Microbiota dampen type 2 immunity by epigenetically restricting tuft cell differentiation

Abstract Type 2 immune responses at mucosal surfaces are both required to expel helminthic parasites and central to allergic disease pathogenesis. Tuft cells are central regulators of type 2 immunity that instruct downstream type 2 innate lymphoid cells (ILC2s). Although the microbiota are known to shape immune responses, the impact of commensal microbes on regulation of tuft cell-dependent immunity remains poorly understood. Here, we find that butyrate-producing commensal bacteria suppress tuft cell-dependent type 2 immunity in the intestine. Butyrate suppression of tuft cells required the microbiota-sensitive epigenetic modifying enzyme histone deacetylase 3 (HDAC3), suggesting that HDAC3 may promote tuft cell-dependent immune defense. Consistent with this, epithelial-intrinsic HDAC3 actively stimulated tuft cell responses, was required to initiate the tuft cell-ILC2 feed-forward response to Nippostrongylus brasiliensis infection, and promoted expulsion of this helminthic parasite. Furthermore, butyrate epigenetically restricted stem cell differentiation into tuft cells, and inhibition of HDAC3 in adult mice and human intestinal organoids was sufficient to block tuft cell differentiation. Collectively, these data reveal a microbiota-sensitive epigenetic pathway in stem cells that dampens tuft cell mediated type 2 immunity, and highlight a new level of regulation through which commensal bacteria can calibrate mucosal inflammation. This research is supported by the National Institutes of Health (DK114123, DK116868 to T.A., and F32AI147591 to E.M.E.), and a Kenneth Rainin Foundation award to T.A. T.A. holds an Investigator in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund. This project is supported in part by PHS grant P30 DK078392 and the CCHMC Trustee Award and Procter Scholar’s Program.