TBD Meeting (5387-20)

During parturient transmission of gut bacteria from mothers to infants, the dominant maternal source of bacteria is rectal, according to investigators.

This challenges the hypothesis that exposure to the birth canal explains major differences in gut bacteria between infants born vaginally and those born via C-section, reported Moran Yassour, PhD, of Hebrew University in Jerusalem.

“It’s not how and if you entered the birth canal, but rather how you exited it,” Dr. Yassour said during a presentation at the annual Gut Microbiota for Health World Summit.

According to Dr. Yassour, a number of investigators have evaluated vertical transmission of gut bacteria from mothers to newborns, but most began collecting data a week or more after birth, potentially missing critical information.

“We wanted to generate large-scale, paired, longitudinal data, which means that we had [samples from] both mothers and children, and we wanted to start at birth,” Dr. Yassour said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.

Dr. Yassour explained that newborns delivered vaginally often exhibit Bacteroides in their gut, whereas babies born via C-section do not exhibit these bacteria until 6-18 months of age; however, the vaginal microbiome typically lacks Bacteroides, making the birth canal an unlikely source. This disconnect served as the impetus for the present investigation, Dr. Yassour said.

The study, which is available as a preprint, involved 73 mothers and their infants. To determine the impact of birth canal exposure, the investigators compared gut bacteria of infants born vaginally with those born via pre-labor C-section (no exposure to the birth canal), and those born via post-labor C-section (exposure to the birth canal).

Initial results were surprising, Dr. Yassour said, as 54% of babies delivered via C-section had Bacteroides in their stool during the first week. But in the second week, 94% of the C-section group lacked Bacteroides, which aligns with characteristic findings and suggests failure of colonization, rather than complete lack of exposure.

Out of the 24 infants with persistent Bacteroides colonization, 22 (92%) were born vaginally, compared with 2 (8%) born via pre-labor C-section, and none born via post-labor C-section. This pattern was maintained in a multivariate analysis that accounted for antibiotic use and exposure to formula, both of which are more common among mothers that give birth via C-section.

The investigators also conducted a strain-level analysis of mothers and infants using metagenomic sequencing. Across all time points, 90% of matched maternal-infant strains were detected in babies delivered vaginally.

“[W]e found evidence for mother-to-child transmission of rectal rather than vaginal strains,” the investigators wrote. “These results challenge birth canal exposure as the dominant factor in infant gut microbiome establishment and implicate colonization efficiency rather than exposure as a dictating factor of the newborn gut microbiome composition.”

Dr. Yassour said that these findings may have an immediate effect on clinical practice.

“People have reported the practice of smearing babies that were born by C-section with vaginal fluids in the sense of trying to recapitulate the microbial signature that we find in kids born vaginally,” Dr. Yassour said. “But it’s probably not the vaginal fluid that we need to smear; it’s probably the proximity to the rectum and the bowel movements that happen during delivery ... and that is what’s causing this initial seeding from mother to child.”

Dr. Yassour disclosed no conflicts of interest.

SOURCE: Yassour M et al. GMFH 2020.

During parturient transmission of gut bacteria from mothers to infants, the dominant maternal source of bacteria is rectal, according to investigators.

This challenges the hypothesis that exposure to the birth canal explains major differences in gut bacteria between infants born vaginally and those born via C-section, reported Moran Yassour, PhD, of Hebrew University in Jerusalem.

“It’s not how and if you entered the birth canal, but rather how you exited it,” Dr. Yassour said during a presentation at the annual Gut Microbiota for Health World Summit.

According to Dr. Yassour, a number of investigators have evaluated vertical transmission of gut bacteria from mothers to newborns, but most began collecting data a week or more after birth, potentially missing critical information.

“We wanted to generate large-scale, paired, longitudinal data, which means that we had [samples from] both mothers and children, and we wanted to start at birth,” Dr. Yassour said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.

Dr. Yassour explained that newborns delivered vaginally often exhibit Bacteroides in their gut, whereas babies born via C-section do not exhibit these bacteria until 6-18 months of age; however, the vaginal microbiome typically lacks Bacteroides, making the birth canal an unlikely source. This disconnect served as the impetus for the present investigation, Dr. Yassour said.

The study, which is available as a preprint, involved 73 mothers and their infants. To determine the impact of birth canal exposure, the investigators compared gut bacteria of infants born vaginally with those born via pre-labor C-section (no exposure to the birth canal), and those born via post-labor C-section (exposure to the birth canal).

Initial results were surprising, Dr. Yassour said, as 54% of babies delivered via C-section had Bacteroides in their stool during the first week. But in the second week, 94% of the C-section group lacked Bacteroides, which aligns with characteristic findings and suggests failure of colonization, rather than complete lack of exposure.

Out of the 24 infants with persistent Bacteroides colonization, 22 (92%) were born vaginally, compared with 2 (8%) born via pre-labor C-section, and none born via post-labor C-section. This pattern was maintained in a multivariate analysis that accounted for antibiotic use and exposure to formula, both of which are more common among mothers that give birth via C-section.

The investigators also conducted a strain-level analysis of mothers and infants using metagenomic sequencing. Across all time points, 90% of matched maternal-infant strains were detected in babies delivered vaginally.

“[W]e found evidence for mother-to-child transmission of rectal rather than vaginal strains,” the investigators wrote. “These results challenge birth canal exposure as the dominant factor in infant gut microbiome establishment and implicate colonization efficiency rather than exposure as a dictating factor of the newborn gut microbiome composition.”

Dr. Yassour said that these findings may have an immediate effect on clinical practice.

“People have reported the practice of smearing babies that were born by C-section with vaginal fluids in the sense of trying to recapitulate the microbial signature that we find in kids born vaginally,” Dr. Yassour said. “But it’s probably not the vaginal fluid that we need to smear; it’s probably the proximity to the rectum and the bowel movements that happen during delivery ... and that is what’s causing this initial seeding from mother to child.”

Dr. Yassour disclosed no conflicts of interest.

SOURCE: Yassour M et al. GMFH 2020.

During parturient transmission of gut bacteria from mothers to infants, the dominant maternal source of bacteria is rectal, according to investigators.

This challenges the hypothesis that exposure to the birth canal explains major differences in gut bacteria between infants born vaginally and those born via C-section, reported Moran Yassour, PhD, of Hebrew University in Jerusalem.

“It’s not how and if you entered the birth canal, but rather how you exited it,” Dr. Yassour said during a presentation at the annual Gut Microbiota for Health World Summit.

According to Dr. Yassour, a number of investigators have evaluated vertical transmission of gut bacteria from mothers to newborns, but most began collecting data a week or more after birth, potentially missing critical information.

“We wanted to generate large-scale, paired, longitudinal data, which means that we had [samples from] both mothers and children, and we wanted to start at birth,” Dr. Yassour said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.

Dr. Yassour explained that newborns delivered vaginally often exhibit Bacteroides in their gut, whereas babies born via C-section do not exhibit these bacteria until 6-18 months of age; however, the vaginal microbiome typically lacks Bacteroides, making the birth canal an unlikely source. This disconnect served as the impetus for the present investigation, Dr. Yassour said.

The study, which is available as a preprint, involved 73 mothers and their infants. To determine the impact of birth canal exposure, the investigators compared gut bacteria of infants born vaginally with those born via pre-labor C-section (no exposure to the birth canal), and those born via post-labor C-section (exposure to the birth canal).

Initial results were surprising, Dr. Yassour said, as 54% of babies delivered via C-section had Bacteroides in their stool during the first week. But in the second week, 94% of the C-section group lacked Bacteroides, which aligns with characteristic findings and suggests failure of colonization, rather than complete lack of exposure.

Out of the 24 infants with persistent Bacteroides colonization, 22 (92%) were born vaginally, compared with 2 (8%) born via pre-labor C-section, and none born via post-labor C-section. This pattern was maintained in a multivariate analysis that accounted for antibiotic use and exposure to formula, both of which are more common among mothers that give birth via C-section.

The investigators also conducted a strain-level analysis of mothers and infants using metagenomic sequencing. Across all time points, 90% of matched maternal-infant strains were detected in babies delivered vaginally.

“[W]e found evidence for mother-to-child transmission of rectal rather than vaginal strains,” the investigators wrote. “These results challenge birth canal exposure as the dominant factor in infant gut microbiome establishment and implicate colonization efficiency rather than exposure as a dictating factor of the newborn gut microbiome composition.”

Dr. Yassour said that these findings may have an immediate effect on clinical practice.

