Moving Beyond One-Size-Fits-All: The Future of Microbiome Therapy for C diff and Beyond

In Part 2 of our interview with Clemson University microbiome researchers Anna Seekatz, PhD, and PhD candidate Sophie Millard, we explore the deeper mechanisms behind why fecal microbiota transplantation (FMT) sometimes fails, even when donor microbes appear to successfully colonize the host gut.

Their new study, published in mBio, highlights a critical insight: functional incompatibility between transplanted microbes and the recipient’s gut environment may limit the therapeutic effectiveness of FMT for recurrent Clostridioides difficile infection (rCDI).

“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,” said Millard. “For FMT to work, the microbes have to perform key functions—like producing certain metabolites or interacting properly with the gut environment.”

Using a controlled mouse model, the team compared outcomes of FMT using stool from healthy mice versus healthy human donors. Despite the human microbes successfully engrafting, only the mouse-derived microbes resolved infection. Further molecular analysis showed the human microbes carried genes for beneficial metabolic functions but failed to express them effectively in the new host.

“These microbes can behave very differently when they’re not adapted to the host’s gut,” Seekatz explained. “Traditionally, we’ve thought that transplanting the right microbes was what mattered most. But our mouse model shows that’s not the whole story.”

These findings suggest that successful FMT requires more than colonization, it requires microbial cooperation and environmental compatibility. “We observed that the microbes transplanted from humans were present, and they even had the genes needed to help,” Millard said. “But their actual metabolic output was deficient. That suggests the host environment is influencing their activity.”

The researchers emphasize that a patient’s immune state, existing microbiome, and even prior antibiotic exposure may influence how newly introduced microbes behave.

“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.”

While FMT has been a major advancement for treating rCDI, about 10% of patients still fail to respond, and failure rates increase dramatically—to 40–60%—in more complex conditions like IBD, IBS, or even non-gastrointestinal diseases where microbiome-based therapies are being explored.

“Every person’s gut microbiome is unique,” Millard explained. “So if the recipient’s environment affects how the microbes cooperate, then a one-size-fits-all approach might not work. We may need more tailored microbial communities based on the recipient’s gut.”

“In C. diff patients, especially those with recurrent infections, the gut has often been depleted by antibiotics and may be more ‘ready’ to accept new microbes,” added Seekatz. “But in patients with more complex or inflammatory diseases, there’s often more microbial competition and immune activity, which can interfere with microbial function.”

This line of research points to the need for precision microbiome therapies—approaches that go beyond just reintroducing “good” bacteria, and instead consider how those microbes will behave in the host.

“Sophie’s work shows that engraftment or colonization alone might not predict treatment success,” said Seekatz. “Understanding the mechanisms that control microbial function in a new host is critical to improving microbial therapies across a wider range of conditions.”

Looking ahead, the Clemson team is focused on defining functionally active microbial consortia that are not only compatible with the recipient gut but also capable of performing the necessary biochemical roles to restore health.

“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,” Seekatz concluded.

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/