Therapeutic immune modulation restores host responsiveness to microbiota transplantation for treatment of C. difficile infection.

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B189
Abstract ID: 6065

Presenting Author:
Michael Abt , Assistant Professor at Univ. of Pennsylvania Perelman Sch. of Med.

Abstract:

Microbiota-based therapeutics to treat enteric bacterial infections requires stable engraftment of transplanted beneficial bacteria that will target and eliminate the pathogen. Successful engraftment is dependent on the recipient’s immune status at the time of transplantation. Here we demonstrate that IL-10 signaling deficiency leads to impaired engraftment following fecal microbiota transplantation (FMT) and failure to resolve Clostridioides difficile infection in mice. In the absence of IL-10 mediated immunoregulation provided by Foxp3⁺ T_reg cells, elevated IFN-γ signaling in the intestine leads to recruitment and activation of reactive oxygen/nitrogen producing neutrophils. Host responsiveness to FMT can be restored by antibody-mediated blockade of IFN-γ signaling or depletion of neutrophils. Combined, these data support a mechanism by which IL-10 released by T_reg cells limits intestinal inflammation driven by IFN-γ activated neutrophils thereby promoting an intestinal microenvironment receptive to FMT engraftment. These data demonstrate that the host’s immune status can be therapeutically manipulated to support microbiota-based approaches to treat infection.