Valeric acid-5-HT-dependent macrophage activation drives intestinal stem cell self-renewal

Abstract Lgr5+ intestinal stem cells 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 regulates ISC stemness remains unclear. Here we show that ISCs are regulated by intestinal nerve cells and macrophage cells in the crypt niche, which are further modulated by microbiota. Enteric serotonergic neurons, along with their secreted neurotransmitter 5-HT, are required for ISC self-renewal. 5-HT activates PGE2 production in macrophages through engagement with its receptors Htr2a/3a, and PGE2 activates Wnt/β-catenin signaling of ISCs via engagement with its receptors Ep1/Ep4. Gut bacterial metabolite valeric acid promotes Tph2 expression through blocking enrichment of NuRD complex onto Tph2 promoter. Our findings reveal the complicated crosstalk between microbiota, intestinal nerve cells, intestinal immune cells and intestinal stem cells, adding a new layer for ISC regulation by niche cells and microbiota.