The gut contains trillions of microbes that enhance metabolic capability, promote immune cell development, and limit colonization by invading pathogens. However, disturbance of this microbial community can lead to serious health challenges such as inflammatory bowel disease, type 1 diabetes, and obesity. The gut epithelium is in continuous contact with the microbiota and is essential for maintaining intestinal homeostasis. Commonly, the intestinal epithelium is described as consisting of four cell subsets, but recent evidence suggests that tuft cells represent a fifth epithelial cell type. Though tuft cels were first described in 1955, only recently have the tools and specific markers become available to unambiguously identify these cells from the rest of the epithelium. Very little is known about tuft cell physiology and their relationship to the microbiota is completely unexplored. Tuft cells express key taste components that are known for their gustatory function. However there is evidence that taste receptors can respond to microbes. This proposal will identify the specific taste receptors expressed on tuft cells and the microbial ligands that stimulate them. One consequence of tuft cell taste signaling may be the alteration of T cell development in the intestinal lamina propria. This will be tested using an in vitro T cell development assays and be verified in the mouse.
The final aim of this fellowship will determine the broader impact of tuft cells on mouse models of colitis. The experiments described in this proposal will lead to an enhanced understanding of the complex relationship between the tuft cells, the immune system, and microorganisms. Tuft cells are completely novel participants in the host-microbiota interaction;consequently these studies may expand therapeutic options to treat gastrointestinal inflammatory disease.
The single-layer of epithelial cells lining the intestine forms the first barrier against pathogens and promotes a symbiotic relationship with the endogenous gut microbiota. The goal of this fellowship is to determine how a poorly understood epithelial cell type, called tuft cells, detects microbes and influences the maturation of neighboring immune cells. A better understanding of the relationship between tuft cells, the immune system, and the microbiota will ultimately uncover new opportunities to treat intestinal inflammatory diseases.
|Howitt, Michael R; Lavoie, Sydney; Michaud, Monia et al. (2016) Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 351:1329-33|
|Smith, Patrick M; Howitt, Michael R; Panikov, Nicolai et al. (2013) The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341:569-73|
|Kostic, Aleksandar D; Howitt, Michael R; Garrett, Wendy S (2013) Exploring host-microbiota interactions in animal models and humans. Genes Dev 27:701-18|