Lei, Weiwei, Ren, Wenwen, Ohmoto, Makoto, Redding, Kevin, Littlewood-Evans, Amanda, Carballido, Jose, Urban, Joseph, Margolskee, Robert, Matsumoto, Ichiro and Jiang, Peihua (2018) Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 immunity in the mouse small intestine. Proceedings of the National Academy of Sciences. ISSN 0027-84241091-6490

Abstract

Until recently, little is known about whether succinate, a key metabolite in the Krebs cycle and microbial propionate synthesis, has any physiological role in the gut. De Vadder et al. (1) showed that dietary succinate or microbiota-produced succinate improves glucose homeostasis via intestinal gluconeogenesis. Given the expression of the succinate receptor Sucnr1 in the intestine, we asked if dietary succinate has additional effects in the intestine. In this report, we find that Sucnr1 is specifically expressed in intestinal tuft cells but not in other types of intestinal epithelial cells. Exogenous succinate induces tuft and goblet cell hyperplasia in wild-type mice, hallmark features of mucosal type 2 immunity in response to parasitic infections. In contrast, monomethyl succinate, a structural analog of succinate but not a ligand for Sucnr1, fails to induce tuft cell hyperplasia. Succinate-induced type 2 responses are mediated by Sucnr1, and tuft cell-expressed chemosensory signaling elements gustducin and Trpm5. Mice deficient for Sucnr1, gustducin or Trpm5 show neither tuft nor goblet cell expansion in response to succinate feeding. Perturbation of microbiota by antibiotics (e.g., streptomycin) or chemically-induced intestinal motility disturbance (e.g., PEG-3350) can lead to an elevated level of succinate in the perturbed intestine. Tuft cells expand in the distal ileum juxtaposed to the cecum in the Sucnr1 heterozygous but not homozygous mice, suggesting that microbiota-produced succinate is sufficient to trigger type 2 immunity. Altogether, our data suggest that dietary and microbiota-produced succinate activates intestinal tuft cell-expressed Sucnr1 to triggers type 2 immunity.

Item Type:	Article
Date Deposited:	23 May 2018 00:45
Last Modified:	23 May 2018 00:45
URI:	https://oak.novartis.com/id/eprint/34536