Dietary fiber is a critical determinant of pathologic ILC2 responses and intestinal inflammation

Innate lymphoid cells (ILCs) can promote host defense, chronic inflammation or tissue protection and are regulated by cytokines and neuropeptides. However, their regulation by diet and microbiota-derived signals remains unclear. We show that an inulin fiber diet promotes Tph1-expressing inflammatory ILC2s (ILC2INFLAM) in the colon which produce IL-5 but not tissue-protective amphiregulin (AREG), resulting in accumulation of eosinophils. This exacerbates inflammation in a murine model of intestinal damage and inflammation in an ILC2- and eosinophil-dependent manner. Mechanistically, inulin fiber diet elevated microbiota-derived bile acids, including cholic acid (CA) that induced expression of ILC2-activating IL-33. In IBD patients, bile acids, their receptor farnesoid X receptor (FXR), IL-33, and eosinophils were all upregulated compared to controls, suggesting relevance of this diet-ILC2 axis in human IBD pathogenesis. Together, these data reveal that dietary fiber-induced changes in microbial metabolites operate as a rheostat that governs protective versus pathologic ILC2 responses with relevance to precision nutrition for inflammatory diseases. Overall design: Single cells suspensions generated from colon biopsies from a non-IBD healthy control and a pan-colitic IBD patient were used for scRNA-seq.