“People have reported the practice of smearing babies that were born by C-section with vaginal fluids in the sense of trying to recapitulate the microbial signature that we find in kids born vaginally,” Dr. Yassour said. “But it’s probably not the vaginal fluid that we need to smear; it’s probably the proximity to the rectum and the bowel movements that happen during delivery ... and that is what’s causing this initial seeding from mother to child.”

Dr. Yassour disclosed no conflicts of interest.

SOURCE: Yassour M et al. GMFH 2020.

Differences in metabolism of levodopa between patients with Parkinson’s disease may be caused by variations in gut bacteria, according to investigators.

Specifically, patients with a higher abundance of Enterococcus faecalis may be converting levodopa into dopamine via decarboxylation before it can cross the blood-brain barrier, reported Emily P. Balskus, PhD, of Harvard University in Cambridge, Mass.

Although existing decarboxylase inhibitors, such as carbidopa, can reduce metabolism of levodopa by host enzymes, these drugs are unable to inhibit the enzymatic activity of E. faecalis in the gut, Dr. Balskus said at the annual Gut Microbiota for Health World Summit, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.

“[Carbidopa] is actually completely ineffective at inhibiting decarboxylation in human fecal suspension,” Dr. Balskus said, referring to research led by PhD student Vayu Maini Rekdal. “We think that this could indicate that patients who are taking carbidopa are not inhibiting any bacterial metabolism that they may have.”

While previous research showed that E. faecalis could decarboxylate levodopa, Dr. Balskus and colleagues linked this process with the tyrosine decarboxylase gene (TyrDC), and showed that the of abundance E. faecalis and TyrDC correlate with levodopa metabolism.

Unlike the human enzyme responsible for decarboxylation of levodopa, the E. faecalis enzyme preferentially binds with L-tyrosine. This could explain why existing decarboxylase inhibitors have little impact on decarboxylation in the gut, Dr. Balskus said.

She also noted that this unique characteristic may open doors to new therapeutics. In the lab, Dr. Balskus and colleagues tested a decarboxylase inhibitor that resembled L-tyrosine, (S)-alpha-fluoromethyltyrosine (AFMT). Indeed, AFMT completely inhibited of decarboxylation of levodopa in both E. faecalis cells and complex human microbiome samples.

“We think this is pretty exciting,” Dr. Balskus said.

Early animal studies support this enthusiasm, as germ-free mice colonized with E. faecalis maintain higher serum levels of levodopa with concurrent administration of AFMT.

“We think that this could indicate that a promising way to improve levodopa therapy for Parkinson’s patients would be to develop compounds that inhibit bacterial drug metabolism activity,” Dr. Balskus said.

Concluding her presentation, Dr. Balskus emphasized the importance of a biochemical approach to microbiome research. “Studying enzymes opens up new, exciting opportunities for microbiome manipulation. We can design or develop inhibitors of enzymes, use those inhibitors as tools to study the roles of individual metabolic activities, and potentially use them as therapeutics. We are very excited about the possibility of treating or preventing human disease not just by manipulating processes in our own cells, but by targeting activities in the microbiota.”

Dr. Balskus reported funding from HHMI, the Bill and Melinda Gates Foundation, the David and Lucile Packard Foundation, and Merck.

Differences in metabolism of levodopa between patients with Parkinson’s disease may be caused by variations in gut bacteria, according to investigators.

Specifically, patients with a higher abundance of Enterococcus faecalis may be converting levodopa into dopamine via decarboxylation before it can cross the blood-brain barrier, reported Emily P. Balskus, PhD, of Harvard University in Cambridge, Mass.

Although existing decarboxylase inhibitors, such as carbidopa, can reduce metabolism of levodopa by host enzymes, these drugs are unable to inhibit the enzymatic activity of E. faecalis in the gut, Dr. Balskus said at the annual Gut Microbiota for Health World Summit, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.

“[Carbidopa] is actually completely ineffective at inhibiting decarboxylation in human fecal suspension,” Dr. Balskus said, referring to research led by PhD student Vayu Maini Rekdal. “We think that this could indicate that patients who are taking carbidopa are not inhibiting any bacterial metabolism that they may have.”

While previous research showed that E. faecalis could decarboxylate levodopa, Dr. Balskus and colleagues linked this process with the tyrosine decarboxylase gene (TyrDC), and showed that the of abundance E. faecalis and TyrDC correlate with levodopa metabolism.

Unlike the human enzyme responsible for decarboxylation of levodopa, the E. faecalis enzyme preferentially binds with L-tyrosine. This could explain why existing decarboxylase inhibitors have little impact on decarboxylation in the gut, Dr. Balskus said.

She also noted that this unique characteristic may open doors to new therapeutics. In the lab, Dr. Balskus and colleagues tested a decarboxylase inhibitor that resembled L-tyrosine, (S)-alpha-fluoromethyltyrosine (AFMT). Indeed, AFMT completely inhibited of decarboxylation of levodopa in both E. faecalis cells and complex human microbiome samples.

“We think this is pretty exciting,” Dr. Balskus said.

Early animal studies support this enthusiasm, as germ-free mice colonized with E. faecalis maintain higher serum levels of levodopa with concurrent administration of AFMT.

“We think that this could indicate that a promising way to improve levodopa therapy for Parkinson’s patients would be to develop compounds that inhibit bacterial drug metabolism activity,” Dr. Balskus said.

Concluding her presentation, Dr. Balskus emphasized the importance of a biochemical approach to microbiome research. “Studying enzymes opens up new, exciting opportunities for microbiome manipulation. We can design or develop inhibitors of enzymes, use those inhibitors as tools to study the roles of individual metabolic activities, and potentially use them as therapeutics. We are very excited about the possibility of treating or preventing human disease not just by manipulating processes in our own cells, but by targeting activities in the microbiota.”

Dr. Balskus reported funding from HHMI, the Bill and Melinda Gates Foundation, the David and Lucile Packard Foundation, and Merck.

Differences in metabolism of levodopa between patients with Parkinson’s disease may be caused by variations in gut bacteria, according to investigators.

Specifically, patients with a higher abundance of Enterococcus faecalis may be converting levodopa into dopamine via decarboxylation before it can cross the blood-brain barrier, reported Emily P. Balskus, PhD, of Harvard University in Cambridge, Mass.

Although existing decarboxylase inhibitors, such as carbidopa, can reduce metabolism of levodopa by host enzymes, these drugs are unable to inhibit the enzymatic activity of E. faecalis in the gut, Dr. Balskus said at the annual Gut Microbiota for Health World Summit, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.

“[Carbidopa] is actually completely ineffective at inhibiting decarboxylation in human fecal suspension,” Dr. Balskus said, referring to research led by PhD student Vayu Maini Rekdal. “We think that this could indicate that patients who are taking carbidopa are not inhibiting any bacterial metabolism that they may have.”

While previous research showed that E. faecalis could decarboxylate levodopa, Dr. Balskus and colleagues linked this process with the tyrosine decarboxylase gene (TyrDC), and showed that the of abundance E. faecalis and TyrDC correlate with levodopa metabolism.

Unlike the human enzyme responsible for decarboxylation of levodopa, the E. faecalis enzyme preferentially binds with L-tyrosine. This could explain why existing decarboxylase inhibitors have little impact on decarboxylation in the gut, Dr. Balskus said.

She also noted that this unique characteristic may open doors to new therapeutics. In the lab, Dr. Balskus and colleagues tested a decarboxylase inhibitor that resembled L-tyrosine, (S)-alpha-fluoromethyltyrosine (AFMT). Indeed, AFMT completely inhibited of decarboxylation of levodopa in both E. faecalis cells and complex human microbiome samples.

“We think this is pretty exciting,” Dr. Balskus said.

Early animal studies support this enthusiasm, as germ-free mice colonized with E. faecalis maintain higher serum levels of levodopa with concurrent administration of AFMT.

“We think that this could indicate that a promising way to improve levodopa therapy for Parkinson’s patients would be to develop compounds that inhibit bacterial drug metabolism activity,” Dr. Balskus said.

Concluding her presentation, Dr. Balskus emphasized the importance of a biochemical approach to microbiome research. “Studying enzymes opens up new, exciting opportunities for microbiome manipulation. We can design or develop inhibitors of enzymes, use those inhibitors as tools to study the roles of individual metabolic activities, and potentially use them as therapeutics. We are very excited about the possibility of treating or preventing human disease not just by manipulating processes in our own cells, but by targeting activities in the microbiota.”

