Fecal microbiota transplant: Study suggests it could have unforeseen effects on other areas of the digestive system

An international study has warned of the potential risks of widespread use of fecal microbiota transplantation without considering the region of the gut the transferred microbes reach. The experiment, conducted on mice and human tissue samples, showed that the transplanted microbes—mostly anaerobic colonic microbes—colonized the small intestine, persisted there for months, and modified this new environment, causing changes in the host's metabolism.

According to research from the University of Chicago, whose study is published in the journal Cell , this can have long-lasting and unforeseen consequences, as well as imbalances in the patients' intestinal ecosystem. "I think it's kind of a wake-up call to the community that maybe we shouldn't be randomly putting microbes from the large intestine into different parts of the gut that shouldn't be there," said Orlando DeLeon, a postdoctoral researcher and lead author of the paper, in a statement.

Fecal microbiota transplants have been touted as a potential treatment for a variety of conditions, from inflammatory bowel disease, obesity, and type 2 diabetes to autism . This process involves transferring microbes from the feces of a healthy person to a sick person, in the hopes of restoring a healthy balance to the gut microbiome.

Because feces primarily contain anaerobic colonic microbes (i.e., they cannot tolerate oxygen), this type of transplant can cause disruptions in the gut ecosystem when those bacteria colonize the small intestine and other parts of the digestive tract. "If we're designing good therapies, we need to be mindful of the importance of adapting the regional microbiota to their appropriate environments so that we provide better overall health benefits," DeLeon cautions.

The scientific community is not entirely in agreement about the risks, although it is clear that answers are lacking. Since the implementation of the new European regulation that stipulates that microbiota is a substance of human origin (SOHO), " the mechanisms for verifying the biological safety of donations and the monitoring of microbiota transplant recipients are perfectly regulated ," Climent Casals-Pascual, head of the Microbiology Department at the Hospital Clínic de Barcelona, ​​associate professor at the University of Barcelona, ​​and researcher at ISGlobal Barcelona, ​​explains to SMC.

In this case, Casals-Pascual is referring to the use of Clostridium difficile , an opportunistic bacteria that often causes severe gastrointestinal symptoms and inflammation in hospitalized patients who have received antibiotics. Seeing the success in treating patients with this bacteria, many physicians have expressed interest in using fecal microbiota transplantation to treat other digestive conditions.

Researchers understand that the health of the gut microbiome can affect every vital organ and system in the body, so the idea is that replacing a "sick" gut microbiome with a "healthy" one could solve the problem in one fell swoop.

How did they find out the risks of fecal transplant?

In experiments with mice and studies with human tissue samples, the researchers behind the new study observed that anaerobic colonic microbes not only colonized the small intestine after a single transplant, but also persisted there for months. These microbes also changed their new intestinal environments to their advantage, "transforming" them in ways that led to changes in the recipient's metabolism, behavior, and energy balance.

Because the gut is not simply a consistent environment with the same microbiota throughout, as researchers point out, but rather has several distinct regions that are very different ecosystems, each adapted to specific pathogens that can provide vital functions for the health of their host.

"There are microbes all along the intestinal tract, and we predominantly only study the last third of it (the colon)," explains DeLeon, who poses the question that underpins his work: "How can you expect an FMT, with microbes from one-third of the intestinal tract to the end, to fix the rest of the gut?"

To test the effects of fecal microbiota transplants on different parts of the gut, DeLeon and Eugene B. Chang, the Martin Boyer Professor of Medicine at the University of Chicago and senior author on the study, and colleagues conducted a series of experiments in mice . One group received a transplant of microbes taken from the jejunum, the first section of the small intestine. A second group received a standard transplant, and a third was assigned a transplant from the cecum, a section connecting the small and large intestines, which has a mix of microbes from both.

Recipients of fecal microbiota transplants are typically first treated with antibiotics to eliminate microbes living in the gut, leaving a clean slate for the newly transplanted microbes to settle, albeit sometimes in the wrong places. Tests showed that the microbes from each of these transplants successfully colonized the mice's entire intestinal tract , not just their native niches. This created regional gut imbalances that persisted for up to three months after a single transplant.

The altered microbiomes also modified metabolite production in each gut region, which can impact host health. The researchers observed changes in liver metabolism, including the activity of genes associated with immune function . They also observed differences in the mice's feeding behavior, activity, and energy expenditure after the transplants.

The most surprising finding was that having the wrong microbes in the wrong place reshaped the tissue's identity to make it more suitable for them. DeLeon observed that the mismatches modified the expression of genes and proteins in the gut lining in ways that more closely resembled the expression levels of the microbes' original or native gut regions. "It's as if they modified their environment to adapt to it ," DeLeon says.

So fecal microbiota transplant: yes or no? When and how?

Toni Gabaldón, ICREA research professor and head of the Comparative Genomics group at the Institute for Research in Biomedicine (IRB Barcelona) and the Barcelona Supercomputing Centre (BSC-CNS), as reported by SMC, points out the limitations of the work, especially "in the part corresponding to human data where the number of patients analyzed is very small (seven). The analyses in mouse models, on the other hand, are very comprehensive and use appropriate techniques."

On the other hand, Gabaldón points out that this work "opens our eyes to how little we still know about the impact of fecal transplants and proposes exploring combined transplants from various sources (omnimicrobial). In general, more clinical and basic research is needed to understand the true therapeutic potential and possible side effects of a fecal transplant."

Clàudia Aràjol, a specialist physician at the Digestive System Service and the Inflammatory Bowel Disease Unit at Bellvitge University Hospital, in her comments to SMC, points out that "this work highlights the need to continue to delve deeper into research on the effects of microbiota transplantation in particular, with regard to its impact on the small intestine and its applicability in other clinical contexts."