Faecalibaculum rodentium remodels retinoic acid signaling to govern eosinophil-dependent intestinal epithelial homeostasis.

The intestinal epithelium plays critical roles in sensing and integrating dietary and microbial signals. How microbiota and intestinal epithelial cell (IEC) interactions regulate host physiology in the proximal small intestine, particularly the duodenum, is unclear. Using single-cell RNA sequencing of duodenal IECs under germ-free (GF) and different conventional microbiota compositions, we show that specific microbiota members alter epithelial homeostasis by increasing epithelial turnover rate, crypt proliferation, and major histocompatibility complex class II (MHCII) expression. Microbiome profiling identified Faecalibaculum rodentium as a key species involved in this regulation. F. rodentium decreases enterocyte expression of retinoic-acid-producing enzymes Adh1, Aldh1a1, and Rdh7, reducing retinoic acid signaling required to maintain certain intestinal eosinophil populations. Eosinophils suppress intraepithelial-lymphocyte-mediated production of interferon-γ that regulates epithelial cell function. Thus, we identify a retinoic acid-eosinophil-interferon-γ-dependent circuit by which the microbiota modulates duodenal epithelial homeostasis.