with IBS were identified with a digestive health questionnaire that included Rome III symptom criteria.

In their cohort of 53,400 IBS cases and 433,201 healthy controls, the researchers identified 6 genetic susceptibility loci for IBS, 3 of which have previously been shown to be associated with depression, neuroticism, and other psychiatric disorders. (Significant associations were replicated in a 23andMe panel.) “The study emphasizes that GI symptoms [of IBS] and mood and anxiety disorders are two sides of the same coin,” Dr. Mayer said.
 

Differences in IBS subtypes

The team’s multi-omics profiles of the intestinal microbiota in IBS and its subtypes, based on bowel habits, have shown that IBS is characterized by “altered abundances of certain bacterial taxa, transcripts, and metabolites,” he said.

The research, awaiting publication, has also shown that IBS metabolites, transcripts, and transcript/gene ratios differentiate IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C) with high accuracy. In addition, the IBS-D subtype is differentiated from IBS-C by “diverse functional shifts including increased polyamines, bile acids, glutamate synthesis, and ethanolamine utilization,” Dr. Mayer said.

In related multi-omics research incorporating brain imaging data, Dr. Mayer’s team has identified greater alterations in measures of brain connectivity in the IBS-D group, “just as we saw for the microbiome parameters as well,” he said at the meeting, which was sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology & Motility.

These “are all associations,” he noted. The microbiome is an established integral player in gut-brain communication, but “a casual role between the gut microbiome and IBS remains to be established.”

Although mechanistic studies are still in earlier stages, it’s clear that the microbiome is a potentially important site for therapeutic interventions. “Microbiome-targeted therapies are likely to be effective in subsets of IBS patients, based on their bowel habits, and on microbiome features,” said Dr. Mayer.

Impact of probiotics

In reviewing key research, Dr. Mayer also pointed to interventional studies that support bidirectional relationships between the brain and the gut microbiome.

Studies of gut microbiome-targeted therapies in patients with IBS have shown mixed results – both positive and negative findings – and have been of variable quality. However, a couple of well-done small studies “have shown that probiotics can modulate brain activity and affect psychiatric symptoms,” Dr. Mayer said.

One of these studies, a randomized, double-blind placebo-controlled study of 44 adults with IBS, found reductions in depression scores and changes in brain activation patterns in those who took the probiotic Bifidobacterium longum.

Studies in healthy women are also telling. One of his team’s studies looked at the impact of 4 weeks of a fermented milk product with a 5-strain probiotic consortium on brain intrinsic connectivity and responses to emotional attention tasks.

“We saw significant changes in the connectivity of multiple brain regions ... networks related to emotional regulation circuits within the brain,” he said. “We have to assume that the perturbation happened at the gut-microbiome level.”

A study from Germany demonstrated that the probiotic Bifidobacterium longum modulated brain activity of healthy individuals during social stress.
 

Impact of cognitive-behavioral therapy

Emanating from the brain, nonpharmaceutical brain-targeted therapies have been shown to reduce IBS symptom severity, he said. In one randomized controlled trial of more than 400 patients with refractory IBS, a primarily home-based version of cognitive behavioral therapy (CBT) produced significant and sustained improvement in symptoms compared with education.

And a study published last year by Dr. Mayer and coinvestigators demonstrated that a positive clinical response to CBT was associated with changes in both the brain (changes in functional and structural connectivity) and the gut microbiota.

Eighty-four IBS patients underwent multimodal brain imaging and psychological assessments before and after CBT, and 34 of the participants underwent microbiome assessments with 16S rRNA A gene sequencing, untargeted metabolomics, and measurement of short-chain fatty acid from fecal samples collected at baseline and post treatment.

In comparing responders (58) and nonresponders (26), the researchers found that response to CBT could be predicted from baseline microbiota composition (including increased Clostridiales and decreased Bacteroides), and that responders had microbial shifts after therapy – including expansion of Bacteroides – in addition to distinct brain changes. “We know which brain networks [in patients with IBS] are sensitive to CBT,” said Dr. Mayer.

Eugene B. Chang, MD, the Martin Boyer Distinguished Professor of Medicine at the University of Chicago and director of the university’s Microbiome Medicine Program, said in an interview after the meeting that the brain-gut-microbiome system “is a very important area for investigation” not only for IBS but for hepatic encephalopathy and other problems and disorders such as neurodegenerative disorders (e.g., Alzheimer’s and Parkinson’s) and circadian disruption, “where gut dysbiosis has been implicated as causative or contributory.”

The specialty still has very little understanding of IBS, and “clinical practice remains largely empirical,” he said, noting that his program is embarking on studies of the brain-gut microbiome system.

Dr. Mayer reported that he serves on the advisory board of Axial Biotherapeutics, Pendulum, Bloom Science, and several other companies. Dr. Chang reported that he has no relevant disclosures.

WASHINGTON – Probiotics are generally used in relatively nontargeted, nonspecific ways. But with the gut microbiome being an integral component of a budding precision medicine model of care, and with “multi-omics” research picking up, this is bound to change, gastroenterologist Purna C. Kashyap, MBBS, said in an interview after the 2022 Gut Microbiota for Health World Summit, organized by the American Gastroenterological Association and the European Society of Neurogastroenterology and Motility.

“There are so many missing pieces of information because, at the very basic level, we don’t know exactly how gut bacteria drive diseases,” he told GI & Hepatology News.

“The idea is to go toward a more precise, accurate approach where the newer generation of probiotics are designed to target a specific process, like block a microbial pathway that contributes to disease pathogenesis, or produce a metabolite that improves host function,” he said. “It’s this shift that is going on in the field. It’s already started, and it has momentum.” Dr. Kashyap is a professor of medicine and physiology at the Mayo Clinic College of Medicine in Rochester, Minn., and codirector of the institution’s microbiome program.

In a keynote lecture at the meeting, Dr. Kashyap said that the current approach to precision medicine, which aims to tailor treatments to defined subgroups of patients, needs to take into account “much more than the human genome.”

To the extent possible, it needs to consider the host (lifestyle, gene variants, etc.), the microbiome, and the exposome (environmental exposures such as diet, medications, and air and water quality).

The microbiome’s relative contribution to any one disease, in turn, likely varies from one individual or subgroup to another, he said.

Researchers are increasingly working with different layers of data and using machine learning methods and artificial intelligence approaches to integrate clinical data and “omics” measurements (e.g., from genome, proteome, metabolome).

Such approaches can help pinpoint the microbiome’s relative contributions, identify microbial-host behaviors and microbial-driven disease mechanisms, and ultimately personalize treatment approaches, Dr. Kashyap said.

For instance, Dr. Kashyap’s team has taken a multi-omics approach to studying patients with irritable bowel syndrome (IBS). Thus far, their research has identified subtype-specific variation in microbial composition and function, and by integrating omics from the host and microbiome, it has confirmed the role of several microbial pathways in subtypes of IBS.

His team has also identified a new pathway – the host and gut microbiota’s modulation of purine metabolism – as a potential driver of symptoms in patients with IBS (Cell 2020;182[6]:1460-73), he said.

Such findings provide opportunities to develop new microbial therapeutics – by engineering bacteria to produce metabolites that target a specific pathway, for instance, he said.
 

Predicting probiotic engraftment

Understanding the extent to which microbes actually engraft in the gut – and the forces governing engraftment – is part of a rational approach to designing future probiotic cocktails and to moving toward personalized, precision medicine, Eric Alm, PhD, said during a plenary session on the future of probiotics, moderated by Dr. Kashyap. Dr. Alm is a professor of biological, civil, and environmental engineering who directs the Center for Microbiome Informatics and Therapeutics at the Massachusetts Institute of Technology in Cambridge.

“One of the best datasets we have when thinking about designing therapeutic microbes is FMT (fecal microbiota transplant) data” in patients with Clostridioides difficile infection (CDI), said Dr. Alm.

“We wondered, can you predict what a patient will look like post FMT given what they looked like before and given what the donor looks like?” he said. “We found that engraftment can be predicted surprisingly well.”

Using computational algorithms and metagenomics sequencing data from donors and recipients, the researchers found that engraftment can be predicted largely from the abundance and strains of bacteria in the donor and the pre-FMT patient microbiome (Cell Host Microbe 2018;23[2]:229-40.e5).

They also observed two behaviors: Previously undetected strains (not transplanted) frequently show up in patients who received FMT, and all donor strains within a species engrafted in an all-or-nothing fashion.

“Seeding a patient with a new species allows them to collect more strains of that species from the environment – this is fairly common,” said Dr. Alm. “But if I give five different strains of Faecalibacterium prausnitzii to a patient who doesn’t have any, they’ll get either zero, or they’ll get all five ... this is an observation we don’t fully understand yet.”

These types of observations “guide our thinking in how to produce rationally designed cocktails,” he said.
 

Other approaches to probiotics

In another type of research, Philippe Langella, PhD, who leads a laboratory of Commensal and Probiotics-Host Interactions at the Micalis Institute in France, has been investigating the use of genetically modified lactic acid bacteria to deliver anti-proteases and other types of molecules to patients with disease, such as the antiprotease elafin to patients with inflammatory bowel disease (IBD).

There is “a lack of elafin in Crohn’s disease and ulcerative colitis patients,” Dr. Langella said during the plenary session. “The idea is to use the genetically modified lactic acid bacteria to counterbalance the protease-antiprotease imbalance in IBD.”

In animal and in vitro models, elafin-expressing lactic acid bacteria decreased elastolytic activity and inflammation in the gut and restored intestinal permeability. The goal now, he said, is to construct biologically contained strains of the engineered bacteria to test in clinical trials.

While today’s probiotics are generally considered to be safe and to have beneficial effects, the next generation will be more targeted – more “rational,“ Dr. Kashyap said in his interview. Each of these researchers,” he said, “is working on different pieces of the puzzle and, eventually, this will allow us to accelerate the development of novel therapies.”

Dr. Kashyap said he has no disclosures relevant to his keynote address or moderation of the plenary session. In his presentation, Dr. Alm disclosed his involvement with Finch Therapeutics, OpenBiome, and Biobot Analytics.

Dr. Langella disclosed in his presentation that he is co-founder of Exeliom Biosciences and has research grants with various pharmaceutical companies, food supplement companies, and agro-food companies.

The 2022 Gut Microbiota for Health World Summit was supported by sponsorships from Danone, Ferring Pharmaceuticals, Aimmune Therapeutics and Seres Therapeutics, Sanofi, and Intrinsic Medicine Inc. with additional support from educational grants provided by Ferring Pharmaceuticals and Salix Pharmaceuticals.

This article was updated 4/5/22.

WASHINGTON – Probiotics are generally used in relatively nontargeted, nonspecific ways. But with the gut microbiome being an integral component of a budding precision medicine model of care, and with “multi-omics” research picking up, this is bound to change, gastroenterologist Purna C. Kashyap, MBBS, said in an interview after the 2022 Gut Microbiota for Health World Summit, organized by the American Gastroenterological Association and the European Society of Neurogastroenterology and Motility.

“There are so many missing pieces of information because, at the very basic level, we don’t know exactly how gut bacteria drive diseases,” he told GI & Hepatology News.

“The idea is to go toward a more precise, accurate approach where the newer generation of probiotics are designed to target a specific process, like block a microbial pathway that contributes to disease pathogenesis, or produce a metabolite that improves host function,” he said. “It’s this shift that is going on in the field. It’s already started, and it has momentum.” Dr. Kashyap is a professor of medicine and physiology at the Mayo Clinic College of Medicine in Rochester, Minn., and codirector of the institution’s microbiome program.

In a keynote lecture at the meeting, Dr. Kashyap said that the current approach to precision medicine, which aims to tailor treatments to defined subgroups of patients, needs to take into account “much more than the human genome.”

To the extent possible, it needs to consider the host (lifestyle, gene variants, etc.), the microbiome, and the exposome (environmental exposures such as diet, medications, and air and water quality).

The microbiome’s relative contribution to any one disease, in turn, likely varies from one individual or subgroup to another, he said.

Researchers are increasingly working with different layers of data and using machine learning methods and artificial intelligence approaches to integrate clinical data and “omics” measurements (e.g., from genome, proteome, metabolome).

Such approaches can help pinpoint the microbiome’s relative contributions, identify microbial-host behaviors and microbial-driven disease mechanisms, and ultimately personalize treatment approaches, Dr. Kashyap said.

For instance, Dr. Kashyap’s team has taken a multi-omics approach to studying patients with irritable bowel syndrome (IBS). Thus far, their research has identified subtype-specific variation in microbial composition and function, and by integrating omics from the host and microbiome, it has confirmed the role of several microbial pathways in subtypes of IBS.

His team has also identified a new pathway – the host and gut microbiota’s modulation of purine metabolism – as a potential driver of symptoms in patients with IBS (Cell 2020;182[6]:1460-73), he said.

Such findings provide opportunities to develop new microbial therapeutics – by engineering bacteria to produce metabolites that target a specific pathway, for instance, he said.
 

Predicting probiotic engraftment

Understanding the extent to which microbes actually engraft in the gut – and the forces governing engraftment – is part of a rational approach to designing future probiotic cocktails and to moving toward personalized, precision medicine, Eric Alm, PhD, said during a plenary session on the future of probiotics, moderated by Dr. Kashyap. Dr. Alm is a professor of biological, civil, and environmental engineering who directs the Center for Microbiome Informatics and Therapeutics at the Massachusetts Institute of Technology in Cambridge.

“One of the best datasets we have when thinking about designing therapeutic microbes is FMT (fecal microbiota transplant) data” in patients with Clostridioides difficile infection (CDI), said Dr. Alm.

“We wondered, can you predict what a patient will look like post FMT given what they looked like before and given what the donor looks like?” he said. “We found that engraftment can be predicted surprisingly well.”

Using computational algorithms and metagenomics sequencing data from donors and recipients, the researchers found that engraftment can be predicted largely from the abundance and strains of bacteria in the donor and the pre-FMT patient microbiome (Cell Host Microbe 2018;23[2]:229-40.e5).

