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Diet’s impact on the microbiome: It’s real, and broad
WASHINGTON – – 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/
WASHINGTON – – 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/
WASHINGTON – – 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/
AT GMFH 2022
Diet’s impact on the microbiome: It’s real, and broad
WASHINGTON – – 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 – – 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 – – 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.
AT GMFH 2022
‘Extensive’ evidence for altered brain-gut-microbiome system in IBS
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.
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.
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.
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.
FROM GMFH 2022
Probiotics of the future: Precision medicine and rational design
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.
REPORTING FROM GMFH 2022
What’s the future of microbiome therapies in C. diff, cancer?
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.
REPORTING FROM GMFH 2022
What’s the future of microbiome therapies in C. diff, cancer?
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.
REPORTING FROM GMFH 2022