Microbiota encoded fatty-acid metabolism expands tuft cells to protect tissues homeostasis during Clostridioides difficile infection in the large intestine.

The microbial metabolite succinate is a driver of tuft cell (TC) hyperplasia-dependent protection against parasites in the small intestine. The role of microbes and their metabolites in modulating TC dynamics in the large intestine and the relevance of this pathway to infection pathophysiology is unknown. Here, we uncover that microbiome-driven colonic TC hyperplasia plays a key protective role in resisting 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 transplants and administration of consortia of succinate-producing bacteria. Succinate-deficient microbes administration shows a reduced response in a Pou2f3-dependent manner despite similar intestinal engraftment. Finally, antibiotic-pretreated mice prophylactically administered with succinate-producing bacteria show better protection against C. difficile-induced morbidity and mortality compared to controls. This effect is nullified in TC-deficient Pou2f3-/- knockout mice confirming that the observed protection occurs via the TC pathway. We propose that activation of TCs by the microbiota-produced succinate in the colon is a mechanism evolved by the host to counterbalance microbiome-derived cues that facilitate invasion by intestinal pathogens.