They also observed two behaviors: Previously undetected strains (not transplanted) frequently show up in patients who received FMT, and all donor strains within a species engrafted in an all-or-nothing fashion.

“Seeding a patient with a new species allows them to collect more strains of that species from the environment – this is fairly common,” said Dr. Alm. “But if I give five different strains of Faecalibacterium prausnitzii to a patient who doesn’t have any, they’ll get either zero, or they’ll get all five ... this is an observation we don’t fully understand yet.”

These types of observations “guide our thinking in how to produce rationally designed cocktails,” he said.
 

Other approaches to probiotics

In another type of research, Philippe Langella, PhD, who leads a laboratory of Commensal and Probiotics-Host Interactions at the Micalis Institute in France, has been investigating the use of genetically modified lactic acid bacteria to deliver anti-proteases and other types of molecules to patients with disease, such as the antiprotease elafin to patients with inflammatory bowel disease (IBD).

There is “a lack of elafin in Crohn’s disease and ulcerative colitis patients,” Dr. Langella said during the plenary session. “The idea is to use the genetically modified lactic acid bacteria to counterbalance the protease-antiprotease imbalance in IBD.”

In animal and in vitro models, elafin-expressing lactic acid bacteria decreased elastolytic activity and inflammation in the gut and restored intestinal permeability. The goal now, he said, is to construct biologically contained strains of the engineered bacteria to test in clinical trials.

While today’s probiotics are generally considered to be safe and to have beneficial effects, the next generation will be more targeted – more “rational,“ Dr. Kashyap said in his interview. Each of these researchers,” he said, “is working on different pieces of the puzzle and, eventually, this will allow us to accelerate the development of novel therapies.”

Dr. Kashyap said he has no disclosures relevant to his keynote address or moderation of the plenary session. In his presentation, Dr. Alm disclosed his involvement with Finch Therapeutics, OpenBiome, and Biobot Analytics.

Dr. Langella disclosed in his presentation that he is co-founder of Exeliom Biosciences and has research grants with various pharmaceutical companies, food supplement companies, and agro-food companies.

The 2022 Gut Microbiota for Health World Summit was supported by sponsorships from Danone, Ferring Pharmaceuticals, Aimmune Therapeutics and Seres Therapeutics, Sanofi, and Intrinsic Medicine Inc. with additional support from educational grants provided by Ferring Pharmaceuticals and Salix Pharmaceuticals.

This article was updated 4/5/22.

WASHINGTON – Probiotics are generally used in relatively nontargeted, nonspecific ways. But with the gut microbiome being an integral component of a budding precision medicine model of care, and with “multi-omics” research picking up, this is bound to change, gastroenterologist Purna C. Kashyap, MBBS, said in an interview after the 2022 Gut Microbiota for Health World Summit, organized by the American Gastroenterological Association and the European Society of Neurogastroenterology and Motility.

“There are so many missing pieces of information because, at the very basic level, we don’t know exactly how gut bacteria drive diseases,” he told GI & Hepatology News.

“The idea is to go toward a more precise, accurate approach where the newer generation of probiotics are designed to target a specific process, like block a microbial pathway that contributes to disease pathogenesis, or produce a metabolite that improves host function,” he said. “It’s this shift that is going on in the field. It’s already started, and it has momentum.” Dr. Kashyap is a professor of medicine and physiology at the Mayo Clinic College of Medicine in Rochester, Minn., and codirector of the institution’s microbiome program.

In a keynote lecture at the meeting, Dr. Kashyap said that the current approach to precision medicine, which aims to tailor treatments to defined subgroups of patients, needs to take into account “much more than the human genome.”

To the extent possible, it needs to consider the host (lifestyle, gene variants, etc.), the microbiome, and the exposome (environmental exposures such as diet, medications, and air and water quality).

The microbiome’s relative contribution to any one disease, in turn, likely varies from one individual or subgroup to another, he said.

Researchers are increasingly working with different layers of data and using machine learning methods and artificial intelligence approaches to integrate clinical data and “omics” measurements (e.g., from genome, proteome, metabolome).

Such approaches can help pinpoint the microbiome’s relative contributions, identify microbial-host behaviors and microbial-driven disease mechanisms, and ultimately personalize treatment approaches, Dr. Kashyap said.

For instance, Dr. Kashyap’s team has taken a multi-omics approach to studying patients with irritable bowel syndrome (IBS). Thus far, their research has identified subtype-specific variation in microbial composition and function, and by integrating omics from the host and microbiome, it has confirmed the role of several microbial pathways in subtypes of IBS.

His team has also identified a new pathway – the host and gut microbiota’s modulation of purine metabolism – as a potential driver of symptoms in patients with IBS (Cell 2020;182[6]:1460-73), he said.

Such findings provide opportunities to develop new microbial therapeutics – by engineering bacteria to produce metabolites that target a specific pathway, for instance, he said.
 

Predicting probiotic engraftment

Understanding the extent to which microbes actually engraft in the gut – and the forces governing engraftment – is part of a rational approach to designing future probiotic cocktails and to moving toward personalized, precision medicine, Eric Alm, PhD, said during a plenary session on the future of probiotics, moderated by Dr. Kashyap. Dr. Alm is a professor of biological, civil, and environmental engineering who directs the Center for Microbiome Informatics and Therapeutics at the Massachusetts Institute of Technology in Cambridge.

“One of the best datasets we have when thinking about designing therapeutic microbes is FMT (fecal microbiota transplant) data” in patients with Clostridioides difficile infection (CDI), said Dr. Alm.

“We wondered, can you predict what a patient will look like post FMT given what they looked like before and given what the donor looks like?” he said. “We found that engraftment can be predicted surprisingly well.”

Using computational algorithms and metagenomics sequencing data from donors and recipients, the researchers found that engraftment can be predicted largely from the abundance and strains of bacteria in the donor and the pre-FMT patient microbiome (Cell Host Microbe 2018;23[2]:229-40.e5).

They also observed two behaviors: Previously undetected strains (not transplanted) frequently show up in patients who received FMT, and all donor strains within a species engrafted in an all-or-nothing fashion.

“Seeding a patient with a new species allows them to collect more strains of that species from the environment – this is fairly common,” said Dr. Alm. “But if I give five different strains of Faecalibacterium prausnitzii to a patient who doesn’t have any, they’ll get either zero, or they’ll get all five ... this is an observation we don’t fully understand yet.”

These types of observations “guide our thinking in how to produce rationally designed cocktails,” he said.
 

Other approaches to probiotics

In another type of research, Philippe Langella, PhD, who leads a laboratory of Commensal and Probiotics-Host Interactions at the Micalis Institute in France, has been investigating the use of genetically modified lactic acid bacteria to deliver anti-proteases and other types of molecules to patients with disease, such as the antiprotease elafin to patients with inflammatory bowel disease (IBD).

There is “a lack of elafin in Crohn’s disease and ulcerative colitis patients,” Dr. Langella said during the plenary session. “The idea is to use the genetically modified lactic acid bacteria to counterbalance the protease-antiprotease imbalance in IBD.”

In animal and in vitro models, elafin-expressing lactic acid bacteria decreased elastolytic activity and inflammation in the gut and restored intestinal permeability. The goal now, he said, is to construct biologically contained strains of the engineered bacteria to test in clinical trials.

While today’s probiotics are generally considered to be safe and to have beneficial effects, the next generation will be more targeted – more “rational,“ Dr. Kashyap said in his interview. Each of these researchers,” he said, “is working on different pieces of the puzzle and, eventually, this will allow us to accelerate the development of novel therapies.”

Dr. Kashyap said he has no disclosures relevant to his keynote address or moderation of the plenary session. In his presentation, Dr. Alm disclosed his involvement with Finch Therapeutics, OpenBiome, and Biobot Analytics.

Dr. Langella disclosed in his presentation that he is co-founder of Exeliom Biosciences and has research grants with various pharmaceutical companies, food supplement companies, and agro-food companies.

The 2022 Gut Microbiota for Health World Summit was supported by sponsorships from Danone, Ferring Pharmaceuticals, Aimmune Therapeutics and Seres Therapeutics, Sanofi, and Intrinsic Medicine Inc. with additional support from educational grants provided by Ferring Pharmaceuticals and Salix Pharmaceuticals.

This article was updated 4/5/22.

WASHINGTON – Research on standardized microbiome-based therapies designed to prevent the recurrence of Clostridioides difficile infection (CDI) is moving “with a lot of momentum,” according to one expert, and modulation of the gut microbiome may even enhance responses to immunotherapy and/or abrogate toxicity, according to another.

Several products for prevention of CDI recurrence are poised for either phase 3 trials or upcoming Food and Drug Administration approval, Sahil Khanna, MBBS, MS, professor of medicine, gastroenterology, and hepatology at the Mayo Clinic in Rochester, Minn., reported at the 2022 Gut Microbiota for Health World Summit, organized by the American Gastroenterological Association and the European Society of Neurogastroenterology and Motility.

Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center, Houston, described her investigations of microbiome modulation’s role in cancer treatment. “I used to say yes [we can do this] somewhat enthusiastically without data, but now we have data to support this,” she said at the meeting. “The answer now is totally yes.”

New approaches for CDI

“Based on how the field is moving, we might be able to [offer our patients] earlier microbiome restoration” than is currently afforded with fecal microbiota transplantation (FMT), Dr. Khanna said. “Right now the [Food and Drug Administration] and our clinical guidelines say we should do FMT after three or more episodes [of CDI] – that’s heartbreaking for patients.”

Several of the microbiome-based therapies under investigation – including two that have completed phase 3 trials – have shown efficacy after a second episode of CDI, and one of these two has also had positive results after one episode of CDI in patients 65 at older, a group at particularly high risk of recurrence, said Dr. Khanna.

The value of standardized, mostly pill-form microbiome therapies has been heightened during the pandemic. “We’ve been doing conventional FMT for recurrent C. difficile for over a decade now, and it’s probably the most effective treatment we have,” said Colleen R. Kelly, MD, associate professor of medicine at Brown University, Providence, R.I., and moderator of the session on microbiota-based therapies.

Prepandemic “it got really hard, with issues of identifying donors, and quality control and safety ... And then when COVID hit the stool banks shut down,” she said in an interview after the meeting. With stool testing for SARS-CoV-2 now in place, some stool is again available, “but it made me realize how fragile our current system is,” Dr. Kelly said. “The fact that companies are putting these products through the FDA pipeline and investigating them in rigorous, scientific randomized controlled trials is really good for the field.”

The products vary in composition; some are live multi-strain biotherapeutics derived from donor stool, for instance, while others are defined live bacterial consortia not from stool. Most are oral formulations, given one or multiple times, that do not require any bowel preparation.

One of the products most advanced in the pipeline, RBX2660 (Rebiotix, Ferring Pharmaceuticals) is stool derived and rectally administered. In phase 3 research, 70.5% of patients who received one active enema after having had two or more CDI recurrences and standard-of-care antibiotic treatment had no additional recurrence at 8 weeks compared to 58.1% in the placebo group, Dr. Khanna said.

The other product with positive phase 3 results, SER-109 (Seres Therapeutics), is a donor stool-derived oral formulation of purified Firmicutes spores that is administered after bowel prep. In results published earlier this year, the percentage of patients with recurrence of CDI up to 8 weeks after standard antibiotic treatment was 12% in the SER-109 group and 40% in the placebo group.

Patients in this trial were required to have had three episodes of CDI, and interestingly, Dr. Khanna said, the diagnosis of CDI was made only by toxin enzyme immunoassay (EIA). Earlier phase 2 research, which allowed either toxin EIA or polymerase chain reaction testing for the diagnosis of CDI (as other trials have done), produced negative results, leading investigators to surmise that some of the included patients had been colonized with C. difficile rather than being actively infected, Dr. Khanna said.

Researchers of these trials are documenting not only resolution of CDI but what they believe are positive shifts in the gut microbiota after microbiome-based therapy, he said. For instance, a phase 1 trial he led of the product RBX7455 (Rebiotix, Ferring Pharmaceuticals) – an oral capsule of lyophilized stool-based bacteria that can be kept for several days at room temperature – showed increases in Bacteroides and Clostridia.

And other trials’ analyses of microbiome engraftment have demonstrated that “you can restore [species] even when these bacteria aren’t [included in the therapy],” he noted. “As the milieu of the gut improves, species that were not detected start coming back up.”

Asked about rates of efficacy in the trials’ placebo arms, Dr. Khanna said that “we’ve become smarter with our antibiotic regimens ... the placebo response rate is the response to newer guideline-based therapies.”

In addition to CDI, microbiome-based therapies are being studied, mostly in phase 1 research, for indications such as Crohn’s disease, ulcerative colitis, autism spectrum disorder, hepatitis B, and hepatic encephalopathy, Dr. Khanna noted.

Dr. Kelly, whose own research has focused on FMT for CDI, said she anticipates an expansion of research into other indications once products to prevent CDI recurrence are on the market. “There have been a couple of promising ulcerative colitis trials that haven’t gone anywhere clinically yet,” she said in the interview. “But will we now identify patients with [ulcerative colitis] who may be more sensitive to microbial manipulation, for whom we can use these microbial therapies along with a biologic?”

Some of her patients with IBD and CDI who are treated with FMT have not only had their CDI eradicated but have subsequently seen improvements in their IBD, she noted.

The role of traditional FMT and of stool banks will likely change in the future with new standardized oral microbiome-based therapies that can be approved and regulated by the FDA, she said. However, “we think the stool banks will still have some value,” she said, certainly for clinical research and probably for some treatment purposes as well. Regarding new therapies, “I just really hope they’re affordable,” she said.

Help your patients understand their C. difficile diagnosis by sending them this resource from the AGA GI Patient Center.

Gut microbiome manipulation for cancer

Dr. Wargo’s research at MD Anderson has focused on metastatic breast cancer and immunotherapeutic checkpoint blockade. By sequencing microbiota samples and performing immune profiling in hundreds of patients, her team found that responders to PD-1 blockage have a greater diversity of gut bacteria and that “favorable signatures in the gut microbiome” are associated with enhanced immune responses in the tumor microenvironment.

