Colonic enterochromaffin cells modulate a neuronal-immune-epithelial cell axis for antimicrobial homeostasis

The intestinal mucosa functions alongside trillions of commensal microbes, with immune and epithelial responses contributing to microbiota homeostasis. Both immune and nerve cells are implicated in this microbial balance, but the regulatory functions of epithelial enteroendocrine cells (EEC) are not understood well. Here we show that EEC depletion in mouse colons via Satb2-mediated Neurog3 deficiency enhances goblet cell expression of prominent antimicrobial peptides, with stronger effects in female than in male mice. Mechanistically, serotonin (5-hydroxytryptamine; 5-HT) derived from enterochromaffin (EC) cells, an EEC-subtype, acts on sensory neurons to suppress the mucosal levels of calcitonin gene-related peptide (CGRP) under physiological conditions. In the absence of local serotonin, elevated CGRP levels promote mast cell infiltration and interleukin-13 (IL-13) secretion in EEC-depleted mice and enhance antimicrobial gene expression in goblet cells. Our findings thus delineate an epithelial–neuronal–immune axis, wherein EC cells fine-tune goblet cell antimicrobial output to preserve gut microbial equilibrium. In the gut, epithelial, neuronal, and immune cells collaborate to maintain microbiota homeostasis, but molecular insights are still lacking. Here the authors deplete epithelial enteroendocrine cells in mouse colons via Satb2-mediated Neurog3 deficiency to uncover a serotonin/CGRP/IL-13 axis of antimicrobial peptide regulation that is validated in organoid cultures.