Dr. Balskus reported funding from HHMI, the Bill and Melinda Gates Foundation, the David and Lucile Packard Foundation, and Merck.

Fecal microbiota transplantation (FMT) appears safe and effective for treating recurrent Clostridioides difficile infection in patients with inflammatory bowel disease (IBD), according to an ongoing prospective trial.

Most patients were cured of C. difficile after one fecal transplant, reported Jessica Allegretti, MD, associate director of the Crohn’s and Colitis Center at Brigham and Women’s Hospital in Boston.

“[For patients without IBD], fecal microbiota transplantation has been shown to be very effective for the treatment of recurrent C. diff,” Dr. Allegretti said at the annual Gut Microbiota for Health World Summit.

But similar data for patients with IBD are scarce, and this knowledge gap has high clinical relevance, Dr. Allegretti said. She noted that C. difficile infections are eight times more common among patients with IBD, and risk of recurrence is increased 4.5-fold.

According to Dr. Allegretti, three small clinical trials have tested FMT for treating recurrent C. difficile infections in patients with IBD.

“[These studies were] somewhat prospective, but [data] mainly retrospectively collected, as they relied heavily on chart review for the assessment of IBD disease activity,” she said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility..

Across the trials, C. difficile infection cure rates were comparable with non-IBD cohorts; but disease flare rates ranged from 17.9% to 54%, which raised concern that FMT may trigger inflammation.

To investigate further, Dr. Allegretti and her colleagues designed a prospective trial that is set to enroll 50 patients with IBD. Among 37 patients treated to date, a slight majority were women (56.8%), about one-third had Crohn’s disease (37.8%), and two-thirds had ulcerative colitis (62.2%). The average baseline calprotectin level, which measures inflammation in the intestines, was 1,804.8 microg/g of feces, which is far above the upper limit of 50 microg/g.

“This is a very inflamed patient population,” Dr. Allegretti said.

Out of these 37 patients, 34 (92%) were cured of C. difficile infection after only one fecal transplant, and the remaining three patients were cured after a second FMT.

“They all did very well,” Dr. Allegretti said.

Concerning IBD clinical scores, all patients with Crohn’s disease either had unchanged or improved disease. Among those with ulcerative colitis, almost all had unchanged or improved disease, except for one patient who had a de novo flare.

Early microbiome analyses showed patients had increased alpha diversity and richness after FMT that was sustained through week 12. Because only three patients had recurrence, numbers were too small to generate predictive data based on relative abundance.

Dr. Allegretti continued her presentation with a review of FMT for IBD in general.

“For Crohn’s disease, the role [of microbiome manipulation] seems a bit more clear,” Dr. Allegretti said, considering multiple effective treatments that alter gut flora, such as antibiotics.

In contrast, the role for microbiome manipulation in treating ulcerative colitis “has remained a bit unclear,” she said. Although some probiotics appear effective for treating mild disease, other microbiome-altering treatments, such as diversion of fecal stream, antibiotics, and bowel rest, have fallen short.

Still, pooled data from four randomized clinical trials showed that FMT led to remission in 28% of patients with ulcerative colitis, compared with 9% who receive placebo.

“You may be thinking that seems a bit underwhelming compared to the 90% or so cure rate we get for C. diff trials,” Dr. Allegretti said. “However, if you look at our other biologic trials in IBD, 28% puts FMT on par with our other IBD therapies.”

According to Dr. Allegretti, at least three stool-based, FMT-like therapeutics are poised to become commercially available in the next few years for the treatment of C. difficile infection, including broad- and narrow-spectrum enema bags and oral capsules.

“I certainly think we will start to see off-label usage in our IBD patients, and we will start to have an easier and more systemic way of utilizing these microbiome-based therapies,” Dr. Allegretti said. “They will be coming to market, and when they do, whether or not we are allowed to still do traditional FMT in its current form remains unseen. The FDA may not allow us to do that in the future when we have an FDA-approved product.”Dr. Allegretti disclosed relationships with Merck, Openbiome, Finch Therapeutics, and others.

aotto@mdedge.com

Fecal microbiota transplantation (FMT) appears safe and effective for treating recurrent Clostridioides difficile infection in patients with inflammatory bowel disease (IBD), according to an ongoing prospective trial.

Most patients were cured of C. difficile after one fecal transplant, reported Jessica Allegretti, MD, associate director of the Crohn’s and Colitis Center at Brigham and Women’s Hospital in Boston.

“[For patients without IBD], fecal microbiota transplantation has been shown to be very effective for the treatment of recurrent C. diff,” Dr. Allegretti said at the annual Gut Microbiota for Health World Summit.

But similar data for patients with IBD are scarce, and this knowledge gap has high clinical relevance, Dr. Allegretti said. She noted that C. difficile infections are eight times more common among patients with IBD, and risk of recurrence is increased 4.5-fold.

According to Dr. Allegretti, three small clinical trials have tested FMT for treating recurrent C. difficile infections in patients with IBD.

“[These studies were] somewhat prospective, but [data] mainly retrospectively collected, as they relied heavily on chart review for the assessment of IBD disease activity,” she said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility..

Across the trials, C. difficile infection cure rates were comparable with non-IBD cohorts; but disease flare rates ranged from 17.9% to 54%, which raised concern that FMT may trigger inflammation.

To investigate further, Dr. Allegretti and her colleagues designed a prospective trial that is set to enroll 50 patients with IBD. Among 37 patients treated to date, a slight majority were women (56.8%), about one-third had Crohn’s disease (37.8%), and two-thirds had ulcerative colitis (62.2%). The average baseline calprotectin level, which measures inflammation in the intestines, was 1,804.8 microg/g of feces, which is far above the upper limit of 50 microg/g.

“This is a very inflamed patient population,” Dr. Allegretti said.

Out of these 37 patients, 34 (92%) were cured of C. difficile infection after only one fecal transplant, and the remaining three patients were cured after a second FMT.

“They all did very well,” Dr. Allegretti said.

Concerning IBD clinical scores, all patients with Crohn’s disease either had unchanged or improved disease. Among those with ulcerative colitis, almost all had unchanged or improved disease, except for one patient who had a de novo flare.

Early microbiome analyses showed patients had increased alpha diversity and richness after FMT that was sustained through week 12. Because only three patients had recurrence, numbers were too small to generate predictive data based on relative abundance.

Dr. Allegretti continued her presentation with a review of FMT for IBD in general.

“For Crohn’s disease, the role [of microbiome manipulation] seems a bit more clear,” Dr. Allegretti said, considering multiple effective treatments that alter gut flora, such as antibiotics.

In contrast, the role for microbiome manipulation in treating ulcerative colitis “has remained a bit unclear,” she said. Although some probiotics appear effective for treating mild disease, other microbiome-altering treatments, such as diversion of fecal stream, antibiotics, and bowel rest, have fallen short.

Still, pooled data from four randomized clinical trials showed that FMT led to remission in 28% of patients with ulcerative colitis, compared with 9% who receive placebo.

“You may be thinking that seems a bit underwhelming compared to the 90% or so cure rate we get for C. diff trials,” Dr. Allegretti said. “However, if you look at our other biologic trials in IBD, 28% puts FMT on par with our other IBD therapies.”

According to Dr. Allegretti, at least three stool-based, FMT-like therapeutics are poised to become commercially available in the next few years for the treatment of C. difficile infection, including broad- and narrow-spectrum enema bags and oral capsules.

“I certainly think we will start to see off-label usage in our IBD patients, and we will start to have an easier and more systemic way of utilizing these microbiome-based therapies,” Dr. Allegretti said. “They will be coming to market, and when they do, whether or not we are allowed to still do traditional FMT in its current form remains unseen. The FDA may not allow us to do that in the future when we have an FDA-approved product.”Dr. Allegretti disclosed relationships with Merck, Openbiome, Finch Therapeutics, and others.

aotto@mdedge.com

Fecal microbiota transplantation (FMT) appears safe and effective for treating recurrent Clostridioides difficile infection in patients with inflammatory bowel disease (IBD), according to an ongoing prospective trial.

Most patients were cured of C. difficile after one fecal transplant, reported Jessica Allegretti, MD, associate director of the Crohn’s and Colitis Center at Brigham and Women’s Hospital in Boston.

“[For patients without IBD], fecal microbiota transplantation has been shown to be very effective for the treatment of recurrent C. diff,” Dr. Allegretti said at the annual Gut Microbiota for Health World Summit.