Studies published last year in Science from investigators in Israel (2021 Feb 5;371[6529]:602-9) and Pittsburgh (2021 Feb 5;371[6529]:595-602), demonstrated that FMT promotes response in immunotherapy-refractory melanoma patients. In one study, FMT provided clinical benefit in 6 of 15 patients whose cancer had progressed on prior anti-PD-1 therapy, “which is pretty remarkable,” Dr. Wargo said.

Both research groups, she noted, saw favorable changes in the gut microbiome and immune cell infiltrates both at the level of the colon and the tumor.

Current research on FMT and other microbiome modulation strategies for cancer is guided in part by knowledge that tumors have microbial signatures – these signatures are now being identified across all tumor types – and by findings of “cross talk” between the gut and tumor microbiomes, she explained.

“Researchers are working hard to identify optimal consortia to enhance immune responses in the cancer setting, with promising work in preclinical models,” she said, and clinical trials are in progress. The role of diet in modulating the microbiome and enhancing anti-tumor immunity, with a focus on high dietary fiber intake, is also being investigated, she said.

Get the latest information on the gut microbiome on the AGA website.

Dr. Wargo reported that she serves on the advisory boards and is a paid speaker of numerous pharmaceutical and biotechnology companies, and is the coinventor of a patent submitted by the Texas MD Anderson Cancer Center on modulating the microbiome to enhance response to checkpoint blockade, and another related patent. Dr. Khanna reported that he is involved in research with Ferring/Rebiotix, Finch, Seres, Pfizer and Vedanta, and does consulting for Immuron and several other companies. Dr. Kelly said she serves as an unpaid adviser for OpenBiome, a nonprofit stool bank, and that her site has enrolled patients in two of the trials testing products for CDI.

WASHINGTON – Research on standardized microbiome-based therapies designed to prevent the recurrence of Clostridioides difficile infection (CDI) is moving “with a lot of momentum,” according to one expert, and modulation of the gut microbiome may even enhance responses to immunotherapy and/or abrogate toxicity, according to another.

Several products for prevention of CDI recurrence are poised for either phase 3 trials or upcoming Food and Drug Administration approval, Sahil Khanna, MBBS, MS, professor of medicine, gastroenterology, and hepatology at the Mayo Clinic in Rochester, Minn., reported at the 2022 Gut Microbiota for Health World Summit, organized by the American Gastroenterological Association and the European Society of Neurogastroenterology and Motility.

Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center, Houston, described her investigations of microbiome modulation’s role in cancer treatment. “I used to say yes [we can do this] somewhat enthusiastically without data, but now we have data to support this,” she said at the meeting. “The answer now is totally yes.”

New approaches for CDI

“Based on how the field is moving, we might be able to [offer our patients] earlier microbiome restoration” than is currently afforded with fecal microbiota transplantation (FMT), Dr. Khanna said. “Right now the [Food and Drug Administration] and our clinical guidelines say we should do FMT after three or more episodes [of CDI] – that’s heartbreaking for patients.”

Several of the microbiome-based therapies under investigation – including two that have completed phase 3 trials – have shown efficacy after a second episode of CDI, and one of these two has also had positive results after one episode of CDI in patients 65 at older, a group at particularly high risk of recurrence, said Dr. Khanna.

The value of standardized, mostly pill-form microbiome therapies has been heightened during the pandemic. “We’ve been doing conventional FMT for recurrent C. difficile for over a decade now, and it’s probably the most effective treatment we have,” said Colleen R. Kelly, MD, associate professor of medicine at Brown University, Providence, R.I., and moderator of the session on microbiota-based therapies.

Prepandemic “it got really hard, with issues of identifying donors, and quality control and safety ... And then when COVID hit the stool banks shut down,” she said in an interview after the meeting. With stool testing for SARS-CoV-2 now in place, some stool is again available, “but it made me realize how fragile our current system is,” Dr. Kelly said. “The fact that companies are putting these products through the FDA pipeline and investigating them in rigorous, scientific randomized controlled trials is really good for the field.”

The products vary in composition; some are live multi-strain biotherapeutics derived from donor stool, for instance, while others are defined live bacterial consortia not from stool. Most are oral formulations, given one or multiple times, that do not require any bowel preparation.

One of the products most advanced in the pipeline, RBX2660 (Rebiotix, Ferring Pharmaceuticals) is stool derived and rectally administered. In phase 3 research, 70.5% of patients who received one active enema after having had two or more CDI recurrences and standard-of-care antibiotic treatment had no additional recurrence at 8 weeks compared to 58.1% in the placebo group, Dr. Khanna said.

The other product with positive phase 3 results, SER-109 (Seres Therapeutics), is a donor stool-derived oral formulation of purified Firmicutes spores that is administered after bowel prep. In results published earlier this year, the percentage of patients with recurrence of CDI up to 8 weeks after standard antibiotic treatment was 12% in the SER-109 group and 40% in the placebo group.

Patients in this trial were required to have had three episodes of CDI, and interestingly, Dr. Khanna said, the diagnosis of CDI was made only by toxin enzyme immunoassay (EIA). Earlier phase 2 research, which allowed either toxin EIA or polymerase chain reaction testing for the diagnosis of CDI (as other trials have done), produced negative results, leading investigators to surmise that some of the included patients had been colonized with C. difficile rather than being actively infected, Dr. Khanna said.

Researchers of these trials are documenting not only resolution of CDI but what they believe are positive shifts in the gut microbiota after microbiome-based therapy, he said. For instance, a phase 1 trial he led of the product RBX7455 (Rebiotix, Ferring Pharmaceuticals) – an oral capsule of lyophilized stool-based bacteria that can be kept for several days at room temperature – showed increases in Bacteroides and Clostridia.

And other trials’ analyses of microbiome engraftment have demonstrated that “you can restore [species] even when these bacteria aren’t [included in the therapy],” he noted. “As the milieu of the gut improves, species that were not detected start coming back up.”

Asked about rates of efficacy in the trials’ placebo arms, Dr. Khanna said that “we’ve become smarter with our antibiotic regimens ... the placebo response rate is the response to newer guideline-based therapies.”

In addition to CDI, microbiome-based therapies are being studied, mostly in phase 1 research, for indications such as Crohn’s disease, ulcerative colitis, autism spectrum disorder, hepatitis B, and hepatic encephalopathy, Dr. Khanna noted.

Dr. Kelly, whose own research has focused on FMT for CDI, said she anticipates an expansion of research into other indications once products to prevent CDI recurrence are on the market. “There have been a couple of promising ulcerative colitis trials that haven’t gone anywhere clinically yet,” she said in the interview. “But will we now identify patients with [ulcerative colitis] who may be more sensitive to microbial manipulation, for whom we can use these microbial therapies along with a biologic?”

Some of her patients with IBD and CDI who are treated with FMT have not only had their CDI eradicated but have subsequently seen improvements in their IBD, she noted.

The role of traditional FMT and of stool banks will likely change in the future with new standardized oral microbiome-based therapies that can be approved and regulated by the FDA, she said. However, “we think the stool banks will still have some value,” she said, certainly for clinical research and probably for some treatment purposes as well. Regarding new therapies, “I just really hope they’re affordable,” she said.

Help your patients understand their C. difficile diagnosis by sending them this resource from the AGA GI Patient Center.

Gut microbiome manipulation for cancer

Dr. Wargo’s research at MD Anderson has focused on metastatic breast cancer and immunotherapeutic checkpoint blockade. By sequencing microbiota samples and performing immune profiling in hundreds of patients, her team found that responders to PD-1 blockage have a greater diversity of gut bacteria and that “favorable signatures in the gut microbiome” are associated with enhanced immune responses in the tumor microenvironment.

Studies published last year in Science from investigators in Israel (2021 Feb 5;371[6529]:602-9) and Pittsburgh (2021 Feb 5;371[6529]:595-602), demonstrated that FMT promotes response in immunotherapy-refractory melanoma patients. In one study, FMT provided clinical benefit in 6 of 15 patients whose cancer had progressed on prior anti-PD-1 therapy, “which is pretty remarkable,” Dr. Wargo said.

Both research groups, she noted, saw favorable changes in the gut microbiome and immune cell infiltrates both at the level of the colon and the tumor.

Current research on FMT and other microbiome modulation strategies for cancer is guided in part by knowledge that tumors have microbial signatures – these signatures are now being identified across all tumor types – and by findings of “cross talk” between the gut and tumor microbiomes, she explained.

“Researchers are working hard to identify optimal consortia to enhance immune responses in the cancer setting, with promising work in preclinical models,” she said, and clinical trials are in progress. The role of diet in modulating the microbiome and enhancing anti-tumor immunity, with a focus on high dietary fiber intake, is also being investigated, she said.

Get the latest information on the gut microbiome on the AGA website.

Dr. Wargo reported that she serves on the advisory boards and is a paid speaker of numerous pharmaceutical and biotechnology companies, and is the coinventor of a patent submitted by the Texas MD Anderson Cancer Center on modulating the microbiome to enhance response to checkpoint blockade, and another related patent. Dr. Khanna reported that he is involved in research with Ferring/Rebiotix, Finch, Seres, Pfizer and Vedanta, and does consulting for Immuron and several other companies. Dr. Kelly said she serves as an unpaid adviser for OpenBiome, a nonprofit stool bank, and that her site has enrolled patients in two of the trials testing products for CDI.

WASHINGTON – Research on standardized microbiome-based therapies designed to prevent the recurrence of Clostridioides difficile infection (CDI) is moving “with a lot of momentum,” according to one expert, and modulation of the gut microbiome may even enhance responses to immunotherapy and/or abrogate toxicity, according to another.

Several products for prevention of CDI recurrence are poised for either phase 3 trials or upcoming Food and Drug Administration approval, Sahil Khanna, MBBS, MS, professor of medicine, gastroenterology, and hepatology at the Mayo Clinic in Rochester, Minn., reported at the 2022 Gut Microbiota for Health World Summit, organized by the American Gastroenterological Association and the European Society of Neurogastroenterology and Motility.

Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center, Houston, described her investigations of microbiome modulation’s role in cancer treatment. “I used to say yes [we can do this] somewhat enthusiastically without data, but now we have data to support this,” she said at the meeting. “The answer now is totally yes.”

New approaches for CDI

“Based on how the field is moving, we might be able to [offer our patients] earlier microbiome restoration” than is currently afforded with fecal microbiota transplantation (FMT), Dr. Khanna said. “Right now the [Food and Drug Administration] and our clinical guidelines say we should do FMT after three or more episodes [of CDI] – that’s heartbreaking for patients.”

Several of the microbiome-based therapies under investigation – including two that have completed phase 3 trials – have shown efficacy after a second episode of CDI, and one of these two has also had positive results after one episode of CDI in patients 65 at older, a group at particularly high risk of recurrence, said Dr. Khanna.

The value of standardized, mostly pill-form microbiome therapies has been heightened during the pandemic. “We’ve been doing conventional FMT for recurrent C. difficile for over a decade now, and it’s probably the most effective treatment we have,” said Colleen R. Kelly, MD, associate professor of medicine at Brown University, Providence, R.I., and moderator of the session on microbiota-based therapies.

Prepandemic “it got really hard, with issues of identifying donors, and quality control and safety ... And then when COVID hit the stool banks shut down,” she said in an interview after the meeting. With stool testing for SARS-CoV-2 now in place, some stool is again available, “but it made me realize how fragile our current system is,” Dr. Kelly said. “The fact that companies are putting these products through the FDA pipeline and investigating them in rigorous, scientific randomized controlled trials is really good for the field.”

The products vary in composition; some are live multi-strain biotherapeutics derived from donor stool, for instance, while others are defined live bacterial consortia not from stool. Most are oral formulations, given one or multiple times, that do not require any bowel preparation.

One of the products most advanced in the pipeline, RBX2660 (Rebiotix, Ferring Pharmaceuticals) is stool derived and rectally administered. In phase 3 research, 70.5% of patients who received one active enema after having had two or more CDI recurrences and standard-of-care antibiotic treatment had no additional recurrence at 8 weeks compared to 58.1% in the placebo group, Dr. Khanna said.

The other product with positive phase 3 results, SER-109 (Seres Therapeutics), is a donor stool-derived oral formulation of purified Firmicutes spores that is administered after bowel prep. In results published earlier this year, the percentage of patients with recurrence of CDI up to 8 weeks after standard antibiotic treatment was 12% in the SER-109 group and 40% in the placebo group.

Patients in this trial were required to have had three episodes of CDI, and interestingly, Dr. Khanna said, the diagnosis of CDI was made only by toxin enzyme immunoassay (EIA). Earlier phase 2 research, which allowed either toxin EIA or polymerase chain reaction testing for the diagnosis of CDI (as other trials have done), produced negative results, leading investigators to surmise that some of the included patients had been colonized with C. difficile rather than being actively infected, Dr. Khanna said.

Researchers of these trials are documenting not only resolution of CDI but what they believe are positive shifts in the gut microbiota after microbiome-based therapy, he said. For instance, a phase 1 trial he led of the product RBX7455 (Rebiotix, Ferring Pharmaceuticals) – an oral capsule of lyophilized stool-based bacteria that can be kept for several days at room temperature – showed increases in Bacteroides and Clostridia.

And other trials’ analyses of microbiome engraftment have demonstrated that “you can restore [species] even when these bacteria aren’t [included in the therapy],” he noted. “As the milieu of the gut improves, species that were not detected start coming back up.”

Asked about rates of efficacy in the trials’ placebo arms, Dr. Khanna said that “we’ve become smarter with our antibiotic regimens ... the placebo response rate is the response to newer guideline-based therapies.”

In addition to CDI, microbiome-based therapies are being studied, mostly in phase 1 research, for indications such as Crohn’s disease, ulcerative colitis, autism spectrum disorder, hepatitis B, and hepatic encephalopathy, Dr. Khanna noted.

