Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
World Premier International Research Center Initiative (WPI) Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
Proc Natl Acad Sci U S A. 2024 Oct 29;121(44):e2318767121. doi: 10.1073/pnas.2318767121. Epub 2024 Oct 21.
The intestinal lumen is rich in gut microbial metabolites that serve as signaling molecules for gut immune cells. G-protein-coupled receptors (GPCRs) sense metabolites and can act as key mediators that translate gut luminal signals into host immune responses. However, the impacts of gut microbe-GPCR interactions on human physiology have not been fully elucidated. Here, we show that GPR31, which is activated by the gut bacterial metabolite pyruvate, is specifically expressed on type 1 conventional dendritic cells (cDC1s) in the lamina propria of the human intestine. Using human induced pluripotent stem cell-derived cDC1s and a monolayer human gut organoid coculture system, we show that cDC1s extend their dendrites toward pyruvate on the luminal side, forming transepithelial dendrites (TED). Accordingly, GPR31 activation via pyruvate enhances the fundamental function of cDC1 by allowing efficient uptake of gut luminal antigens, such as dietary compounds and bacterial particles through TED formation. Our results highlight the role of GPCRs in tuning the human gut immune system according to local metabolic cues.
肠腔富含肠道微生物代谢物，这些代谢物可作为肠道免疫细胞的信号分子。G 蛋白偶联受体（GPCR）可感知代谢物，并可作为关键介质，将肠道腔信号转化为宿主免疫反应。然而，肠道微生物-GPCR 相互作用对人体生理学的影响尚未完全阐明。在这里，我们发现 GPR31 被肠道细菌代谢产物丙酮酸激活，在人类肠道固有层的 1 型传统树突状细胞（cDC1）上特异性表达。使用人诱导多能干细胞衍生的 cDC1 和单层人肠道类器官共培养系统，我们发现 cDC1 向腔侧的丙酮酸伸出树突，形成跨上皮树突（TED）。因此，通过丙酮酸激活 GPR31 通过形成 TED 增强了 cDC1 的基本功能，从而允许有效摄取肠道腔抗原，如饮食化合物和细菌颗粒。我们的研究结果强调了 GPCR 在根据局部代谢线索调节人体肠道免疫系统方面的作用。
