CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China.
Cell Res. 2022 Jun;32(6):555-569. doi: 10.1038/s41422-022-00645-7. Epub 2022 Apr 4.
Lgr5 intestinal stem cells (ISCs) reside within specialized niches at the crypt base and harbor self-renewal and differentiation capacities. ISCs in the crypt base are sustained by their surrounding niche for precise modulation of self-renewal and differentiation. However, how intestinal cells in the crypt niche and microbiota in enteric cavity coordinately regulate ISC stemness remains unclear. Here, we show that ISCs are regulated by microbiota and niche enteric serotonergic neurons. The gut microbiota metabolite valeric acid promotes Tph2 expression in enteric serotonergic neurons via blocking the recruitment of the NuRD complex onto Tph2 promoter. 5-hydroxytryptamine (5-HT) in turn activates PGE2 production in a PGE2 macrophage subset through its receptors HTR2A/3 A; and PGE2 via binding its receptors EP1/EP4, promotes Wnt/β-catenin signaling in ISCs to promote their self-renewal. Our findings illustrate a complex crosstalk among microbiota, intestinal nerve cells, intestinal immune cells and ISCs, revealing a new layer of ISC regulation by niche cells and microbiota.
Lgr5 肠干细胞 (ISC) 位于隐窝底部的特定龛位内，具有自我更新和分化能力。隐窝底部的 ISC 由其周围的龛位维持，以精确调节自我更新和分化。然而，隐窝龛位中的肠道细胞和肠腔中的微生物群如何协调调节 ISC 干性仍然不清楚。在这里，我们表明 ISC 受微生物群和龛位肠嗜铬神经元的调节。肠道微生物群代谢产物戊酸通过阻止 NuRD 复合物募集到 Tph2 启动子上，从而促进肠嗜铬神经元中 Tph2 的表达。5-羟色胺 (5-HT) 通过其受体 HTR2A/3A 在一个 PGE2 巨噬细胞亚群中激活 PGE2 的产生；而 PGE2 通过与其受体 EP1/EP4 结合，促进 ISC 中的 Wnt/β-catenin 信号转导，以促进其自我更新。我们的发现说明了微生物群、肠神经细胞、肠道免疫细胞和 ISC 之间的复杂串扰，揭示了龛位细胞和微生物群对 ISC 调节的新层次。