Dr. Kelly, whose own research has focused on FMT for CDI, said she anticipates an expansion of research into other indications once products to prevent CDI recurrence are on the market. “There have been a couple of promising ulcerative colitis trials that haven’t gone anywhere clinically yet,” she said in the interview. “But will we now identify patients with [ulcerative colitis] who may be more sensitive to microbial manipulation, for whom we can use these microbial therapies along with a biologic?”

Some of her patients with IBD and CDI who are treated with FMT have not only had their CDI eradicated but have subsequently seen improvements in their IBD, she noted.

The role of traditional FMT and of stool banks will likely change in the future with new standardized oral microbiome-based therapies that can be approved and regulated by the FDA, she said. However, “we think the stool banks will still have some value,” she said, certainly for clinical research and probably for some treatment purposes as well. Regarding new therapies, “I just really hope they’re affordable,” she said.

Help your patients understand their C. difficile diagnosis by sending them this resource from the AGA GI Patient Center.

Gut microbiome manipulation for cancer

Dr. Wargo’s research at MD Anderson has focused on metastatic breast cancer and immunotherapeutic checkpoint blockade. By sequencing microbiota samples and performing immune profiling in hundreds of patients, her team found that responders to PD-1 blockage have a greater diversity of gut bacteria and that “favorable signatures in the gut microbiome” are associated with enhanced immune responses in the tumor microenvironment.

Studies published last year in Science from investigators in Israel (2021 Feb 5;371[6529]:602-9) and Pittsburgh (2021 Feb 5;371[6529]:595-602), demonstrated that FMT promotes response in immunotherapy-refractory melanoma patients. In one study, FMT provided clinical benefit in 6 of 15 patients whose cancer had progressed on prior anti-PD-1 therapy, “which is pretty remarkable,” Dr. Wargo said.

Both research groups, she noted, saw favorable changes in the gut microbiome and immune cell infiltrates both at the level of the colon and the tumor.

Current research on FMT and other microbiome modulation strategies for cancer is guided in part by knowledge that tumors have microbial signatures – these signatures are now being identified across all tumor types – and by findings of “cross talk” between the gut and tumor microbiomes, she explained.

“Researchers are working hard to identify optimal consortia to enhance immune responses in the cancer setting, with promising work in preclinical models,” she said, and clinical trials are in progress. The role of diet in modulating the microbiome and enhancing anti-tumor immunity, with a focus on high dietary fiber intake, is also being investigated, she said.

Get the latest information on the gut microbiome on the AGA website.

Dr. Wargo reported that she serves on the advisory boards and is a paid speaker of numerous pharmaceutical and biotechnology companies, and is the coinventor of a patent submitted by the Texas MD Anderson Cancer Center on modulating the microbiome to enhance response to checkpoint blockade, and another related patent. Dr. Khanna reported that he is involved in research with Ferring/Rebiotix, Finch, Seres, Pfizer and Vedanta, and does consulting for Immuron and several other companies. Dr. Kelly said she serves as an unpaid adviser for OpenBiome, a nonprofit stool bank, and that her site has enrolled patients in two of the trials testing products for CDI.

WASHINGTON – Research on standardized microbiome-based therapies designed to prevent the recurrence of Clostridioides difficile infection (CDI) is moving “with a lot of momentum,” according to one expert, and modulation of the gut microbiome may even enhance responses to immunotherapy and/or abrogate toxicity, according to another.

Several products for prevention of CDI recurrence are poised for either phase 3 trials or upcoming Food and Drug Administration approval, Sahil Khanna, MBBS, MS, professor of medicine, gastroenterology, and hepatology at the Mayo Clinic in Rochester, Minn., reported at the annual Gut Microbiota for Health World Summit.

Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center, Houston, described her investigations of microbiome modulation’s role in cancer treatment. “I used to say yes [we can do this] somewhat enthusiastically without data, but now we have data to support this,” she said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “The answer now is totally yes.”
 

New approaches for CDI

“Based on how the field is moving, we might be able to [offer our patients] earlier microbiome restoration” than is currently afforded with fecal microbiota transplantation (FMT), he said. “Right now the [Food and Drug Administration] and our clinical guidelines say we should do FMT after three or more episodes [of CDI] – that’s heartbreaking for patients.”

Several of the microbiome-based therapies under investigation – including two poised for phase 3 trials – have shown efficacy after a second episode of CDI, and one of these two has also had positive results after one episode of CDI in patients 65 at older, a group at particularly high risk of recurrence, said Dr. Khanna.

The value of standardized, mostly pill-form microbiome therapies has been heightened during the pandemic. “We’ve been doing conventional FMT for recurrent C. difficile for over a decade now, and it’s probably the most effective treatment we have,” said Colleen R. Kelly, MD, associate professor of medicine at Brown University, Providence, R.I., and moderator of the session on microbiota-based therapies.

Prepandemic “it got really hard, with issues of identifying donors, and quality control and safety ... And then when COVID hit the stool banks shut down,” she said in an interview after the meeting. With stool testing for SARS-CoV-2 now in place, some stool is again available, “but it made me realize how fragile our current system is,” Dr. Kelly said. “The fact that companies are putting these products through the FDA pipeline and investigating them in rigorous, scientific randomized controlled trials is really good for the field.”

The products vary in composition; some are live multi-strain biotherapeutics derived from donor stool, for instance, while others are defined live bacterial consortia not from stool. Most are oral formulations, given one or multiple times, that do not require any bowel preparation.

One of the products most advanced in the pipeline, RBX2660 (Rebiotix, Ferring Pharmaceuticals) is stool derived and rectally administered. In phase 3 research, 70.5% of patients who received one active enema after having had two or more CDI recurrences and standard-of-care antibiotic treatment had no additional recurrence at 8 weeks compared to 58.1% in the placebo group, Dr. Khanna said.

The other product with positive phase 3 results, SER-109 (Seres Therapeutics), is a donor stool-derived oral formulation of purified Firmicutes spores that is administered after bowel prep. In results published earlier this year, the percentage of patients with recurrence of CDI up to 8 weeks after standard antibiotic treatment was 12% in the SER-109 group and 40% in the placebo group.

Patients in this trial were required to have had three episodes of CDI, and interestingly, Dr. Khanna said, the diagnosis of CDI was made only by toxin enzyme immunoassay (EIA). Earlier phase 2 research, which allowed either toxin EIA or polymerase chain reaction testing for the diagnosis of CDI (as other trials have done), produced negative results, leading investigators to surmise that some of the included patients had been colonized with C. difficile rather than being actively infected, Dr. Khanna said.

Researchers of these trials are documenting not only resolution of CDI but what they believe are positive shifts in the gut microbiota after microbiome-based therapy, he said. For instance, a phase 1 trial he led of the product RBX7455 (Rebiotix, Ferring Pharmaceuticals) – an oral capsule of lyophilized stool-based bacteria that can be kept for several days at room temperature – showed increases in Bacteroidia and Clostridia.

And other trials’ analyses of microbiome engraftment have demonstrated that “you can restore [species] even when these bacteria aren’t [included in the therapy],” he noted. “As the milieu of the gut improves, species that were not detected start coming back up.”

Asked about rates of efficacy in the trials’ placebo arms, Dr. Khanna said that “we’ve become smarter with our antibiotic regimens ... the placebo response rate is the response to newer guideline-based therapies.”

In addition to CDI, microbiome-based therapies are being studied, mostly in phase 1 research, for indications such as Crohn’s disease, ulcerative colitis, autism spectrum disorder, hepatitis B, and hepatic encephalopathy, Dr. Khanna noted.

Dr. Kelly, whose own research has focused on FMT for CDI, said she anticipates an expansion of research into other indications once products to prevent CDI recurrence are on the market. “There have been a couple of promising ulcerative colitis trials that haven’t gone anywhere clinically yet,” she said in the interview. “But will we now identify patients with UC who may be more sensitive to microbial manipulation, for whom we can use these microbial therapies along with a biologic?”

Some of her patients with IBD and CDI who are treated with FMT have not only had their CDI eradicated but have subsequently seen improvements in their IBD, she noted.

The role of traditional FMT and of stool banks will likely change in the future with new standardized oral microbiome-based therapies that can be approved and regulated by the FDA, she said. However, “we think the stool banks will still have some value,” she said, certainly for clinical research and probably for some treatment purposes as well. Regarding new therapies, “I just really hope they’re affordable,” she said.
 

Gut microbiome manipulation for cancer

Dr. Wargo’s research at MD Anderson has focused on metastatic breast cancer and immunotherapeutic checkpoint blockade. By sequencing microbiota samples and performing immune profiling in hundreds of patients, her team found that responders to PD-1 blockage have a greater diversity of gut bacteria and that “favorable signatures in the gut microbiome” are associated with enhanced immune responses in the tumor microenvironment.

Studies published last year in Science from investigators in Israel (2021 Feb 5;371[6529]:602-9) and Pittsburgh (2021 Feb 5;371[6529]:595-602), demonstrated that FMT promotes response in immunotherapy-refractory melanoma patients. In one study, FMT provided clinical benefit in 6 of 15 patients whose cancer had progressed on prior anti-PD-1 therapy, “which is pretty remarkable,” Dr. Wargo said.

Both research groups, she noted, saw favorable changes in the gut microbiome and immune cell infiltrates both at the level of the colon and the tumor.

Current research on FMT and other microbiome modulation strategies for cancer is guided in part by knowledge that tumors have microbial signatures – these signatures are now being identified across all tumor types – and by findings of “cross talk” between the gut and tumor microbiomes, she explained.

“Researchers are working hard to identify optimal consortia to enhance immune responses in the cancer setting, with promising work in preclinical models,” she said, and clinical trials are in progress. The role of diet in modulating the microbiome and enhancing anti-tumor immunity, with a focus on high dietary fiber intake, is also being investigated, she said.

Dr. Wargo reported that she serves on the advisory boards and is a paid speaker of numerous pharmaceutical and biotechnology companies, and is the coinventor of a patent submitted by the Texas MD Anderson Cancer Center on modulating the microbiome to enhance response to checkpoint blockade, and another related patent. Dr. Khanna reported that he is involved in research with Ferring/Rebiotix, Finch, Seres, Pfizer and Vendata, and does consulting for Immuron and several other companies. Dr. Kelly said she serves as an unpaid adviser for OpenBiome, a nonprofit stool bank, and that her site has enrolled patients in two of the trials testing products for CDI.

WASHINGTON – Research on standardized microbiome-based therapies designed to prevent the recurrence of Clostridioides difficile infection (CDI) is moving “with a lot of momentum,” according to one expert, and modulation of the gut microbiome may even enhance responses to immunotherapy and/or abrogate toxicity, according to another.

Several products for prevention of CDI recurrence are poised for either phase 3 trials or upcoming Food and Drug Administration approval, Sahil Khanna, MBBS, MS, professor of medicine, gastroenterology, and hepatology at the Mayo Clinic in Rochester, Minn., reported at the annual Gut Microbiota for Health World Summit.

Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center, Houston, described her investigations of microbiome modulation’s role in cancer treatment. “I used to say yes [we can do this] somewhat enthusiastically without data, but now we have data to support this,” she said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “The answer now is totally yes.”
 

New approaches for CDI

“Based on how the field is moving, we might be able to [offer our patients] earlier microbiome restoration” than is currently afforded with fecal microbiota transplantation (FMT), he said. “Right now the [Food and Drug Administration] and our clinical guidelines say we should do FMT after three or more episodes [of CDI] – that’s heartbreaking for patients.”

Several of the microbiome-based therapies under investigation – including two poised for phase 3 trials – have shown efficacy after a second episode of CDI, and one of these two has also had positive results after one episode of CDI in patients 65 at older, a group at particularly high risk of recurrence, said Dr. Khanna.

The value of standardized, mostly pill-form microbiome therapies has been heightened during the pandemic. “We’ve been doing conventional FMT for recurrent C. difficile for over a decade now, and it’s probably the most effective treatment we have,” said Colleen R. Kelly, MD, associate professor of medicine at Brown University, Providence, R.I., and moderator of the session on microbiota-based therapies.

Prepandemic “it got really hard, with issues of identifying donors, and quality control and safety ... And then when COVID hit the stool banks shut down,” she said in an interview after the meeting. With stool testing for SARS-CoV-2 now in place, some stool is again available, “but it made me realize how fragile our current system is,” Dr. Kelly said. “The fact that companies are putting these products through the FDA pipeline and investigating them in rigorous, scientific randomized controlled trials is really good for the field.”

The products vary in composition; some are live multi-strain biotherapeutics derived from donor stool, for instance, while others are defined live bacterial consortia not from stool. Most are oral formulations, given one or multiple times, that do not require any bowel preparation.

One of the products most advanced in the pipeline, RBX2660 (Rebiotix, Ferring Pharmaceuticals) is stool derived and rectally administered. In phase 3 research, 70.5% of patients who received one active enema after having had two or more CDI recurrences and standard-of-care antibiotic treatment had no additional recurrence at 8 weeks compared to 58.1% in the placebo group, Dr. Khanna said.

The other product with positive phase 3 results, SER-109 (Seres Therapeutics), is a donor stool-derived oral formulation of purified Firmicutes spores that is administered after bowel prep. In results published earlier this year, the percentage of patients with recurrence of CDI up to 8 weeks after standard antibiotic treatment was 12% in the SER-109 group and 40% in the placebo group.

Patients in this trial were required to have had three episodes of CDI, and interestingly, Dr. Khanna said, the diagnosis of CDI was made only by toxin enzyme immunoassay (EIA). Earlier phase 2 research, which allowed either toxin EIA or polymerase chain reaction testing for the diagnosis of CDI (as other trials have done), produced negative results, leading investigators to surmise that some of the included patients had been colonized with C. difficile rather than being actively infected, Dr. Khanna said.

Researchers of these trials are documenting not only resolution of CDI but what they believe are positive shifts in the gut microbiota after microbiome-based therapy, he said. For instance, a phase 1 trial he led of the product RBX7455 (Rebiotix, Ferring Pharmaceuticals) – an oral capsule of lyophilized stool-based bacteria that can be kept for several days at room temperature – showed increases in Bacteroidia and Clostridia.

