Mismatch in fecal transplants could disrupt gut balance and metabolism

Giorgia Guglielmi

21.07.2025

Region-specific microbial transplants may be safer and more effective than standard fecal microbiota transplants.

What is already known

Fecal microbiota transplant is effective for certain infections, but it may cause unintended side effects such as weight gain. Since this procedure usually introduces bacteria from the large intestine, these may not be well suited for the small intestine and could disrupt its normal functions, leading to changes in weight and metabolism.

What this research adds

Researchers investigated how fecal microbiota transplants affect different regions of the gut, particularly the small and large intestine, in mice and people. They found that microbes from microbiota transplants, which typically inhabit the colon, can colonize the small intestine, causing alterations that change local gene expression, metabolism and tissue identity. These shifts influenced nutrient absorption, energy balance and immune responses, with potential long-term effects such as weight gain. In contrast, transplants using microbes that typically inhabit the small intestine better preserved tissue identity and function.

Conclusions

The findings suggest that region-specific microbial transplants may be safer and more effective than standard fecal microbiota transplants.

Fecal microbiota transplant is effective for certain infections, but it may cause unintended side effects such as weight gain. Now, researchers have found that transplanting microbes that match specific gut regions is more effective and safer than standard fecal microbiota transplants, which use mostly microbes from the colon.

The findings, published in Cell, suggest that future microbiota therapies should consider regional differences in gut communities to avoid off-target effects.

Since fecal microbiota transplants usually introduce bacteria from the large intestine, these may not be well suited for the small intestine and could disrupt its normal functions, leading to changes in weight and metabolism. This raises concerns about using fecal microbiota transplants broadly without considering the unique needs of each gut region, the researchers say.

The team, led by Orlando DeLeon at the University of Chicago in Illinois, studied mice and people who received fecal microbiota transplants to see how gut bacteria changed, especially in the small intestine.

Changing communities

After mice received a traditional fecal microbiota transplant, there was an increase of anaerobic bacteria in the small intestine, a region that typically hosts mostly bacteria that need oxygen to survive. Similar effects were seen in human gut tissue samples grown in the lab and in patients after fecal transplants, which caused microbes in the small intestine to become more like those in the colon over time.

The team also tested other types of microbiota transplants in mice, giving them bacteria from either the small intestine, large intestine, or a mix of those after removing the animals’ gut bacteria with antibiotics.

Transplanted bacteria could successfully settle in different parts of the gut, causing shifts in the local bacterial communities. They also changed the types and amounts of metabolites, including bile acids, sugars and amino acids, in the gut and blood. These changes lasted for months, the researchers found.

Microbial-based treatments

Next, the team transplanted microbes from either the small or large intestine in germ-free mice. Each type of microbes colonized different gut regions and had effects on bacterial communities and metabolites.

For example, transplants of small intestine microbiota boosted genes related to metabolism and fat processing, while transplants of large intestine microbiota triggered immune-related genes. Mice that received small intestine microbiota gained more weight and had lower energy use, and those that received large intestine microbiota had higher energy use but ate less.

The findings indicate that transplanting microbes from different gut regions leads to different effects on metabolism, the authors say. “These data strongly support the need for more objective measures to assess short- and long-term consequences of [fecal microbiota transplants] and will likely inform future microbiome-based interventions.”