Epigenetic regulation of intestinal tuft cells

Intestinal epithelial cells reside at the direct interface between the microbiota and mammalian host, and are thus uniquely poised to sense microbial signals that calibrate intestinal immunity and function. Tuft cells are a specialized epithelial cell that have recently been shown to respond to microbial stimuli and initiate and amplify type 2 immune responses in the intestine. However, despite a clear relationship between the microbiota and intestinal health, the mechanisms underlying how the microbiota instruct tuft cell homeostasis and function remain poorly understood. Epigenetics represent a central mechanism that can potentially link microbial triggers in the pathogenesis of intestinal disease. Consistent with this concept, we previously identified that epithelial loss of an epigenetic-modifying enzyme disrupted microbiota-sensitive intestinal homeostasis and increased susceptibility to intestinal damage. Our new preliminary data suggest that regulation of tuft cell development and homeostasis may be epigenetically regulated and dynamically controlled by distinct metabolites produced by the intestinal microbiota. Based on these findings, we hypothesize that (1) tuft cell responses in the intestine may be calibrated by distinct components of the microbiota through an epigenetic sensor and that (2) epigenetic mechanisms in stem cells may regulate tuft cell development and function. To investigate these hypotheses, we will (i) interrogate how distinct commensal bacterial-derived metabolites instruct intestinal stem cell differentiation to tuft cells through an epigenetic-modifying enzyme, and (ii) directly identify and investigate new mechanisms by which the stem cell epigenetic landscape can be modulated to control tuft cell differentiation in the intestine. This work will uncover novel epigenetically-regulated pathways that direct tuft cell biology in the intestine, and therefore guide personalized approaches for treating intestinal diseases.