Innate lymphoid cells (ILCs) rapidly undergo expansion in population size and functional maturation in response to cytokines that signal infection, tissue damage, or changes in physiology. Optimal ILC responses are shaped, in part, by the microbiota but the mechanisms remain unclear. We report that short-chain fatty acids (SCFAs), produced by the commensal microbiota from dietary fibers, support optimal expansion of ILCs, including ILC1, ILC2, and ILC3 in the intestines through their G-protein-coupled receptors (GPCRs). While this function is primarily important for intestinal ILC populations, it can also boost ILC responses in other tissues depending on host condition. ILCs express multiple GPCRs that detect SCFAs. Interestingly, we found that the expression of SCFA receptors, such as Ffar2 and Ffar3, by ILCs is induced by SCFAs. GPCR triggering by SCFAs co-stimulates the activation of phosphoinositide 3-kinase (PI3K), Stat3, Stat5, and mammalian target of rapamycin (mTOR), which is important for ILC proliferation. While Ffar2 signaling promotes ILC2 proliferation, SCFAs can suppress ILC2 proliferation through a non-Ffar2-mediated mechanism. In conclusion, our findings indicate that SCFAs, as the major mediator of healthy microbiota and nutritional status, function to maintain optimal numbers of ILCs in peripheral tissues during infection and inflammatory responses.

先天性淋巴样细胞 (ILC) 响应于发出感染、组织损伤或生理变化信号的细胞因子，会迅速经历种群规模扩张和功能成熟。最佳的 ILC 反应部分是由微生物群决定的，但其机制仍不清楚。我们报告说，由膳食纤维中的共生微生物群产生的短链脂肪酸 (SCFA) 通过其 G 蛋白偶联受体 (GPCR) 支持 ILC（包括 ILC1、ILC2 和 ILC3）在肠道中的最佳扩增。虽然此功能主要对肠道 ILC 种群很重要，但它也可以根据宿主条件增强其他组织的 ILC 反应。ILC 表达多个检测 SCFA 的 GPCR。有趣的是，我们发现 ILC 表达 SCFA 受体，如 Ffar2 和 Ffar3，是由 SCFA 诱导的。由 SCFA 触发的 GPCR 共同刺激磷酸肌醇 3-激酶 (PI3K)、Stat3、Stat5 和哺乳动物雷帕霉素靶标 (mTOR) 的激活，这对 ILC 增殖很重要。虽然 Ffar2 信号促进 ILC2 增殖，但 SCFA 可以通过非 Ffar2 介导的机制抑制 ILC2 增殖。总之，我们的研究结果表明，SCFA 作为健康微生物群和营养状况的主要介质，在感染和炎症反应期间发挥维持外周组织中 ILC 最佳数量的作用。