Fecal transplants: Study is a 'wake-up call' for the field as researchers identify unintended consequences. (Jun 2025, mice) Microbiome mismatches from microbiota transplants lead to persistent off-target metabolic and immunomodulatory effects FMT

[Michael Harrop]

• https://www.dw.com/en/fecal-transplants-study-is-a-wake-up-call-for-the-field/a-72817699
• https://www.the-independent.com/news/health/fecal-transplants-consequences-research-us-b2765279.html
• https://www.genengnews.com/topics/translational-medicine/fmt-may-have-long-lasting-unintended-health-consequences-in-recipients-study-findings-suggest/
• https://medicalxpress.com/news/2025-06-fecal-transplants-treatment-potential-health.html

For their reported study, one group of animals was given a transplant of microbes taken from the jejunum, which is the first portion of the small intestine. A second group was given a standard FMT, and a third group was given a transplant from the cecum, a section connecting the small and large intestine.

Their findings showed that microbes from each of these transplants successfully colonized the entirety of the intestinal tract in the mice, not just their native niches. This created regional gut mismatches persisting up to three months after just one transplant.

The altered microbiomes also changed the production of metabolites in each intestinal region

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Very interesting study.

Researchers warn against widespread use of the transplants due to potential for long-lasting, unintended health consequences

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Since stools contain primarily anaerobic microbes from the colon, FMT can cause mismatches in the gut ecosystem when those bacteria colonize the small intestine and other parts of the digestive system

The authors suggest that the suitability of FMT as an intervention to restore regional gut microbiota, particularly in the small bowel (SB), “… must be questioned because of its predominant anaerobic composition.”

The study’s lead author, Orlando DeLeon at the University of Chicago, said it was a "wake-up call to the field that maybe we shouldn't willy-nilly put large bowel microbes into different parts of the intestine that shouldn't be there."

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There's a large body of evidence concluding that top-down FMT is not more dangerous than lower-route-only https://humanmicrobiome.info/fmt/. So that statement seems misleading at best.

"A more appropriate conclusion would be that FMT induces changes in both the small and large intestines in mice, with systemic effects that vary depending on the region affected. It remains unclear if these changes persist in humans."

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Highlights​

• Microbes alter regional intestinal environments to enhance fitness and engraftment
• Mismatches alter metabolic and immune states of host tissues and regional microbiomes
• Engraftment of FMT (anaerobic) microbes in the small bowel is persistent
• Regionally matched microbiota in the small and large bowel restore homeostasis

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Summary​

Fecal microbiota transplant (FMT) is an increasingly used intervention, but its suitability to restore regional gut microbiota, particularly in the small bowel (SB), must be questioned because of its predominant anaerobic composition. In human subjects receiving FMT by upper endoscopy, duodenal engraftment of anaerobes was observed after 4 weeks. We hypothesized that peroral FMTs create host-microbe mismatches that impact SB homeostasis.

To test this, antibiotic-treated specific-pathogen-free (SPF) mice were given jejunal, cecal, or fecal microbiota transplants (JMTs, CMTs, or FMTs, respectively) and studied 1 or 3 months later. JMT and FMT altered regional microbiota membership and function, energy balance, and intestinal and hepatic transcriptomes; JMT favored host metabolic pathways and FMT favored immune pathways. MTs drove regional intestinal identity (Gata4, Gata6, and Satb2) and downstream differentiation markers. RNA sequencing (RNA-seq) of metabolite-exposed human enteroids and duodenal biopsies post-FMT confirmed transcriptional changes in mice.

Thus, regional microbial mismatches after FMTs can lead to unintended consequences and require rethinking of microbiome-based interventions.

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[SFBayFMT5]

Recently posted by someone in another FMT group.

https://www.cell.com/cell/abstract/S0092-8674(25)00564-1


"Fecal microbiota transplant (FMT) is an increasingly used intervention, but its suitability to restore regional gut microbiota, particularly in the small bowel (SB), must be questioned because of its predominant anaerobic composition."

The first time I've seen someone raise this point...

Clearly from some of our experiences FMT can work for non-colon diseases, but many of us have had trouble repeating our successes and I suspect this could be a big part of why. So alongside FMT, alternative ways of transferring microbiota that don't use stool as a source (or change its composition through processing) need to be looked into.

Good to see that you saw this too--for some reason it wasn't showing up before when I was looking at the latest posts in the studies forum to see if someone else already posted it.

What I take away from this is NOT that upper route is more dangerous than lower route, but rather than quite possibly stool isn't the optimal source at all for healthy small intestinal microbes, no matter HOW it is administered. I was starting to suspect that myself, but it was reassuring to see that someone else had actually done some research that was pointing in the same direction.

That paper I posted earlier this year from an Australian group began to suggest that possibly even the mucosa in the healthy colon isn't as anaerobe-dominated as it was thought to be, and that some of its constituents are not well-represented in stool, and I had speculated in response that this mismatch was likely even greater vs. the small intestine--but here's a study that actually looked directly into that.

So looking into other ways of getting more small intestine-typical microbes is important, as well as possibly shifting the composition of stool-derived microbiota by means of processing. I am curious if part of the reason my OpenBiome FMT worked so much better than anything since was that I was pre-treated with vancomycin, and that some traces of this still in my gut on the day of the transplant (I was off it for < 48 hours) knocked back some of the excess colonic anaerobes from the transplant.