This transcript has been edited for clarity.
Hello. I’m Dr David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia. Welcome back to another GI Common Concerns.
Today, I want to talk about fecal microbiota transplant (FMT), which has been staggeringly effective in Clostridioides difficile infections. In recurrent C difficile, FMT trials have shown it to be approximately 95% effective.
What about other conditions that we believe are caused by dysbiosis? Hypothetically, it makes sense that if a patient has an abnormal biome, we could change that by transplanting in a normal biome and, as a result, mitigate disease response.
However, several recent studies with FMT present a more complicated picture of its potential efficacy across various disease states.
It should be noted that a couple of the studies I’m going to share with you are electronically published ahead of print, meaning they’re not yet available in journal form, although they will be soon, most likely in early 2025.
Inflammatory Bowel Disease
The first study I’ll highlight was performed at three centers in Canada, where researchers randomized 34 patients with mild to moderate Crohn’s disease to receive placebo or initial FMT delivered by a colonoscopy followed by 7 weeks of oral capsule delivery. They employed a composite primary endpoint of clinical remission and endoscopic response at the end of 8 weeks of follow-up.
Although the patient numbers were admittedly small, no one in the FMT group reached the primary endpoint, compared with one patient in the placebo group. This led the researchers to terminate the study early due to FMT’s futility in this indication.
Therefore, for FMT in Crohn’s disease, the most-recent data would suggest that this is not really a viable clinical option going forward.
When it comes FMT for ulcerative colitis, a study with an admirable methodology was conducted by researchers in Belgium. They assessed the delivery of FMT in patients with moderate to severe ulcerative colitis, who were randomly assigned to receive FMT via an autologous specimen or allogenic specimens. The allogenic specimen were obtained from so-called “super-donors.”
There are certain enterotypes in the bacterial microbiome that have been highly associated with ulcerative colitis, including Bacteroides 2 enterotypes, which is observed at a higher prevalence in patients with this condition. Potential super-donors were identified if their samples did not contain Bacteroides 2 enterotypes, in addition to other parameters.
Initial FMT was delivered via sigmoidoscopy, and then by enemas on weeks 1, 2, and 3. The primary endpoint was steroid-free remission.
At week 8, which was two thirds of the way through follow-up, the study was halted due to futility, as no treatment difference was observed in favor of allogenic FMT.
Although the authors concluded that FMT was not worth pursuing in this cohort, they should be credited with brilliantly performing their analysis.
Perhaps we should pause such analyses in this indication, but a systematic literature review and meta-analysis coming out in 2025 in Clinical Gastroenterology and Hepatology offers a more complicated picture about stopping it entirely.
Researchers assessed 29 high-quality papers of FMT’s ability to induce remission in patients with ulcerative colitis. They reported results for FMT response and, where possible, biome analysis. They found that high biome diversity was more predictive of a response to FMT, as opposed to those with low biome diversity, which was more predictive of a poor response.
These results suggest that we’re getting to a point with FMT for inflammatory bowel disease where we should look to identify super-donors to better match the donor and the recipient.
Although FMT isn’t something that we can use universally in this condition, it should still be kept as a possible option in the future.
Irritable Bowel Syndrome
We certainly think that irritable bowel syndrome has an infectious component, with small-intestinal bacterial overgrowth and methanogen overgrowth, and the response to rifaximin and other antibiotics.
A composite meta-analysis of 10 randomized trials just published in 2024 looked at the response to FMT at 12, 24, and 52 weeks in patients with irritable bowel syndrome.
At none of these timepoints was there a significant improvement in irritable bowel syndrome among patients, which means FMT is also probably not effective in this condition.
Reasons for Optimism
Is there hope on the horizon for FMT? And, why does it not work for all these inflammatory conditions and irritable bowel syndrome, yet work so well for C difficile?
Truth be told, we don’t know the reason why it works so well in C difficile. It’s likely related to bile acid metabolism, and the conversion of primarily bile acids into secondary bile acid degradation, which in turn impacts the ability for C difficile germination and toxin formation. Achieving reversal of that process with FMT seems to make sense, which is why it can deliver such durable responses as opposed to these other conditions so far.
Does it mean that FMT doesn’t work outside of C difficile? Two small but interesting studies would indicate otherwise.
The first study comes from researchers in China, who looked at the use of FMT for treating sleep impairment in patients with postacute, or long-haul, COVID-19 syndrome. This is a very interesting analysis using validated instruments of sleep. I’ve published a lot in sleep research and am qualified to comment.
Researchers compared patients receiving FMT with a control group that didn’t receive any treatment over a 12-week period. Lo and behold, there was a dramatic improvement in sleep in these patients who had significant insomnia.
They found notable bacterial alterations among patients receiving FMT. This was particularly true for one bacterial species, Gemmiger formicilis, which is responsible for the regulation of menaquinol-7 (vitamin K2) and is involved in energy activation and electron transfer in the brain. It would make sense that it would result in some improvement in sleep.
