Investigating Immune-Microbiome interactions during treatment of Clostridioides difficile with fecal microbiome transplantation

Project Summary
Hospitalized patients receiving antibiotic treatment experience a disruption in the intestinal microbiome
enabling opportunistic pathogens, such as Clostridioides difficile to colonize the intestinal tract. Complications
resulting from C. difficile associated disease are a major burden on the health care system costing an
estimated one billion dollars and resulting in 12,000-20,000 deaths per year (11, 13). Current antibiotic
treatment options have a high recurrence rate highlighting the need to develop alternative treatment strategies.
Fecal microbiome transplantation (FMT) has proven to be a remarkable effective strategy for treatment of
recurrent C. difficile infection (21). However, the host and microbial factors that contribute to FMT success
remain poorly defined. The murine model of C. difficile infection offers insights into the mechanism of action of
FMT. Data presented in this proposal demonstrates an important role for the host’s immune system,
specifically CD4+ T-regulatory (TReg) cells, in supporting FMT efficacy. In aim 1 of this proposal we will
investigate the immunoregulatory mechanisms through which TReg cells shape the intestinal environment to
promote FMT engraftment and C. difficile resolution. Conversely, aim 2, will assess the innate immune
inflammatory mediators that shape the intestinal environment to inhibit FMT engraftment and C. difficile
resolution. In parallel to murine studies, we will conduct longitudinal profiling of human immune cell populations
in severe C. difficile infected patients before and after FMT. These aims will identify immune mechanisms that
support successful FMT therapy in C. difficile infection and potentially identify novel therapeutic targets in
treating C. difficile associated disease.
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Grant Number: 5R01AI158830-05
NIH Institute/Center: NIH
Principal Investigator: Michael Abt