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

Click to shrink...

Very interesting study.

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

Click to shrink...

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."

Click to shrink...

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."

Click to shrink...

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

Click to shrink...

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.

Click to shrink...

 

[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.

 

[indigo34]

Too bad it's not open access. Results seem way overstated.

• They didn't use normal mice but antibiotic-treated mice. That likely dramatically affected their results and therefore makes them less translatable to situations where FMTs are given without antibiotic pre-treatment.
• Interesting they didn't mention the effects of the cecal transplants in the abstract. Maybe they did not support their conclusion.
• Due to mice eating poop all the time it was initially surprising to me that colon-derived FMT had a persistent negative effect on the mouse small intestine. This makes more sense considering the mice were given a strong antibiotic cocktail right before.
• The authors note engraftment of some anaerobes in the duodenum in humans following FMT as the impetus for this study but some anaerobes are normally in the mouth and small intestine so it's unclear why that in and of itself is seen as pathological. It would make more sense if those patients developed some concerning symptoms or medical conditions associated with the engraftment. I did some brief searching for the study in question and couldn't find it.

I found this quote from the study's author a bit surprising.

“There are microbes along the entire intestinal tract, and we just study predominately the last third of it (the colon),” DeLeon said. “So, how can you expect an FMT, with microbes from a third of the intestinal tract at the end of it, to fix the rest of the intestine?”

It kind of seems like he's a complete idiot? Obviously there are orders of magnitude more bacteria in the colon than other areas of the body. I've heard it hypothesized the colon acts as a reservoir of bacteria for the whole body. It's also a huge part of the immune system, over half, with signalling to the brain, other organs, and throughout the intestines. You would think someone researching the microbiome would know this and could put two and two together. Fix the microbiome in the colon --> proper immune signaling throughout the body --> less inflammation, better circulation, better functioning of organs --> changes in the bacterial composition/ microbiome in other locations of the body.

Although I agree with the author that there are likely benefits to microbial transplants from other locations like the mouth or small intestine. For example, the spouse spit swapping study posted recently showed a negative effect so it's plausible a positive one could occur with healthy people. I think there's enough knowledge and evidence to show FMTs can have massive benefits throughout the body even without that.

 

[Michael Harrop]

I found this quote from the study's author a bit surprising.

It kind of seems like he's a complete idiot?

Click to shrink...

Haha. I was also going to use stronger language at first

I definitely agree they are overstating their results, and the authors seem uninformed about the body of evidence contradicting their statements.

Fix the microbiome in the colon --> proper immune signaling throughout the body --> less inflammation, better circulation, better functioning of organs --> changes in the bacterial composition/ microbiome in other locations of the body.

Click to shrink...

Agree.

Also, my understanding is that there are simply different percentages of microbes in different parts of the intestine, in large part due to transit time and varying amounts of acids and other secretions. So you would expect things to balance out eventually.

 

[SFBayFMT5]

“There are microbes along the entire intestinal tract, and we just study predominately the last third of it (the colon),” DeLeon said.

I've been saying this for years as well! That almost the entire research on the gut is focused on the large intestine, which in turn means largely on just two groups of bacteria--the Bacteroidetes and the members of the various Clostridium clusters--and misses the rest of the picture entirely. I blame this almost single-handedly for the near-complete standstill this field seems to have been in for decades.

It's understandable that this is where the focus has been given how easy stool tests are to perform (at least since 16S sequencing became a thing)--but it's also really limiting.

Yes, it's obviously possible for transplants using stool to succeed--but it's also possible to walk to the grocery store backwards while doing a handstand. And my experience is that when FMT does work, it's not due to any breakthrough on the researchers' part, just serendipity, and it isn't like there's ever any insight coming out of it about how it actually works, that allows it to be reproduced with reasonable certainty. Researchers handwave about this or that bacterium going up, almost always a colonic anaerobe, but there isn't consistency across the studies, which to me screams that they are fundamentally looking in the wrong place.

I spend a lot of time looking at gut microbiome studies wondering whether to be happy that they are even looking into the gut as a factor in disease at all, or frustrated that they seem to be studying the same kinds of bacteria over and over again and not discovering anything new.

Although I agree with the author that there are likely benefits to microbial transplants from other locations like the mouth or small intestine. For example, the spouse spit swapping study posted recently showed a negative effect so it's plausible a positive one could occur with healthy people.

Click to shrink...

That's in fact what I'm predominantly looking for right now--I'm almost at the point where I'm not willing to spend more money on FMT until I've tried that. I've had one local donor offer but I'm not sure if he's a very good donor, and I've also had an old school classmate offer. I'll be sure to let people here know if I get good results from oral microbiome samples.

I think there's enough knowledge and evidence to show FMTs can have massive benefits throughout the body even without that.

Click to shrink...

Well they obviously can--but it's also obvious that it's hit or miss, as I've said. How many people have you heard who tried 5+ FMT donors without truly getting cured? And even people who were successful with a certain donor before, who have gone back to use that donor and something changed?

My experiences last year have shown that the majority of FMTs are helpful to some degree yet at the same time lacking/deficient in more or less the same sorts of ways, despite being from two very different sources (HM vs. Gezonde Darmflora), different age and sex, etc. That is, aside from the ones that actually make things worse. Yes, I had a very successful FMT 10 years ago, but getting back there is clearly a bumpy road.