And other trials’ analyses of microbiome engraftment have demonstrated that “you can restore [species] even when these bacteria aren’t [included in the therapy],” he noted. “As the milieu of the gut improves, species that were not detected start coming back up.”

Asked about rates of efficacy in the trials’ placebo arms, Dr. Khanna said that “we’ve become smarter with our antibiotic regimens ... the placebo response rate is the response to newer guideline-based therapies.”

In addition to CDI, microbiome-based therapies are being studied, mostly in phase 1 research, for indications such as Crohn’s disease, ulcerative colitis, autism spectrum disorder, hepatitis B, and hepatic encephalopathy, Dr. Khanna noted.

Dr. Kelly, whose own research has focused on FMT for CDI, said she anticipates an expansion of research into other indications once products to prevent CDI recurrence are on the market. “There have been a couple of promising ulcerative colitis trials that haven’t gone anywhere clinically yet,” she said in the interview. “But will we now identify patients with UC who may be more sensitive to microbial manipulation, for whom we can use these microbial therapies along with a biologic?”

Some of her patients with IBD and CDI who are treated with FMT have not only had their CDI eradicated but have subsequently seen improvements in their IBD, she noted.

The role of traditional FMT and of stool banks will likely change in the future with new standardized oral microbiome-based therapies that can be approved and regulated by the FDA, she said. However, “we think the stool banks will still have some value,” she said, certainly for clinical research and probably for some treatment purposes as well. Regarding new therapies, “I just really hope they’re affordable,” she said.
 

Gut microbiome manipulation for cancer

Dr. Wargo’s research at MD Anderson has focused on metastatic breast cancer and immunotherapeutic checkpoint blockade. By sequencing microbiota samples and performing immune profiling in hundreds of patients, her team found that responders to PD-1 blockage have a greater diversity of gut bacteria and that “favorable signatures in the gut microbiome” are associated with enhanced immune responses in the tumor microenvironment.

Studies published last year in Science from investigators in Israel (2021 Feb 5;371[6529]:602-9) and Pittsburgh (2021 Feb 5;371[6529]:595-602), demonstrated that FMT promotes response in immunotherapy-refractory melanoma patients. In one study, FMT provided clinical benefit in 6 of 15 patients whose cancer had progressed on prior anti-PD-1 therapy, “which is pretty remarkable,” Dr. Wargo said.

Both research groups, she noted, saw favorable changes in the gut microbiome and immune cell infiltrates both at the level of the colon and the tumor.

Current research on FMT and other microbiome modulation strategies for cancer is guided in part by knowledge that tumors have microbial signatures – these signatures are now being identified across all tumor types – and by findings of “cross talk” between the gut and tumor microbiomes, she explained.

“Researchers are working hard to identify optimal consortia to enhance immune responses in the cancer setting, with promising work in preclinical models,” she said, and clinical trials are in progress. The role of diet in modulating the microbiome and enhancing anti-tumor immunity, with a focus on high dietary fiber intake, is also being investigated, she said.

Dr. Wargo reported that she serves on the advisory boards and is a paid speaker of numerous pharmaceutical and biotechnology companies, and is the coinventor of a patent submitted by the Texas MD Anderson Cancer Center on modulating the microbiome to enhance response to checkpoint blockade, and another related patent. Dr. Khanna reported that he is involved in research with Ferring/Rebiotix, Finch, Seres, Pfizer and Vendata, and does consulting for Immuron and several other companies. Dr. Kelly said she serves as an unpaid adviser for OpenBiome, a nonprofit stool bank, and that her site has enrolled patients in two of the trials testing products for CDI.

WASHINGTON – Research on standardized microbiome-based therapies designed to prevent the recurrence of Clostridioides difficile infection (CDI) is moving “with a lot of momentum,” according to one expert, and modulation of the gut microbiome may even enhance responses to immunotherapy and/or abrogate toxicity, according to another.

Several products for prevention of CDI recurrence are poised for either phase 3 trials or upcoming Food and Drug Administration approval, Sahil Khanna, MBBS, MS, professor of medicine, gastroenterology, and hepatology at the Mayo Clinic in Rochester, Minn., reported at the annual Gut Microbiota for Health World Summit.

Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center, Houston, described her investigations of microbiome modulation’s role in cancer treatment. “I used to say yes [we can do this] somewhat enthusiastically without data, but now we have data to support this,” she said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “The answer now is totally yes.”
 

New approaches for CDI

“Based on how the field is moving, we might be able to [offer our patients] earlier microbiome restoration” than is currently afforded with fecal microbiota transplantation (FMT), he said. “Right now the [Food and Drug Administration] and our clinical guidelines say we should do FMT after three or more episodes [of CDI] – that’s heartbreaking for patients.”

Several of the microbiome-based therapies under investigation – including two poised for phase 3 trials – have shown efficacy after a second episode of CDI, and one of these two has also had positive results after one episode of CDI in patients 65 at older, a group at particularly high risk of recurrence, said Dr. Khanna.

The value of standardized, mostly pill-form microbiome therapies has been heightened during the pandemic. “We’ve been doing conventional FMT for recurrent C. difficile for over a decade now, and it’s probably the most effective treatment we have,” said Colleen R. Kelly, MD, associate professor of medicine at Brown University, Providence, R.I., and moderator of the session on microbiota-based therapies.

Prepandemic “it got really hard, with issues of identifying donors, and quality control and safety ... And then when COVID hit the stool banks shut down,” she said in an interview after the meeting. With stool testing for SARS-CoV-2 now in place, some stool is again available, “but it made me realize how fragile our current system is,” Dr. Kelly said. “The fact that companies are putting these products through the FDA pipeline and investigating them in rigorous, scientific randomized controlled trials is really good for the field.”

The products vary in composition; some are live multi-strain biotherapeutics derived from donor stool, for instance, while others are defined live bacterial consortia not from stool. Most are oral formulations, given one or multiple times, that do not require any bowel preparation.

One of the products most advanced in the pipeline, RBX2660 (Rebiotix, Ferring Pharmaceuticals) is stool derived and rectally administered. In phase 3 research, 70.5% of patients who received one active enema after having had two or more CDI recurrences and standard-of-care antibiotic treatment had no additional recurrence at 8 weeks compared to 58.1% in the placebo group, Dr. Khanna said.

The other product with positive phase 3 results, SER-109 (Seres Therapeutics), is a donor stool-derived oral formulation of purified Firmicutes spores that is administered after bowel prep. In results published earlier this year, the percentage of patients with recurrence of CDI up to 8 weeks after standard antibiotic treatment was 12% in the SER-109 group and 40% in the placebo group.

Patients in this trial were required to have had three episodes of CDI, and interestingly, Dr. Khanna said, the diagnosis of CDI was made only by toxin enzyme immunoassay (EIA). Earlier phase 2 research, which allowed either toxin EIA or polymerase chain reaction testing for the diagnosis of CDI (as other trials have done), produced negative results, leading investigators to surmise that some of the included patients had been colonized with C. difficile rather than being actively infected, Dr. Khanna said.

Researchers of these trials are documenting not only resolution of CDI but what they believe are positive shifts in the gut microbiota after microbiome-based therapy, he said. For instance, a phase 1 trial he led of the product RBX7455 (Rebiotix, Ferring Pharmaceuticals) – an oral capsule of lyophilized stool-based bacteria that can be kept for several days at room temperature – showed increases in Bacteroidia and Clostridia.

And other trials’ analyses of microbiome engraftment have demonstrated that “you can restore [species] even when these bacteria aren’t [included in the therapy],” he noted. “As the milieu of the gut improves, species that were not detected start coming back up.”

Asked about rates of efficacy in the trials’ placebo arms, Dr. Khanna said that “we’ve become smarter with our antibiotic regimens ... the placebo response rate is the response to newer guideline-based therapies.”

In addition to CDI, microbiome-based therapies are being studied, mostly in phase 1 research, for indications such as Crohn’s disease, ulcerative colitis, autism spectrum disorder, hepatitis B, and hepatic encephalopathy, Dr. Khanna noted.

Dr. Kelly, whose own research has focused on FMT for CDI, said she anticipates an expansion of research into other indications once products to prevent CDI recurrence are on the market. “There have been a couple of promising ulcerative colitis trials that haven’t gone anywhere clinically yet,” she said in the interview. “But will we now identify patients with UC who may be more sensitive to microbial manipulation, for whom we can use these microbial therapies along with a biologic?”

Some of her patients with IBD and CDI who are treated with FMT have not only had their CDI eradicated but have subsequently seen improvements in their IBD, she noted.

The role of traditional FMT and of stool banks will likely change in the future with new standardized oral microbiome-based therapies that can be approved and regulated by the FDA, she said. However, “we think the stool banks will still have some value,” she said, certainly for clinical research and probably for some treatment purposes as well. Regarding new therapies, “I just really hope they’re affordable,” she said.
 

Gut microbiome manipulation for cancer

Dr. Wargo’s research at MD Anderson has focused on metastatic breast cancer and immunotherapeutic checkpoint blockade. By sequencing microbiota samples and performing immune profiling in hundreds of patients, her team found that responders to PD-1 blockage have a greater diversity of gut bacteria and that “favorable signatures in the gut microbiome” are associated with enhanced immune responses in the tumor microenvironment.

Studies published last year in Science from investigators in Israel (2021 Feb 5;371[6529]:602-9) and Pittsburgh (2021 Feb 5;371[6529]:595-602), demonstrated that FMT promotes response in immunotherapy-refractory melanoma patients. In one study, FMT provided clinical benefit in 6 of 15 patients whose cancer had progressed on prior anti-PD-1 therapy, “which is pretty remarkable,” Dr. Wargo said.

Both research groups, she noted, saw favorable changes in the gut microbiome and immune cell infiltrates both at the level of the colon and the tumor.

Current research on FMT and other microbiome modulation strategies for cancer is guided in part by knowledge that tumors have microbial signatures – these signatures are now being identified across all tumor types – and by findings of “cross talk” between the gut and tumor microbiomes, she explained.

“Researchers are working hard to identify optimal consortia to enhance immune responses in the cancer setting, with promising work in preclinical models,” she said, and clinical trials are in progress. The role of diet in modulating the microbiome and enhancing anti-tumor immunity, with a focus on high dietary fiber intake, is also being investigated, she said.

Dr. Wargo reported that she serves on the advisory boards and is a paid speaker of numerous pharmaceutical and biotechnology companies, and is the coinventor of a patent submitted by the Texas MD Anderson Cancer Center on modulating the microbiome to enhance response to checkpoint blockade, and another related patent. Dr. Khanna reported that he is involved in research with Ferring/Rebiotix, Finch, Seres, Pfizer and Vendata, and does consulting for Immuron and several other companies. Dr. Kelly said she serves as an unpaid adviser for OpenBiome, a nonprofit stool bank, and that her site has enrolled patients in two of the trials testing products for CDI.

Spironolactone was not associated with any meaningful increase in the risk of breast cancer or other solid organ cancers in a systematic review and meta-analysis covering seven observational studies and a total population of over 4.5 million people.

The data, published in JAMA Dermatology, are “reassuring,” the authors reported, considering that the spironolactone label carries a Food and Drug Administration warning regarding possible tumorigenicity, which is based on animal studies of doses up to 150-fold greater than doses used for humans. The drug’s antiandrogenic properties have driven its off-label use as a treatment for acne, hidradenitis, androgenetic alopecia, and hirsutism.

Spironolactone, a synthetic 17-lactone steroid, is approved for the treatment of heart failure, edema and ascites, hypertension, and primary hyperaldosteronism. Off label, it is also frequently used in gender-affirming care and is included in Endocrine Society guidelines as part of hormonal regimens for transgender women, the authors noted.

The seven eligible studies looked at the occurrence of cancer in men and women who had any exposure to the drug, regardless of the primary indication. Sample sizes ranged from 18,035 to 2.3 million, and the mean age across all studies was 62.6-72 years.

The researchers synthesized the studies, mostly of European individuals, using random effects meta-analysis and found no statistically significant association between spironolactone use and risk of breast cancer (risk ratio, 1.04; 95% confidence interval, 0.86-1.22). Three of the seven studies investigated breast cancer.

There was also no significant association between spironolactone use and risk of ovarian cancer (two studies), bladder cancer (three studies), kidney cancer (two studies), gastric cancer (two studies), or esophageal cancer (two studies).

For prostate cancer, investigated in four studies, use of the drug was associated with decreased risk (RR, 0.79, 95% CI, 0.68-0.90).

Kanthi Bommareddy, MD, of the University of Miami and coauthors concluded that all studies were at low risk of bias after appraising each one using a scale that looks at selection bias, confounding bias, and detection and outcome bias.

In dermatology, the results should “help us to take a collective sigh of relief,” said Julie C. Harper, MD, of the Dermatology and Skin Care Center of Birmingham, Ala., who was asked to comment on the study. The drug has been “safe and effective in our clinics and it is affordable and accessible to our patients,” she said, but with the FDA’s warning and the drug’s antiandrogen capacity, “there has been concern that we might be putting our patients at increased risk of breast cancer [in particular].”

The pooling of seven large studies together and the finding of no substantive increased risk of cancer “gives us evidence and comfort that spironolactone does not increase the risk of cancer in our dermatology patients,” said Dr. Harper, a past president of the American Acne & Rosacea Society.

“With every passing year,” she noted, “dermatologists are prescribing more and more spironolactone for acne, hidradenitis, androgenetic alopecia, and hirsutism.”

Four of the seven studies stratified analyses by sex, and in those without stratification by sex, women accounted for 17.2%-54.4% of the samples.

The studies had long follow-up periods of 5-20 years, but certainty of the evidence was low and since many of the studies included mostly older individuals, “they may not generalize to younger populations, such as those treated with spironolactone for acne,” the investigators wrote.

The authors also noted they were unable to look for dose-dependent associations between spironolactone and cancer risk, and that confidence intervals for rarer cancers like ovarian cancer were wide. “We cannot entirely exclude the potential for a meaningful increase in cancer risk,” and future studies are needed, in populations that include younger patients and those with acne or hirsutism.

