Tuft cells mediate commensal remodeling of the small intestinal antimicrobial landscape

Abstract

Succinate produced by the commensal protistTritrichomonas musculis(T. mu) stimulates chemosensory tuft cells, resulting in intestinal type 2 immunity. Tuft cells express the succinate receptor SUCNR1, yet this receptor does not mediate anti-helminth immunity nor alter protist colonization. Here, we report that microbial-derived succinate increases Paneth cell numbers and profoundly alters the antimicrobial peptide (AMP) landscape in the small intestine. Succinate was sufficient to drive this epithelial remodeling, but not in mice lacking tuft cell chemosensory components required to detect this metabolite. Tuft cells respond to succinate by stimulating type 2 immunity, leading to interleukin-13-mediated epithelial and AMP expression changes. Moreover, type 2 immunity decreases the total number of mucosa-associated bacteria and alters the small intestinal microbiota composition. These findings demonstrate that a single metabolite produced by commensals, likeT. mu, can markedly shift the intestinal AMP profile and suggest that tuft cells utilize SUCNR1 to modulate bacterial homeostasis.

Folate supports IL‐25‐induced tuft cell expansion following enteroviral infections

“…Intestinal tuft cells, as an important epithelial immune cell, expanded aggressively in response to pathogenic infections 6 . Although IL‐25 has been reported as a trigger to induce tuft cell expansion, 21,39 the nutritional mechanism of tuft cell expansion induced by IL‐25 is largely unknown. The investigation of the mechanism of IL‐25‐induced tuft cell expansion from a nutritional and metabolic perspective is pivotal for the exploration of host immune regulation as the gut is known to serve as the initial replication site for many pathogens, such as Nippostrongylus brasiliensis , human immunodeficiency virus (HIV)‐1 and enteroviruses 25,40,41 .…”

“…Enteroviruses, such as enterovirus A71 (EV71), coxsackie virus A16 (CVA16), CVB3, and CVB4, belong to the Picornaviridae family 9,20–22 . As RNA viruses, the viral genomes consist of conserved 5′UTR and 3′UTR on both sides and an open reading frame (ORF) in the center 23 .…”

“…Enteroviruses, such as enterovirus A71 (EV71), coxsackie virus A16 (CVA16), CVB3, and CVB4, belong to the Picornaviridae family. 9,[20][21][22] As RNA viruses, the viral genomes consist of conserved 5′UTR and 3′UTR on both sides and an open reading frame (ORF) in the center. 23 Among ORF-encoded ten proteins, different enteroviruses share structurally similar 3D proteins as their RNA-dependent RNA polymerases.…”

Tuft cell IL-17RB restrains IL-25 bioavailability and reveals context-dependent ILC2 hypoproliferation

“…Indeed, continuous low-grade stimulation of tuft cells by succinate or possibly other microbial agonists may be more common in a natural environment with dynamic alterations in the luminal state compared to the stable and low type 2 tone in mice housed in barrier facilities. Such circuit activation might be sufficient to provoke responses mediating adaptive alteration in antimicrobial programs [47, 48], yet may not promote the very strong expansion of tuft and goblet cells seen with N. brasiliensis infection [3–5]. We hypothesize that the ILC2 response is controlled by the sum of activating signaling pathways engaged, and that they may integrate these during early activation in a way that subsequently governs the magnitude of proliferation, similar to what was proposed for T cells [49].…”

Tuft cell-derived acetylcholine regulates epithelial fluid secretion

“…We could not find any impact of tuft cell Chat deletion on Tritrichomonas burden or distribution, but perhaps tuft cell-mediated fluid secretion, together with IL-13-induced anti-microbial peptides and mucus production, acts more locally to keep microbes away from the epithelium. 83 Succinate levels have also been shown to increase in contexts of bacterial dysbiosis, and inducing tuft cell hyperplasia with succinate treatment reduces inflammation in a model of ileitis. 80 As for the trachea, aberrant release of cellular succinate into the airways, which occurs in some patients with cystic fibrosis, can promote colonization and biofilm formation by the pathosymbiont Pseudomonas aeruginosa.…”