Abstract
Abstract Fecal microbiota transplantation (FMT) is an effective therapy for treating recurrent C. difficile infection. However, the FMT mechanism of action is poorly understood, and the implementation of FMT therapy is limited. A previous study from our lab identified a critical role of CD4+ FoxP3+ regulatory T cells (Treg) in enabling FMT engraftment and subsequent resolution of C. difficile infection. Here, we investigated the cellular and cytokine network regulated by Treg cells to support FMT-mediated resolution of C. difficile infection. On the day of FMT, C. difficile infected mice have increased IL10+ Treg cells in the colon compared to uninfected mice. Further, mice depleted of IL10 and its signaling pathway are defective in resolving C. difficile following FMT, mirroring our observation in Treg-depleted FoxP3-DTR mice. The depletion of Treg cells in C. difficile-infected FoxP3-DTR mice induces a robust type 1 immune response in the colon characterized by IFNγ producing Th1 and type 1 innate lymphoid cells. This immune response drives an increased infiltration of iNOS+ neutrophils into the large intestine. Furthermore, neutralization of IFNγ following Tregs depletion decreases iNOS+ neutrophils in the large intestine, enabling the FMT to resolve C. difficile infection. Last, the depletion of neutrophils in Treg-depleted mice restores the efficacy of FMT to resolve C. difficile. Combined, we provide a mechanism by which IL10+ Treg cells serve as a negative regulator of an IFNγ-neutrophil intestinal inflammatory circuit, thereby supporting the colonic environment to be receptive to FMT and resolution of C. difficile. These results provide a mechanistic example of how immunity can dictate the efficacy of microbiome-based therapies. Supported by grants from NIH (R01 AI158830, R21 AI164385)
Published Version
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