But similar data for patients with IBD are scarce, and this knowledge gap has high clinical relevance, Dr. Allegretti said. She noted that C. difficile infections are eight times more common among patients with IBD, and risk of recurrence is increased 4.5-fold.

According to Dr. Allegretti, three small clinical trials have tested FMT for treating recurrent C. difficile infections in patients with IBD.

“[These studies were] somewhat prospective, but [data] mainly retrospectively collected, as they relied heavily on chart review for the assessment of IBD disease activity,” she said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility..

Across the trials, C. difficile infection cure rates were comparable with non-IBD cohorts; but disease flare rates ranged from 17.9% to 54%, which raised concern that FMT may trigger inflammation.

To investigate further, Dr. Allegretti and her colleagues designed a prospective trial that is set to enroll 50 patients with IBD. Among 37 patients treated to date, a slight majority were women (56.8%), about one-third had Crohn’s disease (37.8%), and two-thirds had ulcerative colitis (62.2%). The average baseline calprotectin level, which measures inflammation in the intestines, was 1,804.8 microg/g of feces, which is far above the upper limit of 50 microg/g.

“This is a very inflamed patient population,” Dr. Allegretti said.

Out of these 37 patients, 34 (92%) were cured of C. difficile infection after only one fecal transplant, and the remaining three patients were cured after a second FMT.

“They all did very well,” Dr. Allegretti said.

Concerning IBD clinical scores, all patients with Crohn’s disease either had unchanged or improved disease. Among those with ulcerative colitis, almost all had unchanged or improved disease, except for one patient who had a de novo flare.

Early microbiome analyses showed patients had increased alpha diversity and richness after FMT that was sustained through week 12. Because only three patients had recurrence, numbers were too small to generate predictive data based on relative abundance.

Dr. Allegretti continued her presentation with a review of FMT for IBD in general.

“For Crohn’s disease, the role [of microbiome manipulation] seems a bit more clear,” Dr. Allegretti said, considering multiple effective treatments that alter gut flora, such as antibiotics.

In contrast, the role for microbiome manipulation in treating ulcerative colitis “has remained a bit unclear,” she said. Although some probiotics appear effective for treating mild disease, other microbiome-altering treatments, such as diversion of fecal stream, antibiotics, and bowel rest, have fallen short.

Still, pooled data from four randomized clinical trials showed that FMT led to remission in 28% of patients with ulcerative colitis, compared with 9% who receive placebo.

“You may be thinking that seems a bit underwhelming compared to the 90% or so cure rate we get for C. diff trials,” Dr. Allegretti said. “However, if you look at our other biologic trials in IBD, 28% puts FMT on par with our other IBD therapies.”

According to Dr. Allegretti, at least three stool-based, FMT-like therapeutics are poised to become commercially available in the next few years for the treatment of C. difficile infection, including broad- and narrow-spectrum enema bags and oral capsules.

“I certainly think we will start to see off-label usage in our IBD patients, and we will start to have an easier and more systemic way of utilizing these microbiome-based therapies,” Dr. Allegretti said. “They will be coming to market, and when they do, whether or not we are allowed to still do traditional FMT in its current form remains unseen. The FDA may not allow us to do that in the future when we have an FDA-approved product.”Dr. Allegretti disclosed relationships with Merck, Openbiome, Finch Therapeutics, and others.

aotto@mdedge.com

Microbiome studies should be correcting statistics to account for proton pump inhibitor (PPI) use, according to a leading expert.

After antibiotics, PPIs are the leading cause of microbiome variance in both research and general populations, and these alterations could have a range of consequences, reported Rinse K. Weersma, MD, PhD, of the University of Groningen (the Netherlands).

About 20% of people are taking a PPI, Dr. Weersma said at the annual Gut Microbiota for Health World Summit, noting that, in countries such as the United States and the United Kingdom, this figure may be higher.

“There’s chronic use of proton pump inhibitors in the population on a massive scale,” Dr. Weersma said.

To complicate matters, estimates suggest that 25%-70% of people who are taking PPIs have no appropriate indication. While this issue is partly because of increasing over-the-counter usage, physicians are also contributing to the problem by prescribing PPIs without adequate follow-up.

“The number of people using proton pump inhibitors is steadily increasing,” Dr. Weersma said. “The number of people getting them prescribed is relatively stable. The problem is, we never stop.”

According to Dr. Weersma, a growing body of research shows that PPI use may increase the risk of developing other conditions. Although many of these relationships are correlative, some are now widely accepted as causal. Most notable and clinically relevant, Dr. Weersma said, are enteric infections. Clostridioides difficile–associated diarrhea, for instance, is 65% more common among PPI users.

While the mechanisms behind this susceptibility to infection are uncertain, Dr. Weersma suggested that the most likely cause is “oralization” of the gut microbiome caused by loss of the acid barrier, which introduces upper gastrointestinal bacteria, or oral bacteria, into the lower intestines.

Perhaps more relevant to clinical trials, PPIs may also influence the safety and efficacy of drugs.

“There is a lot of interaction between the gut microbiome and a lot of drugs,” Dr. Weersma said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “We really don’t know a lot about this at the moment.”

He went on to explain that bidirectional interactions between drugs and the microbiome may actually present clinical opportunities.

“This is a field that people currently call pharmacomicrobiomics,” Dr. Weersma said. “This is very intriguing, of course, because everyone knows about pharmacogenomics ... which lets you stratify your patients, but you cannot intervene; you cannot change your genetic background to increase efficacy or avoid toxicity. But in fact, with the microbiome, we could modulate the microbiome and improve bioavailability, for example.”

Conversely, Dr. Weersma pointed out that PPI use may be interfering with drug efficacy to a life-altering degree.

He cited a recent study by Chalabi and colleagues, which found that PPI use affected responses to immune checkpoint inhibitors (Ann Oncol. 2020 Jan 16. doi: 10.1016/j.annonc.2020.01.006). Among 169 patients with lung cancer who were treated with atezolizumab, overall survival was significantly lower in PPI users (9.6 vs. 14.5 months; P = .001).

A number of other clinical implications are also possible, Dr. Weersma said, although these require further investigation. For example, a 2019 study by Stark and colleagues suggested that childhood use of PPIs may increase obesity risk.

“[There are] no microbiome data here,” Dr. Weersma said, “but it makes you think.”

While considering the downsides of PPIs, Dr. Weersma also emphasized their importance in clinical practice. “[Proton pump inhibitors] are very great drugs. They are cheap, they are safe, they are very effective. So if you have evidence-based indications to use proton pump inhibitors, you should definitely use them and not stop them.”

Dr. Weersma called for responsible use of PPIs, and suggested that clinicians need to prepare for pushback from patients, who, after stopping PPIs, may experience a temporary resurgence of symptoms because of acid rebound.

“You have to make them aware [of acid rebound],” Dr. Weersma said. “Say: ‘Wait 2 or 3 weeks and this rebound is gone.’ We should say that way, way, way more often.”

But clinicians shouldn’t bear the burden of responsible usage alone, Dr. Weersma said.

“There’s a role for clinicians, patients, and regulatory bodies also, to think about the massive use of proton pump inhibitors now and in the future.”

In the discussion that followed the presentation, a summit attendee brought up the realities of clinical practice before PPIs, when patients frequently had gastrointestinal bleeding secondary to nonsteroidal anti-inflammatory use. In response, Dr. Weersma again emphasized that PPIs play a critical role for many patients. After once more encouraging responsible use, Dr. Weersma expressed concern about the risks involved in conveying his message; not only to the medical community, but also to the general public.

“This is a very difficult message [to deliver],” Dr. Weersma said. “In the Netherlands this was taken up by the media and the news, so my email inbox exploded. It’s difficult to get this nuance right.”

Dr. Weersma disclosed relationships with Takeda, Johnson & Johnson, Ferring, and others.

Microbiome studies should be correcting statistics to account for proton pump inhibitor (PPI) use, according to a leading expert.

After antibiotics, PPIs are the leading cause of microbiome variance in both research and general populations, and these alterations could have a range of consequences, reported Rinse K. Weersma, MD, PhD, of the University of Groningen (the Netherlands).

About 20% of people are taking a PPI, Dr. Weersma said at the annual Gut Microbiota for Health World Summit, noting that, in countries such as the United States and the United Kingdom, this figure may be higher.

“There’s chronic use of proton pump inhibitors in the population on a massive scale,” Dr. Weersma said.

