Host origin of microbiota drives functional recovery and Clostridioides difficile clearance in mice (Jun 2025) "human-derived microbiota was less effective in clearing C. difficile compared to a mouse-derived microbiota" FMT

[Michael Harrop]

https://journals.asm.org/doi/10.1128/mbio.01108-25

ABSTRACT​

Colonization resistance provided by the gut microbiota is essential for resisting both initial Clostridioides difficile infection (CDI) and potential recurrent infection (rCDI). Although fecal microbiota transplantation (FMT) has been successful in treating rCDI by restoring microbial composition and function, mechanisms underlying the efficacy of standardized stool-derived products remain poorly understood.

Using a combination of 16S rRNA gene-based and metagenomic sequencing alongside metabolomics, we investigated microbiome recovery following FMT from human and murine donor sources in a mouse model of rCDI. We found that a human-derived microbiota was less effective in clearing C. difficile compared to a mouse-derived microbiota, despite recovery of taxonomic diversity, compositional changes, and bacterial functions typically associated with clearance. Metabolomic analysis revealed deficits in secondary metabolites compared to those that received murine FMT, suggesting a functional remodeling between human microbes in their new host environment.

Collectively, our data revealed additional environmental, ecological, or host factors to consider in FMT-based recovery from rCDI.

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IMPORTANCE​

Clostridioides difficile is a significant healthcare-associated pathogen, with recurrent infections presenting a major treatment challenge due to further disruption of the microbiota after antibiotic administration. Despite the success of fecal microbiota transplantation (FMT) for the treatment of recurrent infection, the mechanisms mediating its efficacy remain underexplored. This study reveals that the effectiveness of FMT may be compromised by a mismatch between donor microbes and the recipient environment, leading to deficits in key microbial metabolites. These findings highlight additional factors to consider when assessing the efficacy of microbial-based therapeutics for C. difficile infection (CDI) and other conditions.

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[Michael Harrop]

Discussion with the researchers:

Why Fecal Transplants Sometimes Fail: Function, Not Just Colonization, May Hold the Key https://www.contagionlive.com/view/why-fecal-transplants-sometimes-fail-function-not-just-colonization-may-hold-the-key

Clemson University researchers Anna Seekatz, PhD, and PhD candidate Sophie Millard uncover how functional mismatches between donor microbes and recipient gut environments could limit the success of microbiome-based therapies

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.

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