The role of microbes and their metabolites in modulating tuft cell (TC) dynamics in the large intestine and the relevance of this pathway to infections is unknown. Here, we uncover that microbiome-driven colonic TC hyperplasia protects against Clostridioides difficile infection. Using selective antibiotics, we demonstrate increased type 2 cytokines and TC hyperplasia in the colon but not in the ileum. We demonstrate the causal role of the microbiome in modulating this phenotype using fecal matter transplantation and administration of consortia of succinate-producing bacteria. Administration of succinate production–deficient microbes shows a reduced response in a Pou2f3-dependent manner despite similar intestinal colonization. Finally, antibiotic-treated mice prophylactically administered with succinate-producing bacteria show increased protection against C. difficile–induced morbidity and mortality. This effect is nullified in Pou2f3−/− mice, confirming that the protection occurs via the TC pathway. We propose that activation of TCs by the microbiota in the colon is a mechanism evolved by the host to counterbalance microbiome-derived cues that facilitate invasion by pathogens.
Succinate-producing microbiota drives tuft cell hyperplasia to protect against Clostridioides difficile
A. Reboldi and V. Bucci are co-corresponding authors. Co-authorship and author order were determined by the recognition that the integration of the nuances of microbiome data, mathematical modeling, and immunology are different skill sets found in different laboratory environments. Each was an important component of the validity and message of this manuscript.
Disclosures: T.D. Kellogg reported a patent to US 63/626,305 pending “Microbiome engineering to induce colonic Tuft Cell expansions protects from C. difficile-induced colitis.” A. Reboldi reported a patent to US 63/626,305 pending “Microbiome engineering to induce colonic Tuft Cell expansions protects from C. difficile-induced colitis.” V. Bucci reported grants from Vedanta Biosciences Inc. and personal fees from Vedanta Biosciences Inc. outside the submitted work; in addition, V. Bucci reported a patent to US 63/626,305 pending “Microbiome engineering to induce colonic Tuft Cell expansions protects from C. difficile-induced colitis.” No other disclosures were reported.
S.E. Foley’s current affiliation is Transformational and Translational Immunology Discovery Department, AbbVie, Cambridge, MA, USA.
- Award Id(s): PRMP W81XWH2020013
- Award Id(s): U01AI172987,R01 AG075283,T32 AI007349-31,R01 AI15572
Tasia D. Kellogg, Simona Ceglia, Benedikt M. Mortzfeld, Tanvi M. Tanna, Abigail L. Zeamer, Matthew R. Mancini, Sage E. Foley, Doyle V. Ward, Shakti K. Bhattarai, Beth A. McCormick, Andrea Reboldi, Vanni Bucci; Succinate-producing microbiota drives tuft cell hyperplasia to protect against Clostridioides difficile. J Exp Med 6 January 2025; 222 (1): e20232055. doi: https://doi.org/10.1084/jem.20232055
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