To complicate matters, estimates suggest that 25%-70% of people who are taking PPIs have no appropriate indication. While this issue is partly because of increasing over-the-counter usage, physicians are also contributing to the problem by prescribing PPIs without adequate follow-up.

“The number of people using proton pump inhibitors is steadily increasing,” Dr. Weersma said. “The number of people getting them prescribed is relatively stable. The problem is, we never stop.”

According to Dr. Weersma, a growing body of research shows that PPI use may increase the risk of developing other conditions. Although many of these relationships are correlative, some are now widely accepted as causal. Most notable and clinically relevant, Dr. Weersma said, are enteric infections. Clostridioides difficile–associated diarrhea, for instance, is 65% more common among PPI users.

While the mechanisms behind this susceptibility to infection are uncertain, Dr. Weersma suggested that the most likely cause is “oralization” of the gut microbiome caused by loss of the acid barrier, which introduces upper gastrointestinal bacteria, or oral bacteria, into the lower intestines.

Perhaps more relevant to clinical trials, PPIs may also influence the safety and efficacy of drugs.

“There is a lot of interaction between the gut microbiome and a lot of drugs,” Dr. Weersma said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “We really don’t know a lot about this at the moment.”

He went on to explain that bidirectional interactions between drugs and the microbiome may actually present clinical opportunities.

“This is a field that people currently call pharmacomicrobiomics,” Dr. Weersma said. “This is very intriguing, of course, because everyone knows about pharmacogenomics ... which lets you stratify your patients, but you cannot intervene; you cannot change your genetic background to increase efficacy or avoid toxicity. But in fact, with the microbiome, we could modulate the microbiome and improve bioavailability, for example.”

Conversely, Dr. Weersma pointed out that PPI use may be interfering with drug efficacy to a life-altering degree.

He cited a recent study by Chalabi and colleagues, which found that PPI use affected responses to immune checkpoint inhibitors (Ann Oncol. 2020 Jan 16. doi: 10.1016/j.annonc.2020.01.006). Among 169 patients with lung cancer who were treated with atezolizumab, overall survival was significantly lower in PPI users (9.6 vs. 14.5 months; P = .001).

A number of other clinical implications are also possible, Dr. Weersma said, although these require further investigation. For example, a 2019 study by Stark and colleagues suggested that childhood use of PPIs may increase obesity risk.

“[There are] no microbiome data here,” Dr. Weersma said, “but it makes you think.”

While considering the downsides of PPIs, Dr. Weersma also emphasized their importance in clinical practice. “[Proton pump inhibitors] are very great drugs. They are cheap, they are safe, they are very effective. So if you have evidence-based indications to use proton pump inhibitors, you should definitely use them and not stop them.”

Dr. Weersma called for responsible use of PPIs, and suggested that clinicians need to prepare for pushback from patients, who, after stopping PPIs, may experience a temporary resurgence of symptoms because of acid rebound.

“You have to make them aware [of acid rebound],” Dr. Weersma said. “Say: ‘Wait 2 or 3 weeks and this rebound is gone.’ We should say that way, way, way more often.”

But clinicians shouldn’t bear the burden of responsible usage alone, Dr. Weersma said.

“There’s a role for clinicians, patients, and regulatory bodies also, to think about the massive use of proton pump inhibitors now and in the future.”

In the discussion that followed the presentation, a summit attendee brought up the realities of clinical practice before PPIs, when patients frequently had gastrointestinal bleeding secondary to nonsteroidal anti-inflammatory use. In response, Dr. Weersma again emphasized that PPIs play a critical role for many patients. After once more encouraging responsible use, Dr. Weersma expressed concern about the risks involved in conveying his message; not only to the medical community, but also to the general public.

“This is a very difficult message [to deliver],” Dr. Weersma said. “In the Netherlands this was taken up by the media and the news, so my email inbox exploded. It’s difficult to get this nuance right.”

Dr. Weersma disclosed relationships with Takeda, Johnson & Johnson, Ferring, and others.

Microbiome studies should be correcting statistics to account for proton pump inhibitor (PPI) use, according to a leading expert.

After antibiotics, PPIs are the leading cause of microbiome variance in both research and general populations, and these alterations could have a range of consequences, reported Rinse K. Weersma, MD, PhD, of the University of Groningen (the Netherlands).

About 20% of people are taking a PPI, Dr. Weersma said at the annual Gut Microbiota for Health World Summit, noting that, in countries such as the United States and the United Kingdom, this figure may be higher.

“There’s chronic use of proton pump inhibitors in the population on a massive scale,” Dr. Weersma said.

To complicate matters, estimates suggest that 25%-70% of people who are taking PPIs have no appropriate indication. While this issue is partly because of increasing over-the-counter usage, physicians are also contributing to the problem by prescribing PPIs without adequate follow-up.

“The number of people using proton pump inhibitors is steadily increasing,” Dr. Weersma said. “The number of people getting them prescribed is relatively stable. The problem is, we never stop.”

According to Dr. Weersma, a growing body of research shows that PPI use may increase the risk of developing other conditions. Although many of these relationships are correlative, some are now widely accepted as causal. Most notable and clinically relevant, Dr. Weersma said, are enteric infections. Clostridioides difficile–associated diarrhea, for instance, is 65% more common among PPI users.

While the mechanisms behind this susceptibility to infection are uncertain, Dr. Weersma suggested that the most likely cause is “oralization” of the gut microbiome caused by loss of the acid barrier, which introduces upper gastrointestinal bacteria, or oral bacteria, into the lower intestines.

Perhaps more relevant to clinical trials, PPIs may also influence the safety and efficacy of drugs.

“There is a lot of interaction between the gut microbiome and a lot of drugs,” Dr. Weersma said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “We really don’t know a lot about this at the moment.”

He went on to explain that bidirectional interactions between drugs and the microbiome may actually present clinical opportunities.

“This is a field that people currently call pharmacomicrobiomics,” Dr. Weersma said. “This is very intriguing, of course, because everyone knows about pharmacogenomics ... which lets you stratify your patients, but you cannot intervene; you cannot change your genetic background to increase efficacy or avoid toxicity. But in fact, with the microbiome, we could modulate the microbiome and improve bioavailability, for example.”

Conversely, Dr. Weersma pointed out that PPI use may be interfering with drug efficacy to a life-altering degree.

He cited a recent study by Chalabi and colleagues, which found that PPI use affected responses to immune checkpoint inhibitors (Ann Oncol. 2020 Jan 16. doi: 10.1016/j.annonc.2020.01.006). Among 169 patients with lung cancer who were treated with atezolizumab, overall survival was significantly lower in PPI users (9.6 vs. 14.5 months; P = .001).

A number of other clinical implications are also possible, Dr. Weersma said, although these require further investigation. For example, a 2019 study by Stark and colleagues suggested that childhood use of PPIs may increase obesity risk.

“[There are] no microbiome data here,” Dr. Weersma said, “but it makes you think.”

While considering the downsides of PPIs, Dr. Weersma also emphasized their importance in clinical practice. “[Proton pump inhibitors] are very great drugs. They are cheap, they are safe, they are very effective. So if you have evidence-based indications to use proton pump inhibitors, you should definitely use them and not stop them.”

Dr. Weersma called for responsible use of PPIs, and suggested that clinicians need to prepare for pushback from patients, who, after stopping PPIs, may experience a temporary resurgence of symptoms because of acid rebound.

“You have to make them aware [of acid rebound],” Dr. Weersma said. “Say: ‘Wait 2 or 3 weeks and this rebound is gone.’ We should say that way, way, way more often.”

But clinicians shouldn’t bear the burden of responsible usage alone, Dr. Weersma said.

“There’s a role for clinicians, patients, and regulatory bodies also, to think about the massive use of proton pump inhibitors now and in the future.”

In the discussion that followed the presentation, a summit attendee brought up the realities of clinical practice before PPIs, when patients frequently had gastrointestinal bleeding secondary to nonsteroidal anti-inflammatory use. In response, Dr. Weersma again emphasized that PPIs play a critical role for many patients. After once more encouraging responsible use, Dr. Weersma expressed concern about the risks involved in conveying his message; not only to the medical community, but also to the general public.

“This is a very difficult message [to deliver],” Dr. Weersma said. “In the Netherlands this was taken up by the media and the news, so my email inbox exploded. It’s difficult to get this nuance right.”

Dr. Weersma disclosed relationships with Takeda, Johnson & Johnson, Ferring, and others.

A growing body of research links the gut with the brain and behavior, but compartmentalization within the medical community may be slowing investigation of the gut-brain axis, according to a leading expert.

