Tuft cells protect against intestinal inflammation through histone deacetylase 3.

While intestinal tuft cells are well known to promote type 2 immunity, their role in inflammatory bowel disease (IBD) remains unclear. Here, we show that tuft cells are reduced in the distal intestine of pediatric IBD patients and that tuft cell-deficient mice exhibited increased susceptibility to intestinal inflammation. Histone deacetylase 3 (HDAC3) expression in intestinal stem cells is essential for tuft cell differentiation. Interestingly, single-cell analyses revealed that HDAC3 was also enriched in mature tuft cells compared to other differentiated epithelial populations. Generation of tuft cell-specific HDAC3 knockout mice (HDAC3ΔTuft) showed that expression of canonical tuft cell pathways were impaired in HDAC3ΔTuft mice, suggesting that HDAC3 regulates tuft cell-intrinsic function. HDAC3ΔTuft mice did not exhibit a significant difference in tuft cell numbers, however loss of HDAC3 specifically in tuft cells promoted colitis. Transcriptional analyses of ileal and colonic epithelium demonstrated dampened repair responses in HDAC3ΔTuft mice relative to control mice. Furthermore, HDAC3 inhibition in human colonoids similarly downregulated tuft cell-associated cytokines and eicosanoid pathways that promote epithelial repair. Collectively, these data indicate that enhancing tuft cell function may prevent or treat IBD, and that tuft cell-intrinsic regulation by HDAC3 limits susceptibility to intestinal damage and inflammation.