Host immunity modulates the efficacy of microbiota transplantation for treatment of Clostridioides difficile infection

Eric R. Littmann, Jung-Jin Lee, Joshua E. Denny, Zahidul Alam, Jeffrey R. Maslanka, Isma Zarin, Rina Matsuda, Rebecca A. Carter, Bože Susac, Miriam S. Saffern, Bryton Fett, Lisa M. Mattei, Kyle Bittinger and Michael C. Abt ()
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Eric R. Littmann: University of Chicago
Jung-Jin Lee: Children’s Hospital of Philadelphia
Joshua E. Denny: University of Pennsylvania
Zahidul Alam: University of Pennsylvania
Jeffrey R. Maslanka: University of Pennsylvania
Isma Zarin: University of Pennsylvania
Rina Matsuda: University of Pennsylvania School of Veterinary Medicine
Rebecca A. Carter: Sloan-Kettering Institute, Memorial Sloan Kettering Cancer Center
Bože Susac: Sloan-Kettering Institute, Memorial Sloan Kettering Cancer Center
Miriam S. Saffern: Sloan-Kettering Institute, Memorial Sloan Kettering Cancer Center
Bryton Fett: Children’s Hospital of Philadelphia
Lisa M. Mattei: Children’s Hospital of Philadelphia
Kyle Bittinger: Children’s Hospital of Philadelphia
Michael C. Abt: University of Pennsylvania

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Fecal microbiota transplantation (FMT) is a successful therapeutic strategy for treating recurrent Clostridioides 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 the immune system in supporting FMT using a murine C. difficile infection system. Following FMT, Rag1 heterozygote mice resolve C. difficile while littermate Rag1−/− mice fail to clear the infection. Targeted ablation of adaptive immune cell subsets reveal a necessary role for CD4+ Foxp3+ T-regulatory cells, but not B cells or CD8+ T cells, in FMT-mediated resolution of C. difficile infection. FMT non-responsive mice exhibit exacerbated inflammation, impaired engraftment of the FMT bacterial community and failed restoration of commensal bacteria-derived secondary bile acid metabolites in the large intestine. These data demonstrate that the host’s inflammatory immune status can limit the efficacy of microbiota-based therapeutics to treat C. difficile infection.

Date: 2021
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DOI: 10.1038/s41467-020-20793-x

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