Why Fecal Transplants Sometimes Fail: Function, Not Just Colonization, May Hold the Key

A recent study from Clemson University, published in mBio, sheds new light on why fecal microbiota transplantation (FMT), a treatment for recurrent Clostridioides difficile infection (rCDI), sometimes fails, despite successful engraftment of donor microbes. The research, led by Anna Seekatz, PhD, and PhD candidate Sophie Millard, highlights a critical issue: functional incompatibility between transplanted microbes and the host’s gut environment may limit therapeutic outcomes.

In an exclusive interview, Millard explained the basis for the research. “From our work, we found that simply getting the microbes from the FMT to colonize the gut isn’t always enough to get C difficile to clear,” she said. “For FMT to work, the microbes have to perform key functions—like producing certain metabolites or interacting properly with the gut environment.”

Using a mouse model of C difficile infection, the team demonstrated that healthy human donor stool failed to resolve infection, even though human microbes successfully colonized the mouse gut. In contrast, stool from healthy mice did clear the infection.

Molecular analyses revealed that while the human microbes carried genes associated with beneficial metabolic functions, such as short-chain fatty acid production and bile acid transformation, those functions weren’t being effectively carried out in the mouse host.

“We observed that the microbes transplanted from humans were present, and they even had the genes needed to help,” Millard noted. “But their actual metabolic output was deficient. That suggests the host environment is influencing their activity.”

Seekatz added further perspective, “Traditionally, we’ve thought that transplanting the right microbes was what mattered most. But our mouse model shows that’s not the whole story,” she said. “These microbes can behave very differently when they’re not adapted to the host’s gut.” Their findings underscore the importance of microbial cooperation, how different microbes interact with each other and with the host, in determining whether FMT will be successful.

“Inside the gut, microbes break down nutrients and produce metabolites that affect both other microbes and host tissues,” said Seekatz. “This network of interactions is essential. If the incoming microbes don’t integrate into that network, they won’t perform the functions needed to fight C diff.”

The researchers emphasized that the recipient’s immune system, nutritional landscape, and existing microbial community all play a role in how well donor microbes function. “Inflammation, immune signaling, and even prior antibiotic exposure can shape microbial behavior,” Seekatz explained. “It’s not just about colonization. It’s about compatibility.”

These insights have important clinical implications. They explain why up to 10% of rCDI patients fail to respond to FMT and why failure rates are even higher, 40% to 60%, when microbiome-based therapies are used to treat more complex conditions like inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS).

“Every person’s microbiome is unique,” said Millard. “That means a standardized treatment might not work for everyone. We need to better understand the recipient’s ecosystem before choosing what microbes to transplant.”

The Clemson team is now working on identifying specific microbial consortia that can both engraft and function effectively in diverse host environments. Their ultimate goal is to help design precision microbiome therapies, customized for both microbial and host factors, to more reliably treat C difficile and other gastrointestinal diseases.

As Seekatz concluded, “This research moves us toward a future where microbiome therapeutics aren’t just about putting the right bacteria in—but also about making sure they work once they’re there.”

Reference

Landrum, C. (2025, June 16). Clemson research could lead to improved treatment for C. diff and other GI illnesses. Clemson University, College of Science. https://news.clemson.edu/clemson-research-could-lead-to-improved-treatment-for-c-diff-and-other-gi-illnesses/