New study warns

New study warns

Fecal microbiota transplants (FMT) have been touted as a potential treatment for a variety of conditions, from inflammatory bowel disease, obesity and type 2 diabetes to autism. However, new research from the University of Chicago warns against the widespread use of FMT due to boring, unintended health consequences for recipients.

FMT involves transferring microbes in the stool from a healthy person to a sick person in the hopes of restoring a healthy balance in the gut microbiome. Because stools contain primarily anaerobic microbes from the large intestine (i.e., they cannot tolerate oxygen), FMT can cause maladaptations in the intestinal ecosystem when these bacteria colonize the small intestine and other parts of the digestive system.

In experiments with mice and studies with human tissue samples, the researchers who conducted the new study saw that colonic anaerobic microbes not only colonized the small intestine after a single transplant, but also persisted there for months. These microbes also modified their new gut environments to their advantage, “terraforming” them in a way that caused changes in the recipient's metabolism, behavior, and energy balance.

"I think it's a bit of a wake-up call in the field that maybe we don't want to put Nile gut microbes in different parts of the gut that shouldn't be there," said Orlando (Landon) Deleon, PhD, a postdoctoral researcher at Uchicago and senior author of the new study, published in the new study.cell. “When designing good therapeutics, we should be aware of the importance of matching regional microbiota with their right environments so that we provide better health benefits.”

A huge and varied ecosystem

FMT is only approved by the Food and Drug Administration to treat recurrent infectionsClostridium difficile (C. diff)an opportunistic bacterium that often causes severe gastrointestinal symptoms and inflammation in hospitalized patients who have had antibiotics. See the success of the treatmentC. diffPatients, many doctors have been eager to use FMT to treat other digestive diseases. Researchers understand that the health of the gut microbiome can affect all of the body's major organs and systems. The idea, therefore, is that replacing a “sick” gut microbiome with a “healthy” one could solve the problem in one fell swoop.

However, the gut is not just a consistent environment with the same microbiota. Instead, they have several distinct regions that are very different microbial ecosystems, each tailored to specific microbes that can provide functions for the health of their host.

There are microbes along the entire intestinal tract, and we only predominantly examine the last third of it (large intestine). So how can you expect an FMT with microbes from a third of the intestinal tract to end up repairing the rest of the intestine? “

Orlando (Landon) Deleon, PhD, a postdoctoral researcher at Uchicago and lead author of the new study

To test the effects of FMT on different parts of the intestine, Deleon, Eugene B. Chang, MD, Martin Boyer Professor of Medicine at Uchicago and senior author of the study, and their team conducted a series of experiments with mice. One group of mice received a transplant of microbes from the jejunum, the first part of the small intestine. A second group received a standard FMT, and a third group received a transplant from the cecum, a section connecting the small and large intestines that contains a mixture of microbes from both.

Recipients of FMT are usually first treated with antibiotics to eliminate the microbes living in the gut, leaving a clean slate for newly transplanted microbes to take up residence - sometimes in the wrong places. Tests showed that microbes from each of these transplants successfully colonized the entire intestinal tract in the mice, not just the native niches. This created regional intestinal maladaptations that persist for up to three months after just one transplant.

The altered microbiomes also altered the production of metabolites in each intestinal region, which can have health effects on the host. The researchers saw changes in liver metabolism, including activity in genes linked to immune function. They also observed differences in eating behavior, activity and energy expenditure in the mice after transplants.

The most striking finding was that the wrong microbes in the wrong place reshaped the tissue identity to make it more suitable for them. Deleon saw that the mismatch changed gene and protein expression in the gut lining in a way that more closely resembled expression levels from the microbes' native or native gut regions.

“It's like they're engineering or terraforming their environments to fit,” DeLeon said.

An “Omni-Microbial” Approach

Chang said this research highlights the need for more caution in FMT before we fully understand the long-term effects of introducing a range of microbes into a new environment.

“We have absolutely no idea what is in FMT other than it is a combination of microbes,” Chang said. "But even a single FMT results in a change in host-microbe relationships in these very different regions of the gut that may be very difficult to reverse."

Both Deleon and Chang advocate “omni-microbial transplantation,” or OMT, instead. This approach would transfer microbes from all different regions of the gut, not just those that are mostly from the colon. Whether via endoscopy or in pill form, microbes naturally settle in the right places, especially when competing alongside others that normally live in a particular region.

“If there’s an open space, something will fill it,” DeLeon said. “But the microbes that should be there are better suited to it, so they will fill it in even in the presence of other microbes.”

Deleon plans to further study how different microbes exert their influence in different parts of the gut, using different approaches such as single-cell sequencing and metabolomics to track their activity. He is also studying how the intestinal regions that are terraformed by microbiota misadaptations can be restored to their original state, which could help restore normal intestinal function. Such deeper understanding could lead to improvements in the application of microbial transplants and ultimately help them fulfill their significant promise.

The study, “Regional microbiota mismatches from fecal microbiota transplants promote persistent off-target consequences for the host,” was supported by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases and the Uchicago GI Research Foundation.

Additional authors include Mora Mocanu, Candace M. Cham, Alan Tan, Ashley M. Sidebottom, Jason Koval, Hugo D. Ceccato, John J. Colgan, Marissa M. St. George, Joash M. Lake, Michael Cooper, Jingwen Xu and David T. Rubin of Uchicago; Julia Moore and Kristina Martinez-Guryn of Midwestern University; and Zhilu Xu, Siew C. Ng, Francis KL Chan, Hein M. Tun and Qi Su from the Chinese University of Hong Kong.

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