Studies have shown that the microbiome may influence a diverse range of behavioral and neurological processes, from acute and chronic stress responses to development of Parkinson’s and Alzheimer’s disease, reported John F. Cryan, PhD, of University College Cork, Ireland.

Dr. Cryan began his presentation at the annual Gut Microbiota for Health World Summit by citing Hippocrates, who is thought to have stated that all diseases begin in the gut.

“That can be quite strange when I talk to my neurology or psychiatry colleagues,” Dr. Cryan said. “They sometimes look at me like I have two heads. Because in medicine we compartmentalize, and if you are studying neurology or psychiatry or [you are] in clinical practice, you are focusing on everything from the neck upwards.”

For more than a decade, Dr. Cryan and colleagues have been investigating the gut-brain axis, predominantly in mouse models, but also across animal species and in humans.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Cryan reviewed a variety of representative studies.

For instance, in both mice and humans, research has shown that C-section, which is associated with poorer microbiome diversity than vaginal delivery, has also been linked with social deficits and elevated stress responses. And in the case of mice, coprophagia, in which cesarean-delivered mice eat the feces of vaginally born mice, has been shown to ameliorate these psychiatric effects.

Dr. Cryan likened this process to an “artificial fecal transplant.”

“You know, co-housing and eating each other’s poo is not the translational approach that we were advocating by any means,” Dr. Cryan said. “But at least it tells us – in a proof-of-concept way – that if we change the microbiome, then we can reverse what’s going on.”

While the mechanisms behind the gut-brain axis remain incompletely understood, Dr. Cryan noted that the vagus nerve, which travels from the gut to the brain, plays a central role, and that transecting this nerve in mice stops the microbiome from affecting the brain.

“What happens in vagus doesn’t just stay in vagus, but will actually affect our emotions in different ways,” Dr. Cryan said.

He emphasized that communication travels both ways along the gut-brain axis, and went on to describe how this phenomenon has been demonstrated across a wide array of animals.

“From insects all the way through to primates, if you start to interfere with social behavior, you change the microbiome,” Dr. Cryan said. “But the opposite is also true; if you start to change the microbiome you can start to have widespread effects on social behavior.”

In humans, manipulating the microbiome could open up new psychiatric frontiers, Dr. Cryan said.

“[In the past 30 years], there really have been no real advances in how we manage mental health,” he said. “That’s very sobering when we are having such a mental health problem across all ages right now. And so perhaps it’s time for what we’ve coined the ‘psychobiotic revolution’ – time for a new way of thinking about mental health.”

According to Dr. Cryan, psychobiotics are interventions that target the microbiome for mental health purposes, including fermented foods, probiotics, prebiotics, synbiotics, parabiotics, and postbiotics.

Among these, probiotics have been a focal point of interventional research. Although results have been mixed, Dr. Cryan suggested that negative probiotic studies are more likely due to bacterial strain than a failure of the concept as a whole.

“Most strains of bacteria will do absolutely nothing,” Dr. Cryan said. “Strain is really important.”

In demonstration of this concept, he recounted a 2017 study conducted at University College Cork in which 22 healthy volunteers were given Bifidobacterium longum 1714, and then subjected to a social stress test. The results, published in Translational Psychiatry, showed that the probiotic, compared with placebo, was associated with attenuated stress responses, reduced daily stress, and enhanced visuospatial memory.

In contrast, a similar study by Dr. Cryan and colleagues, which tested Lactobacillus rhamnosus (JB-1), fell short.

“You [could not have gotten] more negative data into one paper if you tried,” Dr. Cryan said, referring to the study. “It did absolutely nothing.”

To find out which psychobiotics may have an impact, and how, Dr. Cryan called for more research.

“It’s still early days,” he said. “We probably have more meta-analyses and systematic reviews of the field than we have primary research papers.

Dr. Cryan concluded his presentation on an optimistic note.

“Neurology is waking up ... to understand that the microbiome could be playing a key role in many, many other disorders. ... Overall, what we’re beginning to see is that our state of gut markedly affects our state of mind.”

Dr. Cryan disclosed relationships with Abbott Nutrition, Roche Pharma, Nutricia, and others.

A growing body of research links the gut with the brain and behavior, but compartmentalization within the medical community may be slowing investigation of the gut-brain axis, according to a leading expert.

Studies have shown that the microbiome may influence a diverse range of behavioral and neurological processes, from acute and chronic stress responses to development of Parkinson’s and Alzheimer’s disease, reported John F. Cryan, PhD, of University College Cork, Ireland.

Dr. Cryan began his presentation at the annual Gut Microbiota for Health World Summit by citing Hippocrates, who is thought to have stated that all diseases begin in the gut.

“That can be quite strange when I talk to my neurology or psychiatry colleagues,” Dr. Cryan said. “They sometimes look at me like I have two heads. Because in medicine we compartmentalize, and if you are studying neurology or psychiatry or [you are] in clinical practice, you are focusing on everything from the neck upwards.”

For more than a decade, Dr. Cryan and colleagues have been investigating the gut-brain axis, predominantly in mouse models, but also across animal species and in humans.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Cryan reviewed a variety of representative studies.

For instance, in both mice and humans, research has shown that C-section, which is associated with poorer microbiome diversity than vaginal delivery, has also been linked with social deficits and elevated stress responses. And in the case of mice, coprophagia, in which cesarean-delivered mice eat the feces of vaginally born mice, has been shown to ameliorate these psychiatric effects.

Dr. Cryan likened this process to an “artificial fecal transplant.”

“You know, co-housing and eating each other’s poo is not the translational approach that we were advocating by any means,” Dr. Cryan said. “But at least it tells us – in a proof-of-concept way – that if we change the microbiome, then we can reverse what’s going on.”

While the mechanisms behind the gut-brain axis remain incompletely understood, Dr. Cryan noted that the vagus nerve, which travels from the gut to the brain, plays a central role, and that transecting this nerve in mice stops the microbiome from affecting the brain.

“What happens in vagus doesn’t just stay in vagus, but will actually affect our emotions in different ways,” Dr. Cryan said.

He emphasized that communication travels both ways along the gut-brain axis, and went on to describe how this phenomenon has been demonstrated across a wide array of animals.

“From insects all the way through to primates, if you start to interfere with social behavior, you change the microbiome,” Dr. Cryan said. “But the opposite is also true; if you start to change the microbiome you can start to have widespread effects on social behavior.”

In humans, manipulating the microbiome could open up new psychiatric frontiers, Dr. Cryan said.

“[In the past 30 years], there really have been no real advances in how we manage mental health,” he said. “That’s very sobering when we are having such a mental health problem across all ages right now. And so perhaps it’s time for what we’ve coined the ‘psychobiotic revolution’ – time for a new way of thinking about mental health.”

According to Dr. Cryan, psychobiotics are interventions that target the microbiome for mental health purposes, including fermented foods, probiotics, prebiotics, synbiotics, parabiotics, and postbiotics.

Among these, probiotics have been a focal point of interventional research. Although results have been mixed, Dr. Cryan suggested that negative probiotic studies are more likely due to bacterial strain than a failure of the concept as a whole.

“Most strains of bacteria will do absolutely nothing,” Dr. Cryan said. “Strain is really important.”

In demonstration of this concept, he recounted a 2017 study conducted at University College Cork in which 22 healthy volunteers were given Bifidobacterium longum 1714, and then subjected to a social stress test. The results, published in Translational Psychiatry, showed that the probiotic, compared with placebo, was associated with attenuated stress responses, reduced daily stress, and enhanced visuospatial memory.

In contrast, a similar study by Dr. Cryan and colleagues, which tested Lactobacillus rhamnosus (JB-1), fell short.

“You [could not have gotten] more negative data into one paper if you tried,” Dr. Cryan said, referring to the study. “It did absolutely nothing.”

To find out which psychobiotics may have an impact, and how, Dr. Cryan called for more research.

“It’s still early days,” he said. “We probably have more meta-analyses and systematic reviews of the field than we have primary research papers.

Dr. Cryan concluded his presentation on an optimistic note.

“Neurology is waking up ... to understand that the microbiome could be playing a key role in many, many other disorders. ... Overall, what we’re beginning to see is that our state of gut markedly affects our state of mind.”

Dr. Cryan disclosed relationships with Abbott Nutrition, Roche Pharma, Nutricia, and others.

A growing body of research links the gut with the brain and behavior, but compartmentalization within the medical community may be slowing investigation of the gut-brain axis, according to a leading expert.