It should be noted that this is a very limited study; it’s not a randomized controlled trial. Nonetheless, it’s worth being aware of these findings, given that we know there are biome variations that influence post–COVID-19 response.
Another very interesting and exciting study was presented at the most-recent American Association for the Study of Liver Diseases annual meeting in November 2024.[1]
Researchers studied the use of FMT in patients with severe alcohol-associated hepatitis, who were randomized to receive FMT via nasal duodenal tube for 7 consecutive days.
Patients were ineligible for steroids, as they had been hospitalized for drinking alcohol within the last 30 days and had a Model for End-Stage Liver Disease (MELD) score ≥ 20, a modified Maddrey discriminant function (mDF) score ≥ 80, renal dysfunction, infection requiring antibiotics, a gastrointestinal bleed, or severe comorbidities. Essentially, when it comes to comorbidities, these were the worst of the worst.
Researchers reported that there was a dramatic improvement in the FMT group in MELD scores at 3 and 6 months, mDF score at 6 months, and Glasgow Alcoholic Hepatitis Score at 6 months. There were major improvements seen in all these endpoints, which were highly statistically significant.
Interestingly, there was a notable risk reduction for hepatic encephalopathy, with the incidence reduced from 40% to 6% in the FMT group, as well as alcohol relapses, which fell from 40% to 10%.
It should be noted that this was also a very limited study, which still needs to be validated. However, FMT may make sense in this indication.
Future Directions
We need to obtain a better understanding of how to achieve a quality match between the recipient and the donor in all conditions that are related to the biome. To do so, we need to solve the remaining puzzles and identify which bridges to cross before we determine the best treatment strategies.
Another thing to consider is that, as of the end of December 2024, OpenBiome is no longer distributing FMT, after a US Food and Drug Administration (FDA) policy change.
This leaves us with Vowst and Rebyota as our only FDA-approved options. However, they are not approved for severe or fulminant C difficile or for pediatric indications, so it leaves us in a bit in a lurch. As a result, I’m not quite sure where we should go for our patients with C difficile.
In conclusion, don’t give up on FMT, even though most new data indicate it’s not currently an option for several indications. There’s still much for us to learn about its potential.
I’m Dr David Johnson. Thanks for listening.
David A. Johnson, MD, a regular contributor to Medscape, is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia, and a past president of the American College of Gastroenterology. His primary focus is the clinical practice of gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with principal research interests in esophageal and colon disease, and more recently in sleep and microbiome effects on gastrointestinal health and disease.
COMMENTARY
Don’t Give Up On FMT for GI Conditions Beyond C difficile
DISCLOSURES
| January 29, 2025This transcript has been edited for clarity.
Hello. I’m Dr David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia. Welcome back to another GI Common Concerns.
Today, I want to talk about fecal microbiota transplant (FMT), which has been staggeringly effective in Clostridioides difficile infections. In recurrent C difficile, FMT trials have shown it to be approximately 95% effective.
What about other conditions that we believe are caused by dysbiosis? Hypothetically, it makes sense that if a patient has an abnormal biome, we could change that by transplanting in a normal biome and, as a result, mitigate disease response.
However, several recent studies with FMT present a more complicated picture of its potential efficacy across various disease states.
It should be noted that a couple of the studies I’m going to share with you are electronically published ahead of print, meaning they’re not yet available in journal form, although they will be soon, most likely in early 2025.
Inflammatory Bowel Disease
The first study I’ll highlight was performed at three centers in Canada, where researchers randomized 34 patients with mild to moderate Crohn’s disease to receive placebo or initial FMT delivered by a colonoscopy followed by 7 weeks of oral capsule delivery. They employed a composite primary endpoint of clinical remission and endoscopic response at the end of 8 weeks of follow-up.
Although the patient numbers were admittedly small, no one in the FMT group reached the primary endpoint, compared with one patient in the placebo group. This led the researchers to terminate the study early due to FMT’s futility in this indication.
Therefore, for FMT in Crohn’s disease, the most-recent data would suggest that this is not really a viable clinical option going forward.
When it comes FMT for ulcerative colitis, a study with an admirable methodology was conducted by researchers in Belgium. They assessed the delivery of FMT in patients with moderate to severe ulcerative colitis, who were randomly assigned to receive FMT via an autologous specimen or allogenic specimens. The allogenic specimen were obtained from so-called “super-donors.”
There are certain enterotypes in the bacterial microbiome that have been highly associated with ulcerative colitis, including Bacteroides 2 enterotypes, which is observed at a higher prevalence in patients with this condition. Potential super-donors were identified if their samples did not contain Bacteroides 2 enterotypes, in addition to other parameters.
Initial FMT was delivered via sigmoidoscopy, and then by enemas on weeks 1, 2, and 3. The primary endpoint was steroid-free remission.
At week 8, which was two thirds of the way through follow-up, the study was halted due to futility, as no treatment difference was observed in favor of allogenic FMT.
Although the authors concluded that FMT was not worth pursuing in this cohort, they should be credited with brilliantly performing their analysis.
