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 ⁺肠道干细胞 (ISC) 存在于隐窝基部的特殊壁龛内，具有自我更新和分化能力。隐窝基底中的 ISC 由其周围的生态位维持，以精确调节自我更新和分化。然而，隐窝生态位中的肠细胞和肠腔中的微生物群如何协调调节 ISC 干性仍不清楚。在这里，我们表明 ISC 受微生物群和生态位肠道血清素能神经元的调节。肠道微生物群代谢物戊酸通过阻断 NuRD 复合物募集到Tph2启动子上来促进Tph2在肠道血清素能神经元中的表达。5-羟色胺 (5-HT) 反过来激活 PGE2 ^{+中 PGE2 的产生}巨噬细胞亚群通过其受体 HTR2A/3 A；和 PGE2 通过与其受体 EP1/EP4 结合，促进 ISCs 中的 Wnt/β-catenin 信号传导，从而促进其自我更新。我们的研究结果说明了微生物群、肠道神经细胞、肠道免疫细胞和 ISC 之间的复杂串扰，揭示了生态位细胞和微生物群对 ISC 的新调控层。