Small intestinal resident eosinophils maintain gut homeostasis following microbial colonization

The intestine harbors a large population of resident eosinophils, yet the function of intestinal eosinophils has not been explored. Flow cytometry and whole-mount imaging identified eosinophils residing in the lamina propria along the length of the intestine prior to postnatal microbial colonization. Microscopy, transcriptomic analysis, and mass spectrometry of intestinal tissue revealed villus blunting, altered extracellular matrix, decreased epithelial cell turnover, increased gastrointestinal motility, and decreased lipid absorption in eosinophil-deficient mice. Mechanistically, intestinal epithelial cells released IL-33 in a microbiota-dependent manner, which led to eosinophil activation. The colonization of germ-free mice demonstrated that eosinophil activation in response to microbes regulated villous size alterations, macrophage maturation, epithelial barrier integrity, and intestinal transit. Collectively, our findings demonstrate a critical role for eosinophils in facilitating the mutualistic interactions between the host and microbiota and provide a rationale for the functional significance of their early life recruitment in the small intestine. [Display omitted] •Colonization of GF mice activates small intestinal eosinophils•Whole-mount microscopy of SI reveals villus blunting in the absence of eosinophils•Loss of eosinophils leads to reduced numbers of mature intestinal macrophages•Transfer of bone-marrow-derived eosinophils rescues the loss of intestinal homeostasis Eosinophils are resident cells found in high numbers in the small intestine. Ignacio et al. reveal that in response to microbial colonization, eosinophils sense the IL-33 released by epithelial cells to maintain the integrity of the intestinal villi, epithelial cell turnover, intestinal barrier function, and recruitment of mature macrophages to maintain homeostasis.