Studies have shown that the microbiome may influence a diverse range of behavioral and neurological processes, from acute and chronic stress responses to development of Parkinson’s and Alzheimer’s disease, reported John F. Cryan, PhD, of University College Cork, Ireland.

Dr. Cryan began his presentation at the annual Gut Microbiota for Health World Summit by citing Hippocrates, who is thought to have stated that all diseases begin in the gut.

“That can be quite strange when I talk to my neurology or psychiatry colleagues,” Dr. Cryan said. “They sometimes look at me like I have two heads. Because in medicine we compartmentalize, and if you are studying neurology or psychiatry or [you are] in clinical practice, you are focusing on everything from the neck upwards.”

For more than a decade, Dr. Cryan and colleagues have been investigating the gut-brain axis, predominantly in mouse models, but also across animal species and in humans.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Cryan reviewed a variety of representative studies.

For instance, in both mice and humans, research has shown that C-section, which is associated with poorer microbiome diversity than vaginal delivery, has also been linked with social deficits and elevated stress responses. And in the case of mice, coprophagia, in which cesarean-delivered mice eat the feces of vaginally born mice, has been shown to ameliorate these psychiatric effects.

Dr. Cryan likened this process to an “artificial fecal transplant.”

“You know, co-housing and eating each other’s poo is not the translational approach that we were advocating by any means,” Dr. Cryan said. “But at least it tells us – in a proof-of-concept way – that if we change the microbiome, then we can reverse what’s going on.”

While the mechanisms behind the gut-brain axis remain incompletely understood, Dr. Cryan noted that the vagus nerve, which travels from the gut to the brain, plays a central role, and that transecting this nerve in mice stops the microbiome from affecting the brain.

“What happens in vagus doesn’t just stay in vagus, but will actually affect our emotions in different ways,” Dr. Cryan said.

He emphasized that communication travels both ways along the gut-brain axis, and went on to describe how this phenomenon has been demonstrated across a wide array of animals.

“From insects all the way through to primates, if you start to interfere with social behavior, you change the microbiome,” Dr. Cryan said. “But the opposite is also true; if you start to change the microbiome you can start to have widespread effects on social behavior.”

In humans, manipulating the microbiome could open up new psychiatric frontiers, Dr. Cryan said.

“[In the past 30 years], there really have been no real advances in how we manage mental health,” he said. “That’s very sobering when we are having such a mental health problem across all ages right now. And so perhaps it’s time for what we’ve coined the ‘psychobiotic revolution’ – time for a new way of thinking about mental health.”

According to Dr. Cryan, psychobiotics are interventions that target the microbiome for mental health purposes, including fermented foods, probiotics, prebiotics, synbiotics, parabiotics, and postbiotics.

Among these, probiotics have been a focal point of interventional research. Although results have been mixed, Dr. Cryan suggested that negative probiotic studies are more likely due to bacterial strain than a failure of the concept as a whole.

“Most strains of bacteria will do absolutely nothing,” Dr. Cryan said. “Strain is really important.”

In demonstration of this concept, he recounted a 2017 study conducted at University College Cork in which 22 healthy volunteers were given Bifidobacterium longum 1714, and then subjected to a social stress test. The results, published in Translational Psychiatry, showed that the probiotic, compared with placebo, was associated with attenuated stress responses, reduced daily stress, and enhanced visuospatial memory.

In contrast, a similar study by Dr. Cryan and colleagues, which tested Lactobacillus rhamnosus (JB-1), fell short.

“You [could not have gotten] more negative data into one paper if you tried,” Dr. Cryan said, referring to the study. “It did absolutely nothing.”

To find out which psychobiotics may have an impact, and how, Dr. Cryan called for more research.

“It’s still early days,” he said. “We probably have more meta-analyses and systematic reviews of the field than we have primary research papers.

Dr. Cryan concluded his presentation on an optimistic note.

“Neurology is waking up ... to understand that the microbiome could be playing a key role in many, many other disorders. ... Overall, what we’re beginning to see is that our state of gut markedly affects our state of mind.”

Dr. Cryan disclosed relationships with Abbott Nutrition, Roche Pharma, Nutricia, and others.

Standards and technology are now available for microbiome profiling to take personalized medicine to the next level, but prospective trials are needed to realize this possibility, according to a leading expert.

The need for prospective microbiomics trials is increasing with the incidence of immune disorders, many of which have been linked with disturbances in the gut, reported Jöel Doré, PhD, at the annual Gut Microbiota for Health World Summit.

“In spite of considerable progress in medicine, together with hygiene, antibiotics, and vaccination developments, we are still seeing an increasing incidence – uncontrolled, that started over 60 years ago – of immune-mediated conditions,” said Dr. Doré, research director at the French National Research Institute for Agriculture, Food, and the Environment.

According to the World Health Organization, one out of four people will be affected by such a disorder in their lifetime, and the incidence rate of some conditions is accelerating faster than others, with geographical distributions that suggest environmental risk factors.

“The rate of incidence of autism in the U.S.A. is a quite scary exponential curve, where less than 1 birth per 5,000 was [affected] in the 1970s, where today it is 1 birth out of 50,” Dr. Doré said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “Prevention is an urgent need, and possibly if we do not manage to understand what’s going on, human longevity might be at stake.”

Multiple studies have shown that transferring microbiota from humans with immune disorders to healthy mice can induce clinical signs of immune disorders, he said. And between humans, fecal transplants from healthy donors have reduced symptoms in patients with conditions such as inflammatory bowel disease.

While these studies support the link between microbe-host relationships and immune function, most of the underlying mechanisms remain unknown, Dr. Doré said. He highlighted the fact that the complex network of interactions involved separates microbiomics research from conventional approaches to disease.

“I want to stress the fact that clinical trials [in the past] have been designed in the situation where infection was the problem, [but] infection is essentially a linear thing; one agent, one risk, one disease,” Dr. Doré said. “What we are dealing with – with the increasing incidence of immune disorders – is host-microbe interaction at the center of everything, and alteration of host-microbe leading to risk, which may lead to disease. But host-microbe interaction is under the control of a vast number of environmental aspects ... so tools to deal with innovation and translation in a totally different or systemic configuration have yet to be invented.”

According to Dr. Doré, to develop clinical applications, research procedures must first be standardized.

“To be of use for the clinician and general practitioner, microbiome profiling will have to rely on pipelines of standardized preanalytical and analytical procedures,” he said. “This starts from sample collection and shipment.”

For the past 5 years, Dr. Doré and colleagues have been working to standardize procedures with a number of organizations around the world, and progress has been made.

“Today we have very good standards for shotgun sequencing,” he said.

With standards solidifying, microbiomics may lead to new clinical strategies for a range of conditions, even beyond immune disorders, Dr. Doré said. He noted that, as a relatively simple measure, gene richness in the microbiome may be used as a health stratifier. Studies have shown that low gene count has been associated with more severe metabolic and inflammatory traits among overweight patients, a lack of response to low-calorie diets among overweight and obese patients, severity of related conditions and risk of mortality among patients with liver cirrhosis, and poorer responses to immunotherapy among patients with cancer.

Certain patterns of flora may be prognostic, Dr. Doré said, citing a study by Gopalakrishnan et al. that involved 112 melanoma patients, in which those with a high abundance of Faecalibacterium had significantly longer progression-free survival than patients with a low abundance of the same bacteria. Further, a multivariate model showed that a high abundance of Faecalibacterium was the strongest predictor of response to immunotherapy, (hazard ratio, 2.95; P = .03), followed closely by prior immunotherapy (HR, 2.87; P = .03). In contrast, patients with a high abundance of Bacteroidales had shorter progression-free survival than patients with a low abundance of the same bacteria.

Dr. Doré also referred to one of the first interventional microbiomics studies in oncology. Mohty et al. conducted the ODYSSEE phase 1b/2a trial involving 25 patients with acute myeloid leukemia, in which patients were given autologous fecal microbiota transplants after induction chemotherapy and antibiotics. The treatment recovered 90% of original microbiota, and the estimated 1-year overall survival rate was 84%, compared with a historical rate of 70%.

The ODYSSEE study serves as proof of concept that microbiomics may eventually offer the next level of personalized medicine, Dr. Doré said. And now, with standards and technology available, researchers can move forward.

Dr. Doré disclosed relationships with BioFortis, Janssen, Sanofi, and other pharmaceutical companies.

Standards and technology are now available for microbiome profiling to take personalized medicine to the next level, but prospective trials are needed to realize this possibility, according to a leading expert.