Dr. Bommareddy reported no disclosures. Other coauthors reported grants from the National Cancer Institute outside the submitted work, and personal fees as a Cancer Prevention and Research Institute of Texas Scholar in Cancer Research. There was no funding reported for the study. Dr. Harper said she had no disclosures.

Spironolactone was not associated with any meaningful increase in the risk of breast cancer or other solid organ cancers in a systematic review and meta-analysis covering seven observational studies and a total population of over 4.5 million people.

The data, published in JAMA Dermatology, are “reassuring,” the authors reported, considering that the spironolactone label carries a Food and Drug Administration warning regarding possible tumorigenicity, which is based on animal studies of doses up to 150-fold greater than doses used for humans. The drug’s antiandrogenic properties have driven its off-label use as a treatment for acne, hidradenitis, androgenetic alopecia, and hirsutism.

Spironolactone, a synthetic 17-lactone steroid, is approved for the treatment of heart failure, edema and ascites, hypertension, and primary hyperaldosteronism. Off label, it is also frequently used in gender-affirming care and is included in Endocrine Society guidelines as part of hormonal regimens for transgender women, the authors noted.

The seven eligible studies looked at the occurrence of cancer in men and women who had any exposure to the drug, regardless of the primary indication. Sample sizes ranged from 18,035 to 2.3 million, and the mean age across all studies was 62.6-72 years.

The researchers synthesized the studies, mostly of European individuals, using random effects meta-analysis and found no statistically significant association between spironolactone use and risk of breast cancer (risk ratio, 1.04; 95% confidence interval, 0.86-1.22). Three of the seven studies investigated breast cancer.

There was also no significant association between spironolactone use and risk of ovarian cancer (two studies), bladder cancer (three studies), kidney cancer (two studies), gastric cancer (two studies), or esophageal cancer (two studies).

For prostate cancer, investigated in four studies, use of the drug was associated with decreased risk (RR, 0.79, 95% CI, 0.68-0.90).

Kanthi Bommareddy, MD, of the University of Miami and coauthors concluded that all studies were at low risk of bias after appraising each one using a scale that looks at selection bias, confounding bias, and detection and outcome bias.

In dermatology, the results should “help us to take a collective sigh of relief,” said Julie C. Harper, MD, of the Dermatology and Skin Care Center of Birmingham, Ala., who was asked to comment on the study. The drug has been “safe and effective in our clinics and it is affordable and accessible to our patients,” she said, but with the FDA’s warning and the drug’s antiandrogen capacity, “there has been concern that we might be putting our patients at increased risk of breast cancer [in particular].”

The pooling of seven large studies together and the finding of no substantive increased risk of cancer “gives us evidence and comfort that spironolactone does not increase the risk of cancer in our dermatology patients,” said Dr. Harper, a past president of the American Acne & Rosacea Society.

“With every passing year,” she noted, “dermatologists are prescribing more and more spironolactone for acne, hidradenitis, androgenetic alopecia, and hirsutism.”

Four of the seven studies stratified analyses by sex, and in those without stratification by sex, women accounted for 17.2%-54.4% of the samples.

The studies had long follow-up periods of 5-20 years, but certainty of the evidence was low and since many of the studies included mostly older individuals, “they may not generalize to younger populations, such as those treated with spironolactone for acne,” the investigators wrote.

The authors also noted they were unable to look for dose-dependent associations between spironolactone and cancer risk, and that confidence intervals for rarer cancers like ovarian cancer were wide. “We cannot entirely exclude the potential for a meaningful increase in cancer risk,” and future studies are needed, in populations that include younger patients and those with acne or hirsutism.

Dr. Bommareddy reported no disclosures. Other coauthors reported grants from the National Cancer Institute outside the submitted work, and personal fees as a Cancer Prevention and Research Institute of Texas Scholar in Cancer Research. There was no funding reported for the study. Dr. Harper said she had no disclosures.

Spironolactone was not associated with any meaningful increase in the risk of breast cancer or other solid organ cancers in a systematic review and meta-analysis covering seven observational studies and a total population of over 4.5 million people.

The data, published in JAMA Dermatology, are “reassuring,” the authors reported, considering that the spironolactone label carries a Food and Drug Administration warning regarding possible tumorigenicity, which is based on animal studies of doses up to 150-fold greater than doses used for humans. The drug’s antiandrogenic properties have driven its off-label use as a treatment for acne, hidradenitis, androgenetic alopecia, and hirsutism.

Spironolactone, a synthetic 17-lactone steroid, is approved for the treatment of heart failure, edema and ascites, hypertension, and primary hyperaldosteronism. Off label, it is also frequently used in gender-affirming care and is included in Endocrine Society guidelines as part of hormonal regimens for transgender women, the authors noted.

The seven eligible studies looked at the occurrence of cancer in men and women who had any exposure to the drug, regardless of the primary indication. Sample sizes ranged from 18,035 to 2.3 million, and the mean age across all studies was 62.6-72 years.

The researchers synthesized the studies, mostly of European individuals, using random effects meta-analysis and found no statistically significant association between spironolactone use and risk of breast cancer (risk ratio, 1.04; 95% confidence interval, 0.86-1.22). Three of the seven studies investigated breast cancer.

There was also no significant association between spironolactone use and risk of ovarian cancer (two studies), bladder cancer (three studies), kidney cancer (two studies), gastric cancer (two studies), or esophageal cancer (two studies).

For prostate cancer, investigated in four studies, use of the drug was associated with decreased risk (RR, 0.79, 95% CI, 0.68-0.90).

Kanthi Bommareddy, MD, of the University of Miami and coauthors concluded that all studies were at low risk of bias after appraising each one using a scale that looks at selection bias, confounding bias, and detection and outcome bias.

In dermatology, the results should “help us to take a collective sigh of relief,” said Julie C. Harper, MD, of the Dermatology and Skin Care Center of Birmingham, Ala., who was asked to comment on the study. The drug has been “safe and effective in our clinics and it is affordable and accessible to our patients,” she said, but with the FDA’s warning and the drug’s antiandrogen capacity, “there has been concern that we might be putting our patients at increased risk of breast cancer [in particular].”

The pooling of seven large studies together and the finding of no substantive increased risk of cancer “gives us evidence and comfort that spironolactone does not increase the risk of cancer in our dermatology patients,” said Dr. Harper, a past president of the American Acne & Rosacea Society.

“With every passing year,” she noted, “dermatologists are prescribing more and more spironolactone for acne, hidradenitis, androgenetic alopecia, and hirsutism.”

Four of the seven studies stratified analyses by sex, and in those without stratification by sex, women accounted for 17.2%-54.4% of the samples.

The studies had long follow-up periods of 5-20 years, but certainty of the evidence was low and since many of the studies included mostly older individuals, “they may not generalize to younger populations, such as those treated with spironolactone for acne,” the investigators wrote.

The authors also noted they were unable to look for dose-dependent associations between spironolactone and cancer risk, and that confidence intervals for rarer cancers like ovarian cancer were wide. “We cannot entirely exclude the potential for a meaningful increase in cancer risk,” and future studies are needed, in populations that include younger patients and those with acne or hirsutism.

Dr. Bommareddy reported no disclosures. Other coauthors reported grants from the National Cancer Institute outside the submitted work, and personal fees as a Cancer Prevention and Research Institute of Texas Scholar in Cancer Research. There was no funding reported for the study. Dr. Harper said she had no disclosures.

A practice guideline update from the ENT community on tympanostomy tubes in children reaffirms that tube insertion should not be considered in cases of otitis media with effusion (OME) lasting less than 3 months, or in children with recurrent acute otitis media (AOM) without middle ear effusion at the time of assessment for the procedure.

New in the update from the American Academy of Otolaryngology–Head and Neck Surgery Foundation (AAO-HNSF) is a strong recommendation for timely follow-up after surgery and recommendations against both routine use of prophylactic antibiotic ear drops after surgery and the initial use of long-term tubes except when there are specific reasons for doing so.

The update also expands the list of risk factors that place children with OME at increased risk of developmental difficulties – and often in need of timely ear tube placement – to include intellectual disability, learning disorder, and attention-deficit/hyperactivity disorder.

“Most of what we said in the 2013 [original] guideline was good and still valid ... and [important for] pediatricians, who are the key players” in managing otitis media, Jesse Hackell, MD, one of two general pediatricians who served on the Academy’s guideline update committee, said in an interview.

OME spontaneously clears up to 90% of the time within 3 months, said Dr. Hackell, of Pomona (New York) Pediatrics, and chair of the American Academy of Pediatrics (AAP) Committee on Practice and Ambulatory Medicine.

The updated guideline, for children 6 months to 12 years, reaffirms a recommendation that tube insertion be offered to children with “bilateral OME for 3 months or longer AND documented hearing difficulties.”

It also reaffirms “options” (a lesser quality of evidence) that in the absence of hearing difficulties, surgery may be performed for children with chronic OME (3 months or longer) in one or both ears if 1) they are at increased risk of developmental difficulties from OME or 2) effusion is likely contributing to balance problems, poor school performance, behavioral problems, ear discomfort, or reduced quality of life.

Children with chronic OME who do not undergo surgery should be reevaluated at 3- to 6-month intervals and monitored until effusion is no longer present, significant hearing loss is detected, or structural abnormalities of the tympanic membrane or middle ear are detected, the update again recommends.

Tympanostomy tube placement is the most common ambulatory surgery performed on children in the United States, the guideline authors say. In 2014, about 9% of children had undergone the surgery, they wrote, noting also that “tubes were placed in 25%-30% of children with frequent ear infections.”

Recurrent AOM

The AAO-HNSF guidance regarding tympanostomy tubes for OME is similar overall to management guidance issued by the AAP in its clinical practice guideline on OME.

The organizations differ, however, on their guidance for tube insertion for recurrent AOM. In its 2013 clinical practice guideline on AOM, the AAP recommends that clinicians may offer tube insertion for recurrent AOM, with no mention of the presence or absence of persistent fluid as a consideration.

According to the AAO-HNSF update, grade A evidence, including some research published since its original 2013 guideline, has shown little benefit to tube insertion in reducing the incidence of AOM in otherwise healthy children who don’t have middle ear effusion.

One study published in 2019 assessed outcomes after watchful waiting and found that only one-third of 123 children eventually went on to tympanostomy tube placement, noted Richard M. Rosenfeld, MD, distinguished professor and chairman of otolaryngology at SUNY Downstate Health Sciences University in Brooklyn, N.Y., and lead author of the original and updated guidelines.

In practice, “the real question [for the ENT] is the future. If the ears are perfectly clear, will tubes really reduce the frequency of infections going forward?” Dr. Rosenfeld said in an interview. “All the evidence seems to say no, it doesn’t make much of a difference.”

Dr. Hackell said he’s confident that the question “is settled enough.” While there “could be stronger research and higher quality studies, the evidence is still pretty good to suggest you gain little to no benefit with tubes when you’re dealing with recurrent AOM without effusion,” he said.

Asked to comment on the ENT update and its guidance on tympanostomy tubes for children with recurrent AOM, an AAP spokesperson said the “issue is under review” and that the AAP did not currently have a statement.
 

At-risk children

The AAO-HNSF update renews a recommendation to evaluate children with either recurrent AOM or OME of any duration for increased risk for speech, language, or learning problems from OME because of baseline factors (sensory, physical, cognitive, or behavioral).

When OME becomes chronic – or when a tympanogram gives a flat-line reading – OME is likely to persist, and families of at-risk children especially should be encouraged to pursue tube placement, Dr. Rosenfeld said.

Despite prior guidance to this effect, he said, ear tubes are being underutilized in at-risk children, with effusion being missed in primary care and with ENTs not expediting tube placement upon referral.

“These children have learning issues, cognitive issues, developmental issues,” he said in the interview. “It’s a population that does very poorly with ears full of fluid ... and despite guidance suggesting these children should be prioritized with tubes, it doesn’t seem to be happening enough.”

Formulating guidelines for at-risk children is challenging because they are often excluded from trials, Dr. Rosenfeld said, which limits evidence about the benefits of tubes and limits the strength of recommendations.

The addition of attention-deficit/hyperactivity disorder, intellectual disability, and learning disorder to the list of risk factors is notable, Dr. Hackell said. (The list includes autism spectrum disorder, developmental delay, and suspected or confirmed speech and language delay or disorder.)

“We know that kids with ADHD take in and process information a little differently ... it may be harder to get their attention with auditory stimulation,” he said. “So anything that would impact the taking in of information even for a short period of time increases their risk.”

Surgical practice

ENTs are advised in the new guidance to use long-term tubes and perioperative antibiotic ear drops more judiciously. “Long-term tubes have a role, but there are some doctors who routinely use them, even for a first-time surgery,” said Dr. Rosenfeld.

Overuse of long-term tubes results in a higher incidence of tympanic membrane perforation, chronic drainage, and other complications, as well as greater need for long-term follow-up. “There needs to be a reason – something to justify the need for prolonged ventilation,” he said.

Perioperative antibiotic ear drops are often administered during surgery and then prescribed routinely for all children afterward, but research has shown that saline irrigation during surgery and a single application of antibiotic/steroid drops is similarly efficacious in preventing otorrhea, the guideline says. Antibiotic ear drops are also “expensive,” noted Dr. Hackell. “There’s not enough benefit to justify it.”

The update also more explicitly advises selective use of adenoidectomy. A new option says that clinicians may perform the procedure as an adjunct to tube insertion for children 4 years or older to potentially reduce the future incidence of recurrent OME or the need for repeat surgery.

However, in younger children, it should not be offered unless there are symptoms directly related to adenoid infection or nasal obstruction. “Under 4 years, there’s no primary benefit for the ears,” said Dr. Rosenfeld.

Follow-up with the surgeon after tympanostomy tube insertion should occur within 3 months to assess outcomes and educate the family, the update strongly recommends.

And pediatricians should know, Dr. Hackell notes, that clinical evidence continues to show that earplugs and other water precautions are not routinely needed for children who have tubes in place. A good approach, the guideline says, is to “first avoid water precautions and instead reserve them for children with recurrent or persistent tympanostomy tube otorrhea.”

