Microbiota-Epithelial-Eosinophil Interactions in the Gut

Abstract

The gut is a critical interface between the host and its environment that requires a fine balance between nutrient absorption and barrier integrity in the face of exogenous dietary and microbial components. The intestinal epithelium, supported by interactions with intestinal immune cells, plays a central role in maintaining this equilibrium. Given their proximity to the gut lumen, the many specialized cell types of the epithelium sense and integrate external environmental signals. In this dissertation, I explore mechanisms by which intestinal epithelial cells (IECs) sense microbial components and relay signals to immune cells to regulate gut physiology. Compared to the colon, microbiota-epithelial cell interactions in the small intestine are less well characterized. Using single-cell RNA sequencing of duodenal IECs under germ-free and different conventional microbiota compositions, we show that specific microbiota members alter epithelial homeostasis by increasing epithelial turnover rate, proliferation, and major histocompatibility complex class II expression. Microbiome profiling identified Faecalibaculum rodentium as a species that regulates these processes by decreasing retinoic acid-producing enzymes in enterocytes. Retinoic acid is required for the presence of certain intestinal eosinophil populations, which suppress interferon-γ production by intraepithelial lymphocytes that regulates epithelial cell function. Another context in which IECs receiving microbial inputs influence gut immune cells is tuft cells in the ileum, which activate a type 2 immune response to commensal protozoa via an interleukin-25, type 2 innate lymphoid cell, and interleukin-13-dependent pathway. We found that TAS1R3, a taste receptor expressed on intestinal tuft cells, is required for the induction of tuft cells in response to the protozoa Tritrichomonas muris and succinate. This requirement may be due to a severe reduction in tuft cells in the distal small intestine at homeostasis in Tas1r3-/- mice. Overall, this thesis elucidates two mechanisms by which IECs tune gut immune responses to microbial inputs in order to maintain gut homeostasis.