Abstract
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 coordinatelyregulate ISC stemness remains unclear. Here, we show that ISCs are regulated by microbiota and niche enteric serotonergic neurons. Thegut 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 turnactivates PGE2 production in aPGE2+ 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 theirself-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.
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