Asked to comment on the guideline update, Tim Joos, MD, MPH, who practices combined internal medicine/pediatrics in Seattle and is an editorial advisory board member of Pediatric News, noted the inclusion of patient information sheets with frequently asked questions – resources that can be useful for guiding parents through what’s often a shared decision-making process.

Neither Dr. Rosenfeld nor Dr. Hackell reported any disclosures. Other members of the guideline update committee reported various book royalties, consulting fees, and other disclosures. Dr. Joos reported he has no connections to the guideline authors.

A practice guideline update from the ENT community on tympanostomy tubes in children reaffirms that tube insertion should not be considered in cases of otitis media with effusion (OME) lasting less than 3 months, or in children with recurrent acute otitis media (AOM) without middle ear effusion at the time of assessment for the procedure.

New in the update from the American Academy of Otolaryngology–Head and Neck Surgery Foundation (AAO-HNSF) is a strong recommendation for timely follow-up after surgery and recommendations against both routine use of prophylactic antibiotic ear drops after surgery and the initial use of long-term tubes except when there are specific reasons for doing so.

The update also expands the list of risk factors that place children with OME at increased risk of developmental difficulties – and often in need of timely ear tube placement – to include intellectual disability, learning disorder, and attention-deficit/hyperactivity disorder.

“Most of what we said in the 2013 [original] guideline was good and still valid ... and [important for] pediatricians, who are the key players” in managing otitis media, Jesse Hackell, MD, one of two general pediatricians who served on the Academy’s guideline update committee, said in an interview.

OME spontaneously clears up to 90% of the time within 3 months, said Dr. Hackell, of Pomona (New York) Pediatrics, and chair of the American Academy of Pediatrics (AAP) Committee on Practice and Ambulatory Medicine.

The updated guideline, for children 6 months to 12 years, reaffirms a recommendation that tube insertion be offered to children with “bilateral OME for 3 months or longer AND documented hearing difficulties.”

It also reaffirms “options” (a lesser quality of evidence) that in the absence of hearing difficulties, surgery may be performed for children with chronic OME (3 months or longer) in one or both ears if 1) they are at increased risk of developmental difficulties from OME or 2) effusion is likely contributing to balance problems, poor school performance, behavioral problems, ear discomfort, or reduced quality of life.

Children with chronic OME who do not undergo surgery should be reevaluated at 3- to 6-month intervals and monitored until effusion is no longer present, significant hearing loss is detected, or structural abnormalities of the tympanic membrane or middle ear are detected, the update again recommends.

Tympanostomy tube placement is the most common ambulatory surgery performed on children in the United States, the guideline authors say. In 2014, about 9% of children had undergone the surgery, they wrote, noting also that “tubes were placed in 25%-30% of children with frequent ear infections.”

Recurrent AOM

The AAO-HNSF guidance regarding tympanostomy tubes for OME is similar overall to management guidance issued by the AAP in its clinical practice guideline on OME.

The organizations differ, however, on their guidance for tube insertion for recurrent AOM. In its 2013 clinical practice guideline on AOM, the AAP recommends that clinicians may offer tube insertion for recurrent AOM, with no mention of the presence or absence of persistent fluid as a consideration.

According to the AAO-HNSF update, grade A evidence, including some research published since its original 2013 guideline, has shown little benefit to tube insertion in reducing the incidence of AOM in otherwise healthy children who don’t have middle ear effusion.

One study published in 2019 assessed outcomes after watchful waiting and found that only one-third of 123 children eventually went on to tympanostomy tube placement, noted Richard M. Rosenfeld, MD, distinguished professor and chairman of otolaryngology at SUNY Downstate Health Sciences University in Brooklyn, N.Y., and lead author of the original and updated guidelines.

In practice, “the real question [for the ENT] is the future. If the ears are perfectly clear, will tubes really reduce the frequency of infections going forward?” Dr. Rosenfeld said in an interview. “All the evidence seems to say no, it doesn’t make much of a difference.”

Dr. Hackell said he’s confident that the question “is settled enough.” While there “could be stronger research and higher quality studies, the evidence is still pretty good to suggest you gain little to no benefit with tubes when you’re dealing with recurrent AOM without effusion,” he said.

Asked to comment on the ENT update and its guidance on tympanostomy tubes for children with recurrent AOM, an AAP spokesperson said the “issue is under review” and that the AAP did not currently have a statement.
 

At-risk children

The AAO-HNSF update renews a recommendation to evaluate children with either recurrent AOM or OME of any duration for increased risk for speech, language, or learning problems from OME because of baseline factors (sensory, physical, cognitive, or behavioral).

When OME becomes chronic – or when a tympanogram gives a flat-line reading – OME is likely to persist, and families of at-risk children especially should be encouraged to pursue tube placement, Dr. Rosenfeld said.

Despite prior guidance to this effect, he said, ear tubes are being underutilized in at-risk children, with effusion being missed in primary care and with ENTs not expediting tube placement upon referral.

“These children have learning issues, cognitive issues, developmental issues,” he said in the interview. “It’s a population that does very poorly with ears full of fluid ... and despite guidance suggesting these children should be prioritized with tubes, it doesn’t seem to be happening enough.”

Formulating guidelines for at-risk children is challenging because they are often excluded from trials, Dr. Rosenfeld said, which limits evidence about the benefits of tubes and limits the strength of recommendations.

The addition of attention-deficit/hyperactivity disorder, intellectual disability, and learning disorder to the list of risk factors is notable, Dr. Hackell said. (The list includes autism spectrum disorder, developmental delay, and suspected or confirmed speech and language delay or disorder.)

“We know that kids with ADHD take in and process information a little differently ... it may be harder to get their attention with auditory stimulation,” he said. “So anything that would impact the taking in of information even for a short period of time increases their risk.”

Surgical practice

ENTs are advised in the new guidance to use long-term tubes and perioperative antibiotic ear drops more judiciously. “Long-term tubes have a role, but there are some doctors who routinely use them, even for a first-time surgery,” said Dr. Rosenfeld.

Overuse of long-term tubes results in a higher incidence of tympanic membrane perforation, chronic drainage, and other complications, as well as greater need for long-term follow-up. “There needs to be a reason – something to justify the need for prolonged ventilation,” he said.

Perioperative antibiotic ear drops are often administered during surgery and then prescribed routinely for all children afterward, but research has shown that saline irrigation during surgery and a single application of antibiotic/steroid drops is similarly efficacious in preventing otorrhea, the guideline says. Antibiotic ear drops are also “expensive,” noted Dr. Hackell. “There’s not enough benefit to justify it.”

The update also more explicitly advises selective use of adenoidectomy. A new option says that clinicians may perform the procedure as an adjunct to tube insertion for children 4 years or older to potentially reduce the future incidence of recurrent OME or the need for repeat surgery.

However, in younger children, it should not be offered unless there are symptoms directly related to adenoid infection or nasal obstruction. “Under 4 years, there’s no primary benefit for the ears,” said Dr. Rosenfeld.

Follow-up with the surgeon after tympanostomy tube insertion should occur within 3 months to assess outcomes and educate the family, the update strongly recommends.

And pediatricians should know, Dr. Hackell notes, that clinical evidence continues to show that earplugs and other water precautions are not routinely needed for children who have tubes in place. A good approach, the guideline says, is to “first avoid water precautions and instead reserve them for children with recurrent or persistent tympanostomy tube otorrhea.”

Asked to comment on the guideline update, Tim Joos, MD, MPH, who practices combined internal medicine/pediatrics in Seattle and is an editorial advisory board member of Pediatric News, noted the inclusion of patient information sheets with frequently asked questions – resources that can be useful for guiding parents through what’s often a shared decision-making process.

Neither Dr. Rosenfeld nor Dr. Hackell reported any disclosures. Other members of the guideline update committee reported various book royalties, consulting fees, and other disclosures. Dr. Joos reported he has no connections to the guideline authors.

A practice guideline update from the ENT community on tympanostomy tubes in children reaffirms that tube insertion should not be considered in cases of otitis media with effusion (OME) lasting less than 3 months, or in children with recurrent acute otitis media (AOM) without middle ear effusion at the time of assessment for the procedure.

New in the update from the American Academy of Otolaryngology–Head and Neck Surgery Foundation (AAO-HNSF) is a strong recommendation for timely follow-up after surgery and recommendations against both routine use of prophylactic antibiotic ear drops after surgery and the initial use of long-term tubes except when there are specific reasons for doing so.

The update also expands the list of risk factors that place children with OME at increased risk of developmental difficulties – and often in need of timely ear tube placement – to include intellectual disability, learning disorder, and attention-deficit/hyperactivity disorder.

“Most of what we said in the 2013 [original] guideline was good and still valid ... and [important for] pediatricians, who are the key players” in managing otitis media, Jesse Hackell, MD, one of two general pediatricians who served on the Academy’s guideline update committee, said in an interview.

OME spontaneously clears up to 90% of the time within 3 months, said Dr. Hackell, of Pomona (New York) Pediatrics, and chair of the American Academy of Pediatrics (AAP) Committee on Practice and Ambulatory Medicine.

The updated guideline, for children 6 months to 12 years, reaffirms a recommendation that tube insertion be offered to children with “bilateral OME for 3 months or longer AND documented hearing difficulties.”

It also reaffirms “options” (a lesser quality of evidence) that in the absence of hearing difficulties, surgery may be performed for children with chronic OME (3 months or longer) in one or both ears if 1) they are at increased risk of developmental difficulties from OME or 2) effusion is likely contributing to balance problems, poor school performance, behavioral problems, ear discomfort, or reduced quality of life.

Children with chronic OME who do not undergo surgery should be reevaluated at 3- to 6-month intervals and monitored until effusion is no longer present, significant hearing loss is detected, or structural abnormalities of the tympanic membrane or middle ear are detected, the update again recommends.

Tympanostomy tube placement is the most common ambulatory surgery performed on children in the United States, the guideline authors say. In 2014, about 9% of children had undergone the surgery, they wrote, noting also that “tubes were placed in 25%-30% of children with frequent ear infections.”

Recurrent AOM

The AAO-HNSF guidance regarding tympanostomy tubes for OME is similar overall to management guidance issued by the AAP in its clinical practice guideline on OME.

The organizations differ, however, on their guidance for tube insertion for recurrent AOM. In its 2013 clinical practice guideline on AOM, the AAP recommends that clinicians may offer tube insertion for recurrent AOM, with no mention of the presence or absence of persistent fluid as a consideration.

According to the AAO-HNSF update, grade A evidence, including some research published since its original 2013 guideline, has shown little benefit to tube insertion in reducing the incidence of AOM in otherwise healthy children who don’t have middle ear effusion.

One study published in 2019 assessed outcomes after watchful waiting and found that only one-third of 123 children eventually went on to tympanostomy tube placement, noted Richard M. Rosenfeld, MD, distinguished professor and chairman of otolaryngology at SUNY Downstate Health Sciences University in Brooklyn, N.Y., and lead author of the original and updated guidelines.

In practice, “the real question [for the ENT] is the future. If the ears are perfectly clear, will tubes really reduce the frequency of infections going forward?” Dr. Rosenfeld said in an interview. “All the evidence seems to say no, it doesn’t make much of a difference.”

Dr. Hackell said he’s confident that the question “is settled enough.” While there “could be stronger research and higher quality studies, the evidence is still pretty good to suggest you gain little to no benefit with tubes when you’re dealing with recurrent AOM without effusion,” he said.

Asked to comment on the ENT update and its guidance on tympanostomy tubes for children with recurrent AOM, an AAP spokesperson said the “issue is under review” and that the AAP did not currently have a statement.
 

At-risk children

The AAO-HNSF update renews a recommendation to evaluate children with either recurrent AOM or OME of any duration for increased risk for speech, language, or learning problems from OME because of baseline factors (sensory, physical, cognitive, or behavioral).

When OME becomes chronic – or when a tympanogram gives a flat-line reading – OME is likely to persist, and families of at-risk children especially should be encouraged to pursue tube placement, Dr. Rosenfeld said.

Despite prior guidance to this effect, he said, ear tubes are being underutilized in at-risk children, with effusion being missed in primary care and with ENTs not expediting tube placement upon referral.

“These children have learning issues, cognitive issues, developmental issues,” he said in the interview. “It’s a population that does very poorly with ears full of fluid ... and despite guidance suggesting these children should be prioritized with tubes, it doesn’t seem to be happening enough.”

Formulating guidelines for at-risk children is challenging because they are often excluded from trials, Dr. Rosenfeld said, which limits evidence about the benefits of tubes and limits the strength of recommendations.

The addition of attention-deficit/hyperactivity disorder, intellectual disability, and learning disorder to the list of risk factors is notable, Dr. Hackell said. (The list includes autism spectrum disorder, developmental delay, and suspected or confirmed speech and language delay or disorder.)

“We know that kids with ADHD take in and process information a little differently ... it may be harder to get their attention with auditory stimulation,” he said. “So anything that would impact the taking in of information even for a short period of time increases their risk.”

Surgical practice

ENTs are advised in the new guidance to use long-term tubes and perioperative antibiotic ear drops more judiciously. “Long-term tubes have a role, but there are some doctors who routinely use them, even for a first-time surgery,” said Dr. Rosenfeld.

Overuse of long-term tubes results in a higher incidence of tympanic membrane perforation, chronic drainage, and other complications, as well as greater need for long-term follow-up. “There needs to be a reason – something to justify the need for prolonged ventilation,” he said.

Perioperative antibiotic ear drops are often administered during surgery and then prescribed routinely for all children afterward, but research has shown that saline irrigation during surgery and a single application of antibiotic/steroid drops is similarly efficacious in preventing otorrhea, the guideline says. Antibiotic ear drops are also “expensive,” noted Dr. Hackell. “There’s not enough benefit to justify it.”

The update also more explicitly advises selective use of adenoidectomy. A new option says that clinicians may perform the procedure as an adjunct to tube insertion for children 4 years or older to potentially reduce the future incidence of recurrent OME or the need for repeat surgery.

