CD4+ T cells modulates efficacy of microbiome transplantation in treatment of Clostridiodes difficile infection

Abstract

Abstract Clostridiodes difficile is an opportunistic pathogen that infects the large intestine following perturbation of the intestinal microbiome causing epithelial damage and debilitating, potentially fatal, colitis. Fecal microbiome transplantation (FMT) is a clinically proven therapy to treat recurrent C. difficile infection. Despite remarkable efficacy, implementation of FMT therapy is limited and the mechanism of action remains poorly understood. Here, we demonstrate a critical role for CD4+ T cells in supporting FMT success using a murine C. difficile infection system. Following FMT, chronically infected wild-type mice resolve C. difficile while cohoused, littermate Rag1−/− mice fail to clear the infection. FMT in C. difficile infected mice that lack B cells, CD8+ T cells or CD4+ T cells reveals a necessary role for CD4+ T cells, but not B cells or CD8+ T cells, in resolution of C. difficile following FMT. Analysis of intestinal bacterial communities demonstrate the microbiota of FMT-responsive mice assimilates toward the composition of the FMT donor, while the non-responsive Rag1−/− and CD4+ T cell deficient mice exhibit impaired FMT engraftment. Further, FMT does not restore secondary bile acid pools in the cecum of non-responsive mice, an important metabolite associated with FMT efficacy. Combined, these data support a role for host immunity in determining efficacy of microbiota-based therapeutics.