2. Academic Validation
  3. Gut microbiota drives macrophage-dependent self-renewal of intestinal stem cells via niche enteric serotonergic neurons

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

  • Cell Res. 2022 Jun;32(6):555-569. doi: 10.1038/s41422-022-00645-7.
Pingping Zhu  # 1 2 3,  Tiankun Lu  # 4 5,  Jiayi Wu  # 4 6,  Dongdong Fan  # 7,  Benyu Liu 4 8,  Xiaoxiao Zhu 7,  Hui Guo 4,  Ying Du 4,  Feng Liu 9,  Yong Tian 10 11,  Zusen Fan 12 13
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. zhup@zzu.edu.cn.
  • 2 School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China. zhup@zzu.edu.cn.
  • 3 State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan, China. zhup@zzu.edu.cn.
  • 4 CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 5 University of Chinese Academy of Sciences, Beijing, China.
  • 6 School of Medicine, Nankai University, 94 Weijin Road, Tianjin, China.
  • 7 CAS Key Laboratory of RNA Biology; Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 8 Research Center of Basic Medicine, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
  • 9 State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  • 10 University of Chinese Academy of Sciences, Beijing, China. ytian@ibp.ac.cn.
  • 11 CAS Key Laboratory of RNA Biology; Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. ytian@ibp.ac.cn.
  • 12 CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. fanz@moon.ibp.ac.cn.
  • 13 University of Chinese Academy of Sciences, Beijing, China. fanz@moon.ibp.ac.cn.
  • # Contributed equally.
PMID: 35379903 DOI: 10.1038/s41422-022-00645-7
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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