Microbiota shape the colon epithelium controlling inter-crypt absorptive goblet cells via butyrate–GP R109A signalling

The colonic epithelium is a key interface between the gut microbiota and the host. How microbiota-derived signals influence epithelial cell identity and function remains incompletely understood. Here, we used single-cell transcriptomics, antibiotic-mediated microbiota depletion, germ-free mice and colonization experiments in mice to uncover cell-type-specific responses to microbiota changes, highlighting changes in the cell composition and functional diversities in enterocytes. Our analysis demonstrates that the microbiota control the absorptive profile of the colon epithelial cells and reveals non-canonical inter-crypt goblet cells as microbiota-responsive constituents that combine absorptive and secretory features and whose abundance is regulated by the gut microbiota. We found that their number is suppressed through the short-chain fatty acid butyrate and its receptor GPR109A. Analysis in mouse and humans indicates that the expansion of this hybrid population increases with age and that this expansion is driven by microbiome changes. Our work reveals a previously unrecognized level of epithelial plasticity driven by microbial triggers and highlights butyrate, acting as a signaling molecule that shapes the colon micro-anatomy.