A Metabolite-Triggered Tuft Cell-ILC2 Circuit Drives Small Intestinal Remodeling

Abstract

SUMMARY The small intestinal tuft cell-ILC2 circuit mediates epithelial responses to intestinal helminths and protists by tuft cell chemosensory-like sensing and IL-25-mediated activation of lamina propria ILC2s. Small intestine ILC2s constitutively express the IL-25 receptor, which is negatively regulated by A20 (Tnfaip3). A20-deficiency in ILC2s spontaneously triggers the circuit, and, unexpectedly, promotes adaptive small intestinal lengthening and remodeling. Circuit activation occurs upon weaning, and is enabled by dietary polysaccharides that render mice permissive for Tritrichomonas colonization, resulting in luminal accumulation of acetate and succinate, metabolites of the protist hydrogenosome. Tuft cells express GPR91, the succinate receptor, and dietary succinate, but not acetate, activates ILC2s via a tuft-, TRPM5-, and IL-25-dependent pathway. Also induced by parasitic helminths, circuit activation and small intestinal remodeling impairs infestation by new helminths, consistent with the phenomenon of concomitant immunity. We describe a metabolic sensing circuit that may have evolved to facilitate mutualistic responses to luminal pathosymbionts.

Metabolism at the centre of the host–microbe relationship

“…In the small intestine they have been described to produce interleukin (IL)-25 upon helminth infection. Recent reports found that the tuft cell-ILC2 circuit could be induced by microbial-derived succinate binding to G-protein coupled receptor 91 (GPR91, also known as succinate receptor 1, SUCNR1) [97][98][99][100]. Recent reports found that the tuft cell-ILC2 circuit could be induced by microbial-derived succinate binding to G-protein coupled receptor 91 (GPR91, also known as succinate receptor 1, SUCNR1) [97][98][99][100].…”

“…This initiates IL-13 production by ILC2s, which feeds back on epithelial progenitor cells and biases their differentiation into goblet and tuft cells, thus promoting a positive feed-forward loop that promotes worm clearance [93][94][95]. In the context of helminth infection, however, SUCNR1 signalling appeared redundant or absent, although downstream activation of Trpm5 and IL-25 occurs [99,100], although one of these studies showed that activation of this type 2 circuit by Tritrichomonas-derived succinate protected from subsequent infection with helminths [97]. SUCNR1 is specifically expressed on small intestinal tuft cells, and ligation with succinate induces a downstream chemosensing pathway involving α-gustducin (Gnat3) and Trpm5.…”

Thinking differently about ILCs—Not just tissue resident and not just the same as CD4+ T‐cell effectors

“…In addition, receptor activator of nuclear factor κB ligand (RANKL) expressed by CCR6 + ILC3s negatively regulate ILC3 abundance and activity through interaction with its receptor RANK on adjacent ILC3s . Besides these inhibitory receptors, signaling molecules such as Ikaros, A20, and microRNA miR17~92 have also been shown to control ILC3 and ILC2 homeostasis and effector functions under various conditions . Beyond these intrinsic control mechanisms, regulatory T cells extrinsically inhibit innate lymphocytes activation by various mechanisms.…”

Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

“…In addition to mechanosensing, a recent study demonstrated that several metabolites from a consortium of commensal spore‐forming bacteria (predominantly Clostridial species) promote 5‐HT biosynthesis by colonic enterochromaffin cells in colonized mice . In response to microbes, IECs also secrete a number of cytokines and effector molecules including interleukin‐25 (IL‐25) and SAA . These effectors regulate the development and function of intestinal immune cells, as described in the next section of this review.…”

“…37 In response to microbes, IECs also secrete a number of cytokines and effector molecules including interleukin-25 (IL-25) and SAA. 38,39 These effectors regulate the development and function of intestinal immune cells, as described in the next section of this review. Collectively, these recent findings indicate that a broad range of IEC functions are affected by sensing of intestinal microbes (Table 1); however, it is worth noting that many of these studies were performed in the context of pathogenic microbial infection.…”