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 (HDAC3^ΔTuft) showed that expression of canonical tuft cell pathways were impaired in HDAC3^ΔTuft mice, suggesting that HDAC3 regulates tuft cell-intrinsic function. HDAC3^ΔTuft 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 HDAC3^ΔTuft 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.