Volume 32, No 6, Jun 2022

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 32 Issue 6, June 2022: 555-569

ORIGINAL ARTICLES

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

Pingping Zhu^1,2,3,†,* , Tiankun Lu^1,4,† , Jiayi Wu^1,5,† , Dongdong Fan^6,† , Benyu Liu^1,7 , Xiaoxiao Zhu⁶ , Hui Guo¹ , Ying Du¹ , Feng Liu⁸ , Yong Tian^4,6,* , Zusen Fan^1,4,*

¹CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
²School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China
³State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan, China
⁴University of Chinese Academy of Sciences, Beijing, China
⁵School of Medicine, Nankai University, 94 Weijin Road, Tianjin, China
⁶CAS Key Laboratory of RNA Biology; Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
⁷Research Center of Basic Medicine, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
⁸State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
^†These authors contributed equally: Pingping Zhu, Tiankun Lu, Jiayi Wu, Dongdong Fan
Correspondence: Pingping Zhu(zhup@zzu.edu.cn)Yong Tian(ytian@ibp.ac.cn)Zusen Fan(fanz@moon.ibp.ac.cn)

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.

https://doi.org/10.1038/s41422-022-00645-7

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