Perhaps we should pause such analyses in this indication, but a systematic literature review and meta-analysis coming out in 2025 in Clinical Gastroenterology and Hepatology offers a more complicated picture about stopping it entirely.
Researchers assessed 29 high-quality papers of FMT’s ability to induce remission in patients with ulcerative colitis. They reported results for FMT response and, where possible, biome analysis. They found that high biome diversity was more predictive of a response to FMT, as opposed to those with low biome diversity, which was more predictive of a poor response.
These results suggest that we’re getting to a point with FMT for inflammatory bowel disease where we should look to identify super-donors to better match the donor and the recipient.
Although FMT isn’t something that we can use universally in this condition, it should still be kept as a possible option in the future.
Irritable Bowel Syndrome
We certainly think that irritable bowel syndrome has an infectious component, with small-intestinal bacterial overgrowth and methanogen overgrowth, and the response to rifaximin and other antibiotics.
A composite meta-analysis of 10 randomized trials just published in 2024 looked at the response to FMT at 12, 24, and 52 weeks in patients with irritable bowel syndrome.
At none of these timepoints was there a significant improvement in irritable bowel syndrome among patients, which means FMT is also probably not effective in this condition.
Reasons for Optimism
Is there hope on the horizon for FMT? And, why does it not work for all these inflammatory conditions and irritable bowel syndrome, yet work so well for C difficile?
Truth be told, we don’t know the reason why it works so well in C difficile. It’s likely related to bile acid metabolism, and the conversion of primarily bile acids into secondary bile acid degradation, which in turn impacts the ability for C difficile germination and toxin formation. Achieving reversal of that process with FMT seems to make sense, which is why it can deliver such durable responses as opposed to these other conditions so far.
Does it mean that FMT doesn’t work outside of C difficile? Two small but interesting studies would indicate otherwise.
The first study comes from researchers in China, who looked at the use of FMT for treating sleep impairment in patients with postacute, or long-haul, COVID-19 syndrome. This is a very interesting analysis using validated instruments of sleep. I’ve published a lot in sleep research and am qualified to comment.
Researchers compared patients receiving FMT with a control group that didn’t receive any treatment over a 12-week period. Lo and behold, there was a dramatic improvement in sleep in these patients who had significant insomnia.
They found notable bacterial alterations among patients receiving FMT. This was particularly true for one bacterial species, Gemmiger formicilis, which is responsible for the regulation of menaquinol-7 (vitamin K2) and is involved in energy activation and electron transfer in the brain. It would make sense that it would result in some improvement in sleep.
It should be noted that this is a very limited study; it’s not a randomized controlled trial. Nonetheless, it’s worth being aware of these findings, given that we know there are biome variations that influence post–COVID-19 response.
Another very interesting and exciting study was presented at the most-recent American Association for the Study of Liver Diseases annual meeting in November 2024.[1]
Researchers studied the use of FMT in patients with severe alcohol-associated hepatitis, who were randomized to receive FMT via nasal duodenal tube for 7 consecutive days.
Patients were ineligible for steroids, as they had been hospitalized for drinking alcohol within the last 30 days and had a Model for End-Stage Liver Disease (MELD) score ≥ 20, a modified Maddrey discriminant function (mDF) score ≥ 80, renal dysfunction, infection requiring antibiotics, a gastrointestinal bleed, or severe comorbidities. Essentially, when it comes to comorbidities, these were the worst of the worst.
Researchers reported that there was a dramatic improvement in the FMT group in MELD scores at 3 and 6 months, mDF score at 6 months, and Glasgow Alcoholic Hepatitis Score at 6 months. There were major improvements seen in all these endpoints, which were highly statistically significant.
Interestingly, there was a notable risk reduction for hepatic encephalopathy, with the incidence reduced from 40% to 6% in the FMT group, as well as alcohol relapses, which fell from 40% to 10%.
It should be noted that this was also a very limited study, which still needs to be validated. However, FMT may make sense in this indication.
Future Directions
We need to obtain a better understanding of how to achieve a quality match between the recipient and the donor in all conditions that are related to the biome. To do so, we need to solve the remaining puzzles and identify which bridges to cross before we determine the best treatment strategies.
Another thing to consider is that, as of the end of December 2024, OpenBiome is no longer distributing FMT, after a US Food and Drug Administration (FDA) policy change.
This leaves us with Vowst and Rebyota as our only FDA-approved options. However, they are not approved for severe or fulminant C difficile or for pediatric indications, so it leaves us in a bit in a lurch. As a result, I’m not quite sure where we should go for our patients with C difficile.
In conclusion, don’t give up on FMT, even though most new data indicate it’s not currently an option for several indications. There’s still much for us to learn about its potential.
I’m Dr David Johnson. Thanks for listening.
David A. Johnson, MD, a regular contributor to Medscape, is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia, and a past president of the American College of Gastroenterology. His primary focus is the clinical practice of gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with principal research interests in esophageal and colon disease, and more recently in sleep and microbiome effects on gastrointestinal health and disease.
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
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