The need for prospective microbiomics trials is increasing with the incidence of immune disorders, many of which have been linked with disturbances in the gut, reported Jöel Doré, PhD, at the annual Gut Microbiota for Health World Summit.

“In spite of considerable progress in medicine, together with hygiene, antibiotics, and vaccination developments, we are still seeing an increasing incidence – uncontrolled, that started over 60 years ago – of immune-mediated conditions,” said Dr. Doré, research director at the French National Research Institute for Agriculture, Food, and the Environment.

According to the World Health Organization, one out of four people will be affected by such a disorder in their lifetime, and the incidence rate of some conditions is accelerating faster than others, with geographical distributions that suggest environmental risk factors.

“The rate of incidence of autism in the U.S.A. is a quite scary exponential curve, where less than 1 birth per 5,000 was [affected] in the 1970s, where today it is 1 birth out of 50,” Dr. Doré said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “Prevention is an urgent need, and possibly if we do not manage to understand what’s going on, human longevity might be at stake.”

Multiple studies have shown that transferring microbiota from humans with immune disorders to healthy mice can induce clinical signs of immune disorders, he said. And between humans, fecal transplants from healthy donors have reduced symptoms in patients with conditions such as inflammatory bowel disease.

While these studies support the link between microbe-host relationships and immune function, most of the underlying mechanisms remain unknown, Dr. Doré said. He highlighted the fact that the complex network of interactions involved separates microbiomics research from conventional approaches to disease.

“I want to stress the fact that clinical trials [in the past] have been designed in the situation where infection was the problem, [but] infection is essentially a linear thing; one agent, one risk, one disease,” Dr. Doré said. “What we are dealing with – with the increasing incidence of immune disorders – is host-microbe interaction at the center of everything, and alteration of host-microbe leading to risk, which may lead to disease. But host-microbe interaction is under the control of a vast number of environmental aspects ... so tools to deal with innovation and translation in a totally different or systemic configuration have yet to be invented.”

According to Dr. Doré, to develop clinical applications, research procedures must first be standardized.

“To be of use for the clinician and general practitioner, microbiome profiling will have to rely on pipelines of standardized preanalytical and analytical procedures,” he said. “This starts from sample collection and shipment.”

For the past 5 years, Dr. Doré and colleagues have been working to standardize procedures with a number of organizations around the world, and progress has been made.

“Today we have very good standards for shotgun sequencing,” he said.

With standards solidifying, microbiomics may lead to new clinical strategies for a range of conditions, even beyond immune disorders, Dr. Doré said. He noted that, as a relatively simple measure, gene richness in the microbiome may be used as a health stratifier. Studies have shown that low gene count has been associated with more severe metabolic and inflammatory traits among overweight patients, a lack of response to low-calorie diets among overweight and obese patients, severity of related conditions and risk of mortality among patients with liver cirrhosis, and poorer responses to immunotherapy among patients with cancer.

Certain patterns of flora may be prognostic, Dr. Doré said, citing a study by Gopalakrishnan et al. that involved 112 melanoma patients, in which those with a high abundance of Faecalibacterium had significantly longer progression-free survival than patients with a low abundance of the same bacteria. Further, a multivariate model showed that a high abundance of Faecalibacterium was the strongest predictor of response to immunotherapy, (hazard ratio, 2.95; P = .03), followed closely by prior immunotherapy (HR, 2.87; P = .03). In contrast, patients with a high abundance of Bacteroidales had shorter progression-free survival than patients with a low abundance of the same bacteria.

Dr. Doré also referred to one of the first interventional microbiomics studies in oncology. Mohty et al. conducted the ODYSSEE phase 1b/2a trial involving 25 patients with acute myeloid leukemia, in which patients were given autologous fecal microbiota transplants after induction chemotherapy and antibiotics. The treatment recovered 90% of original microbiota, and the estimated 1-year overall survival rate was 84%, compared with a historical rate of 70%.

The ODYSSEE study serves as proof of concept that microbiomics may eventually offer the next level of personalized medicine, Dr. Doré said. And now, with standards and technology available, researchers can move forward.

Dr. Doré disclosed relationships with BioFortis, Janssen, Sanofi, and other pharmaceutical companies.

Standards and technology are now available for microbiome profiling to take personalized medicine to the next level, but prospective trials are needed to realize this possibility, according to a leading expert.

The need for prospective microbiomics trials is increasing with the incidence of immune disorders, many of which have been linked with disturbances in the gut, reported Jöel Doré, PhD, at the annual Gut Microbiota for Health World Summit.

“In spite of considerable progress in medicine, together with hygiene, antibiotics, and vaccination developments, we are still seeing an increasing incidence – uncontrolled, that started over 60 years ago – of immune-mediated conditions,” said Dr. Doré, research director at the French National Research Institute for Agriculture, Food, and the Environment.

According to the World Health Organization, one out of four people will be affected by such a disorder in their lifetime, and the incidence rate of some conditions is accelerating faster than others, with geographical distributions that suggest environmental risk factors.

“The rate of incidence of autism in the U.S.A. is a quite scary exponential curve, where less than 1 birth per 5,000 was [affected] in the 1970s, where today it is 1 birth out of 50,” Dr. Doré said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “Prevention is an urgent need, and possibly if we do not manage to understand what’s going on, human longevity might be at stake.”

Multiple studies have shown that transferring microbiota from humans with immune disorders to healthy mice can induce clinical signs of immune disorders, he said. And between humans, fecal transplants from healthy donors have reduced symptoms in patients with conditions such as inflammatory bowel disease.

While these studies support the link between microbe-host relationships and immune function, most of the underlying mechanisms remain unknown, Dr. Doré said. He highlighted the fact that the complex network of interactions involved separates microbiomics research from conventional approaches to disease.

“I want to stress the fact that clinical trials [in the past] have been designed in the situation where infection was the problem, [but] infection is essentially a linear thing; one agent, one risk, one disease,” Dr. Doré said. “What we are dealing with – with the increasing incidence of immune disorders – is host-microbe interaction at the center of everything, and alteration of host-microbe leading to risk, which may lead to disease. But host-microbe interaction is under the control of a vast number of environmental aspects ... so tools to deal with innovation and translation in a totally different or systemic configuration have yet to be invented.”

According to Dr. Doré, to develop clinical applications, research procedures must first be standardized.

“To be of use for the clinician and general practitioner, microbiome profiling will have to rely on pipelines of standardized preanalytical and analytical procedures,” he said. “This starts from sample collection and shipment.”

For the past 5 years, Dr. Doré and colleagues have been working to standardize procedures with a number of organizations around the world, and progress has been made.

“Today we have very good standards for shotgun sequencing,” he said.

With standards solidifying, microbiomics may lead to new clinical strategies for a range of conditions, even beyond immune disorders, Dr. Doré said. He noted that, as a relatively simple measure, gene richness in the microbiome may be used as a health stratifier. Studies have shown that low gene count has been associated with more severe metabolic and inflammatory traits among overweight patients, a lack of response to low-calorie diets among overweight and obese patients, severity of related conditions and risk of mortality among patients with liver cirrhosis, and poorer responses to immunotherapy among patients with cancer.

Certain patterns of flora may be prognostic, Dr. Doré said, citing a study by Gopalakrishnan et al. that involved 112 melanoma patients, in which those with a high abundance of Faecalibacterium had significantly longer progression-free survival than patients with a low abundance of the same bacteria. Further, a multivariate model showed that a high abundance of Faecalibacterium was the strongest predictor of response to immunotherapy, (hazard ratio, 2.95; P = .03), followed closely by prior immunotherapy (HR, 2.87; P = .03). In contrast, patients with a high abundance of Bacteroidales had shorter progression-free survival than patients with a low abundance of the same bacteria.

Dr. Doré also referred to one of the first interventional microbiomics studies in oncology. Mohty et al. conducted the ODYSSEE phase 1b/2a trial involving 25 patients with acute myeloid leukemia, in which patients were given autologous fecal microbiota transplants after induction chemotherapy and antibiotics. The treatment recovered 90% of original microbiota, and the estimated 1-year overall survival rate was 84%, compared with a historical rate of 70%.

The ODYSSEE study serves as proof of concept that microbiomics may eventually offer the next level of personalized medicine, Dr. Doré said. And now, with standards and technology available, researchers can move forward.

Dr. Doré disclosed relationships with BioFortis, Janssen, Sanofi, and other pharmaceutical companies.