Rethinking Fecal Transplants for Better Gut Health
New research shows transplanting microbes from one section of the gut can cause lasting unintended effects.
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A fecal microbiota transplant (FMT), also known as a stool transplant, is a procedure where healthy bacteria and other microbes from a feces sample are transferred to a patient’s intestines.
FMTs have been touted as a potential treatment for a variety of conditions, including inflammatory bowel disease, obesity, type 2 diabetes and autism.
However, new research, published in Cell, from the University of Chicago cautions against the widespread use of FMTs due to the long-lasting, unintended health consequences for recipients.
Why FMTs scope might need a reset
FMTs aim to restore a balanced gut microbiome. The US Food and Drug Administration currently approves FMT solely for treating recurrent Clostridium difficile (C. diff) infections. This opportunistic bacterium frequently causes severe gastrointestinal symptoms and inflammation in hospitalized patients on antibiotics.
Encouraged by the success of FMT in combating C. diff, many physicians are exploring its potential for other digestive disorders. Since gut microbiome health influences multiple vital organs and bodily systems, the hope is that replacing a “diseased” microbiome with a “healthy” one could provide a comprehensive solution.
However, the gut is not a uniform environment; it consists of several distinct regions, each hosting unique microbial ecosystems tailored to support specific microbes essential for the host’s overall health.
“There are microbes along the entire intestinal tract, and we just study predominately the last third of it (the colon),” said Dr. Orlando (Landon) DeLeon, a postdoctoral researcher at the University of Chicago and lead author of the study. “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?”
When gut microbes go rogue
Patients undergoing FMT are typically pretreated with antibiotics to “strip” existing gut microbes, creating a blank slate for the transplanted microbes to colonize. However, this process can sometimes lead to microbes settling in unintended regions.
To investigate how FMT affects different sections of the intestine, DeLeon and colleagues conducted a series of experiments in mice. Each group received a microbial transplant from a distinct part of the digestive tract: the jejunum (the first segment of the small intestine), the colon (the standard source for FMT) or the cecum (the junction between small and large intestines, containing a mixed microbial population).
The researchers demonstrated that microbes from each transplant colonized the entire intestinal tract, not just their native niches, resulting in regional mismatches that persisted for up to three months after a single transplant. Because fecal samples mainly contain anaerobic microbes from the colon, FMT can introduce these bacteria into the small intestine and other areas where they don’t normally reside, disrupting the natural gut ecosystem.
These altered microbiomes also affected metabolite production in different intestinal regions, influencing the host’s health. The researchers observed changes in liver metabolism, including shifts in gene activity linked to immune function, as well as variations in the mice’s eating behavior, activity levels and energy expenditure post-transplant.
The presence of microbes in the “wrong” locations also reshaped the intestinal tissue itself. DeLeon found that these mismatches altered gene and protein expression in the gut lining, causing it to more closely resemble the microbial community’s original native environment.
“It’s like they’re engineering or terraforming their environments to help them fit in,” DeLeon said.
“I think it's a bit of a wakeup 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,” he continued. “If we're designing good therapeutics, we should be aware of the importance of matching the regional microbiota to their proper environments, so that we provide better overall health benefits.”
An “omni-microbial” approach
The researchers emphasized that the study underscores the importance of exercising greater caution with FMT until we have a clearer understanding of the long-term effects of introducing a new microbial community into the gut.
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“We have absolutely no idea what’s in FMT, except that it’s a combination of microbes,” said Dr. Eugene Chang, the Martin Boyer Professor of Medicine at the University of Chicago and senior author of the study. “But even a single FMT will cause a change in the host-microbe relationships in these very different regions of the bowel that may be very difficult to reverse.”
Both DeLeon and Chang instead advocate for “omni-microbial transplants,” or OMT. This approach involves the transfer of microbes from different regions of the intestine, not just those largely from the colon.
Whether given via an endoscopy or in pill form, microbes naturally settle in the right places, especially when they are competing side by side with others that normally inhabit a certain region.
“If there's an open space, something's going to fill it,” DeLeon said. “But the microbes that were supposed to be there are better suited for it, so they're more naturally going to fill it even in the presence of other microbes.”
The researchers plan to continue investigating how various microbes impact different regions of the intestine, employing techniques such as single-cell sequencing and metabolomics to monitor their activity. DeLeon is also exploring ways to restore gut regions altered by microbial mismatches back to their original state, which may help recover normal gut function. Gaining a deeper understanding of these processes could enhance the effectiveness of microbial transplants, helping them realize their full therapeutic potential.
Reference: DeLeon O, Mocanu M, Tan A, et al. Microbiome mismatches from microbiota transplants lead to persistent off-target metabolic and immunomodulatory effects. Cell. 2025. doi: 10.1016/j.cell.2025.05.014
This article is a rework of a press release issued by the University of Chicago. Material has been edited for length and content.
