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Gut microbiota drives macrophage-dependent self-renewal of intestinal stem cells via niche enteric serotonergic neurons

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 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.

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Fig. 1: Microbiota promotes ISC self-renewal.
Fig. 2: 5-HT drives self-renewal of ISCs.
Fig. 3: 5-HT generated by enteric serotonergic neurons contributes to ISC self-renewal.
Fig. 4: VA reduces enrichment of the NuRD complex onto Thp2 promoter to initiate its expression.
Fig. 5: 5-HT functions through macrophages.
Fig. 6: 5-HT promotes PGE2 expression with engagement with its receptors HTR2A and HTR3A.
Fig. 7: PGE2 drives Wnt signaling activation to maintain ISC stemness.

Data availability

All other data supporting the findings of this study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Drs. Yihui Xu and Yan Teng for technical support. We thank Zixin Zhao, Zheng Liu, Jiajia Hou, Xinyi Wu, Ke Zhang and Xing Gao for providing GF and SPF mouse strains.We thank the staff of the Antibody Engineering Laboratory in Core Facility for Protein Sciences (Institute of Biophysics, CAS). We thank Jing Li (Cnkingbio Company Ltd, Beijing, China) for technical support. This work was supported by the National Key R&D Program of China (2020YFA0803501, 2019YFA0508501), the National Natural Science Foundation of China (31922024, 31930036, 82173176, 32170874, 31870883, 81921003, 92042302, 91940305, 82130088, 31771638, 31870883), and Strategic Priority Research Programs of the Chinese Academy of Sciences (XDB19030203). We are thankful for the supportinggrants from Zhengzhou University to P.Z. and the technical support from Modern Analysis and Computer Center of Zhengzhou University.

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P.Z. designed and performed experiments, analyzed data, and wrote the paper; J.W. and T.L. performed experiments and analyzed data; D.F. and X.Z. generated genome modified mice; F.L. provided Tph2 KO mice; B.L., H.G., and Y.D. performed some experiments; Y.T. initiated and analyzed data; Z.F. initiated the study, organized, designed, and wrote the paper.

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Correspondence to Pingping Zhu, Yong Tian or Zusen Fan.

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Zhu, P., Lu, T., Wu, J. et al. Gut microbiota drives macrophage-dependent self-renewal of intestinal stem cells via niche enteric serotonergic neurons. Cell Res 32, 555–569 (2022). https://doi.org/10.1038/s41422-022-00645-7

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