However, in younger children, it should not be offered unless there are symptoms directly related to adenoid infection or nasal obstruction. “Under 4 years, there’s no primary benefit for the ears,” said Dr. Rosenfeld.

Follow-up with the surgeon after tympanostomy tube insertion should occur within 3 months to assess outcomes and educate the family, the update strongly recommends.

And pediatricians should know, Dr. Hackell notes, that clinical evidence continues to show that earplugs and other water precautions are not routinely needed for children who have tubes in place. A good approach, the guideline says, is to “first avoid water precautions and instead reserve them for children with recurrent or persistent tympanostomy tube otorrhea.”

Asked to comment on the guideline update, Tim Joos, MD, MPH, who practices combined internal medicine/pediatrics in Seattle and is an editorial advisory board member of Pediatric News, noted the inclusion of patient information sheets with frequently asked questions – resources that can be useful for guiding parents through what’s often a shared decision-making process.

Neither Dr. Rosenfeld nor Dr. Hackell reported any disclosures. Other members of the guideline update committee reported various book royalties, consulting fees, and other disclosures. Dr. Joos reported he has no connections to the guideline authors.

Global climate change is hitting home for dermatologists, according to a recent survey in which the majority of participants said their patients are already being impacted.

Almost 80% of the 148 participants who responded to an electronic survey reported this belief.

The survey was designed and distributed to the membership of various dermatological organizations by Misha Rosenbach, MD, and coauthors. The results were published in the British Journal of Dermatology.

Asked also about specific types of climate-driven phenomena with a current – or future – impact on their patients, 80.1% reported that they believed that increased exposure to ultraviolet radiation (UVR) is impactful, or will be. Changes in temporal or geographic patterns of vector-borne illnesses were affirmed by 78.7%, and an increase in social displacement caused by extreme weather or other events was affirmed by 67.1% as having an impact on their patients currently or in the future.

Other phenomena affirmed by respondents as already having an impact or impacting patients in the future were an increased incidence of heat exposure or heat-related illness (58.2%); an increase in rates of inflammatory skin disease flares (43.2%); increased incidence of waterborne infections (42.5%); and increased rates of allergic contact dermatitis (29.5%).

The survey was sent to the membership of the American Society of Dermatologic Surgery, the Society for Pediatric Dermatology, the Society for Investigative Dermatology, and the American Academy of Dermatology’s Climate Change Expert Resource Group (ERG), among other organizations.

The study design and membership overlap made it impossible to calculate a response rate, the authors said, but they estimated it to be about 10%.

Almost all respondents were from the United States, and most (86.3%) practiced in an academic setting. The findings are similar to those of an online survey of members of the International Society of Dermatology (ISD), published in 2020, which found that 89% of 158 respondents believed climate change will impact the incidence of skin diseases in their area.

“Physicians, including dermatologists, are starting to understand the impact of the climate crisis on both their patients and themselves ... both through lived experiences and [issues raised] more in the scientific literature and in meetings,” Dr. Rosenbach, associate professor of dermatology at the University of Pennsylvania, Philadelphia, said in an interview.

A majority of participants in the U.S. survey agreed they have a responsibility to bring awareness of the health effects of climate change to patients (77.2%) and to policymakers (88.6%). (In the ISD survey, 88% said they believed that dermatologists should play an advocacy role in climate change-related issues).

Only a minority of respondents in the U.S. survey said that they would feel comfortable discussing climate change with their patients (37.2%). Almost one-third of the respondents said they would like to be better informed about climate change before doing so. And 81.8% said they would like to read more about the dermatological effects of climate change in scientific journals.

“There continues to be unfilled interest in education and advocacy regarding climate change, suggesting a ‘practice gap’ even among dermatologists,” Dr. Rosenbach and his colleagues wrote, noting opportunities for professional organizations and journals to provide more resources and “actionable items” regarding climate change.

Some dermatologists have been taking action, in the meantime, to reduce the carbon footprint of their practices and institutions. Reductions in facility energy consumption, and reductions in medical waste/optimization of recycling, were each reported by more than one-third of survey respondents.

And almost half indicated that their practice or institution had increased capacity for telemedicine or telecommuting in response to climate change. Only 8% said their practice or institution had divested from fossil fuel stocks and/or bonds.

“There are a lot of sustainability-in-medicine solutions that are actually cost-neutral or cost-saving for practices,” said Dr. Rosenbach, who is a founder and co-chair of the AAD’s ERG on Climate Change and Environmental Issues.

Research in dermatology is starting to quantify the environmental impact of some of these changes. In a research letter also published in the British Journal of Dermatology, researchers from Cardiff University and the department of dermatology at University Hospital of Wales, described how they determined that reusable surgical packs used for skin surgery are more sustainable than single-use packs because of their reduced cost and reduced greenhouse gas emissions.

Such single-site reports are “early feeders” into what will become a stream of larger studies quantifying the impact of measures taken in dermatology, Dr. Rosenbach said.

Across medicine, there is evidence that health care professionals are now seeing climate change as a threat to their patients. In a multinational survey published last year in The Lancet Planetary Health, 77% of 3,977 participants said that climate change will cause a moderate or great deal of harm for their patients.

Climate change will be discussed at the AAD’s annual meeting in late March in a session devoted to the topic, and as part of a broader session on controversies in dermatology.

Dr. Rosenbach and two of the five authors of the dermatology research letter are members of the AAD’s ERG on climate change, but in the publication they noted that they were not writing on behalf of the AAD. None of the authors reported any disclosures, and there was no funding source for the survey.

Global climate change is hitting home for dermatologists, according to a recent survey in which the majority of participants said their patients are already being impacted.

Almost 80% of the 148 participants who responded to an electronic survey reported this belief.

The survey was designed and distributed to the membership of various dermatological organizations by Misha Rosenbach, MD, and coauthors. The results were published in the British Journal of Dermatology.

Asked also about specific types of climate-driven phenomena with a current – or future – impact on their patients, 80.1% reported that they believed that increased exposure to ultraviolet radiation (UVR) is impactful, or will be. Changes in temporal or geographic patterns of vector-borne illnesses were affirmed by 78.7%, and an increase in social displacement caused by extreme weather or other events was affirmed by 67.1% as having an impact on their patients currently or in the future.

Other phenomena affirmed by respondents as already having an impact or impacting patients in the future were an increased incidence of heat exposure or heat-related illness (58.2%); an increase in rates of inflammatory skin disease flares (43.2%); increased incidence of waterborne infections (42.5%); and increased rates of allergic contact dermatitis (29.5%).

The survey was sent to the membership of the American Society of Dermatologic Surgery, the Society for Pediatric Dermatology, the Society for Investigative Dermatology, and the American Academy of Dermatology’s Climate Change Expert Resource Group (ERG), among other organizations.

The study design and membership overlap made it impossible to calculate a response rate, the authors said, but they estimated it to be about 10%.

Almost all respondents were from the United States, and most (86.3%) practiced in an academic setting. The findings are similar to those of an online survey of members of the International Society of Dermatology (ISD), published in 2020, which found that 89% of 158 respondents believed climate change will impact the incidence of skin diseases in their area.

“Physicians, including dermatologists, are starting to understand the impact of the climate crisis on both their patients and themselves ... both through lived experiences and [issues raised] more in the scientific literature and in meetings,” Dr. Rosenbach, associate professor of dermatology at the University of Pennsylvania, Philadelphia, said in an interview.

A majority of participants in the U.S. survey agreed they have a responsibility to bring awareness of the health effects of climate change to patients (77.2%) and to policymakers (88.6%). (In the ISD survey, 88% said they believed that dermatologists should play an advocacy role in climate change-related issues).

Only a minority of respondents in the U.S. survey said that they would feel comfortable discussing climate change with their patients (37.2%). Almost one-third of the respondents said they would like to be better informed about climate change before doing so. And 81.8% said they would like to read more about the dermatological effects of climate change in scientific journals.

“There continues to be unfilled interest in education and advocacy regarding climate change, suggesting a ‘practice gap’ even among dermatologists,” Dr. Rosenbach and his colleagues wrote, noting opportunities for professional organizations and journals to provide more resources and “actionable items” regarding climate change.

Some dermatologists have been taking action, in the meantime, to reduce the carbon footprint of their practices and institutions. Reductions in facility energy consumption, and reductions in medical waste/optimization of recycling, were each reported by more than one-third of survey respondents.

And almost half indicated that their practice or institution had increased capacity for telemedicine or telecommuting in response to climate change. Only 8% said their practice or institution had divested from fossil fuel stocks and/or bonds.

“There are a lot of sustainability-in-medicine solutions that are actually cost-neutral or cost-saving for practices,” said Dr. Rosenbach, who is a founder and co-chair of the AAD’s ERG on Climate Change and Environmental Issues.

Research in dermatology is starting to quantify the environmental impact of some of these changes. In a research letter also published in the British Journal of Dermatology, researchers from Cardiff University and the department of dermatology at University Hospital of Wales, described how they determined that reusable surgical packs used for skin surgery are more sustainable than single-use packs because of their reduced cost and reduced greenhouse gas emissions.

Such single-site reports are “early feeders” into what will become a stream of larger studies quantifying the impact of measures taken in dermatology, Dr. Rosenbach said.

Across medicine, there is evidence that health care professionals are now seeing climate change as a threat to their patients. In a multinational survey published last year in The Lancet Planetary Health, 77% of 3,977 participants said that climate change will cause a moderate or great deal of harm for their patients.

Climate change will be discussed at the AAD’s annual meeting in late March in a session devoted to the topic, and as part of a broader session on controversies in dermatology.

Dr. Rosenbach and two of the five authors of the dermatology research letter are members of the AAD’s ERG on climate change, but in the publication they noted that they were not writing on behalf of the AAD. None of the authors reported any disclosures, and there was no funding source for the survey.

Global climate change is hitting home for dermatologists, according to a recent survey in which the majority of participants said their patients are already being impacted.

Almost 80% of the 148 participants who responded to an electronic survey reported this belief.

The survey was designed and distributed to the membership of various dermatological organizations by Misha Rosenbach, MD, and coauthors. The results were published in the British Journal of Dermatology.

Asked also about specific types of climate-driven phenomena with a current – or future – impact on their patients, 80.1% reported that they believed that increased exposure to ultraviolet radiation (UVR) is impactful, or will be. Changes in temporal or geographic patterns of vector-borne illnesses were affirmed by 78.7%, and an increase in social displacement caused by extreme weather or other events was affirmed by 67.1% as having an impact on their patients currently or in the future.

Other phenomena affirmed by respondents as already having an impact or impacting patients in the future were an increased incidence of heat exposure or heat-related illness (58.2%); an increase in rates of inflammatory skin disease flares (43.2%); increased incidence of waterborne infections (42.5%); and increased rates of allergic contact dermatitis (29.5%).

The survey was sent to the membership of the American Society of Dermatologic Surgery, the Society for Pediatric Dermatology, the Society for Investigative Dermatology, and the American Academy of Dermatology’s Climate Change Expert Resource Group (ERG), among other organizations.

The study design and membership overlap made it impossible to calculate a response rate, the authors said, but they estimated it to be about 10%.

Almost all respondents were from the United States, and most (86.3%) practiced in an academic setting. The findings are similar to those of an online survey of members of the International Society of Dermatology (ISD), published in 2020, which found that 89% of 158 respondents believed climate change will impact the incidence of skin diseases in their area.

“Physicians, including dermatologists, are starting to understand the impact of the climate crisis on both their patients and themselves ... both through lived experiences and [issues raised] more in the scientific literature and in meetings,” Dr. Rosenbach, associate professor of dermatology at the University of Pennsylvania, Philadelphia, said in an interview.

A majority of participants in the U.S. survey agreed they have a responsibility to bring awareness of the health effects of climate change to patients (77.2%) and to policymakers (88.6%). (In the ISD survey, 88% said they believed that dermatologists should play an advocacy role in climate change-related issues).

Only a minority of respondents in the U.S. survey said that they would feel comfortable discussing climate change with their patients (37.2%). Almost one-third of the respondents said they would like to be better informed about climate change before doing so. And 81.8% said they would like to read more about the dermatological effects of climate change in scientific journals.

“There continues to be unfilled interest in education and advocacy regarding climate change, suggesting a ‘practice gap’ even among dermatologists,” Dr. Rosenbach and his colleagues wrote, noting opportunities for professional organizations and journals to provide more resources and “actionable items” regarding climate change.

Some dermatologists have been taking action, in the meantime, to reduce the carbon footprint of their practices and institutions. Reductions in facility energy consumption, and reductions in medical waste/optimization of recycling, were each reported by more than one-third of survey respondents.

And almost half indicated that their practice or institution had increased capacity for telemedicine or telecommuting in response to climate change. Only 8% said their practice or institution had divested from fossil fuel stocks and/or bonds.

“There are a lot of sustainability-in-medicine solutions that are actually cost-neutral or cost-saving for practices,” said Dr. Rosenbach, who is a founder and co-chair of the AAD’s ERG on Climate Change and Environmental Issues.

Research in dermatology is starting to quantify the environmental impact of some of these changes. In a research letter also published in the British Journal of Dermatology, researchers from Cardiff University and the department of dermatology at University Hospital of Wales, described how they determined that reusable surgical packs used for skin surgery are more sustainable than single-use packs because of their reduced cost and reduced greenhouse gas emissions.

Such single-site reports are “early feeders” into what will become a stream of larger studies quantifying the impact of measures taken in dermatology, Dr. Rosenbach said.

Across medicine, there is evidence that health care professionals are now seeing climate change as a threat to their patients. In a multinational survey published last year in The Lancet Planetary Health, 77% of 3,977 participants said that climate change will cause a moderate or great deal of harm for their patients.

Climate change will be discussed at the AAD’s annual meeting in late March in a session devoted to the topic, and as part of a broader session on controversies in dermatology.

Dr. Rosenbach and two of the five authors of the dermatology research letter are members of the AAD’s ERG on climate change, but in the publication they noted that they were not writing on behalf of the AAD. None of the authors reported any disclosures, and there was no funding source for the survey.