Author affiliations: aGene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037; bStorr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead NSW 2145, Australia; and cImmunobiology and Microbial Pathogenesis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037

The pleiotropic actions of the Farnesoid X Receptor (FXR) are required for gut health, and reciprocally, reduced intestinal FXR signaling is seen in inflammatory bowel diseases (IBDs). Here, we show that activation of FXR selectively in the intestine is protective in inflammation-driven models of IBD. Prophylactic activation of FXR restored homeostatic levels of pro-inflammatory cytokines, most notably IL17. Importantly, these changes were attributed to FXR regulation of innate lymphoid cells (ILCs), with both the inflammation-driven increases in ILCs, and ILC3s in particular, and the induction of Il17a and Il17f in ILC3s blocked by FXR activation. Moreover, a population of ILC precursor-like cells increased with treatment, implicating FXR in the maturation/ differentiation of ILC precursors. These findings identify FXR as an intrinsic regulator of intestinal ILCs and a potential therapeutic target in inflammatory intestinal diseases.

Automated summary

The activation of FXR selectively in the intestine has been shown to be protective in inflammation-driven models of IBD. FXR regulates innate lymphoid cells, blocking the increase of ILCs and the production of inflammatory cytokines. In addition, FXR is involved in the maturation/differentiation of ILC precursor cells.