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Lactobacillus accelerates ISCs regeneration to protect the integrity of intestinal mucosa through activation of STAT3 signaling pathway induced by LPLs secretion of IL-22

Cell Death & Differentiation (2018) | Download Citation

Summary

The regeneration of intestinal epithelial are maintained by continuous differentiation and proliferation of intestinal stem cells (ISCs) under physiological and pathological conditions. However, little is known about the regulatory effect of intestinal microbiota on its recovery ability to repair damaged mucosal barrier. In this study, we established intestinal organoids and lamina propria lymphocytes (LPLs) co-cultured system, plus mice experiments, to explore the protective effect of Lactobacillus reuteri D8 on integrity of intestinal mucosa. We found that only live L. reuteri D8 was effective in protecting the morphology of intestinal organoids and normal proliferation of epithelial stained with EdU under TNF-α treatment, which was also further verified in mice experiments. L. reuteri D8 colonized in the intestinal mucosa and ameliorated intestinal mucosa damage caused by DSS treatment, including improvement of body weight, colon length, pathological change, and proliferation level. The repair process stimulated by L. reuteri D8 was also accompanied with increased numbers of Lgr5+ and lysozyme+ cells both in intestinal organoids and mice intestine. Furthermore, we demonstrated that D8 metabolite indole-3-aldehyde stimulated LPLs to secret IL-22 through aryl hydrocarbon receptor (AhR) and then induced phosphorylation of STAT3 to accelerate proliferation of intestinal epithelial, thus recovering damaged intestinal mucosa. Our findings indicate L. reuteri protects intestinal barrier and activates intestinal epithelial proliferation, which sheds light on treatment approaches for intestinal inflammation based on ISCs with probiotics Lactobacillus and daily probiotic consumption in heath foods.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (31502024), Jiangsu Agriculture Science and Technology Innovation Fund (JASTIF, CX[15]1066), and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Author contributions

QH was responsible for performing the experiments, data analysis and writing the manuscript. LY established the co-cultured system of organoids and LPLs. HL and LH were responsible for animal experiments. QY provided suggestions regarding the experimental procedures. TJR give suggestions to the experiments performance and article review. QY was responsible for the conception and design of the study, data collection, drafting the article, and final approval of the version submitted.

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Author notes

  1. Edited by D. Aberdam.

Affiliations

  1. MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, Jiangsu, 210095, China

    • Qihang Hou
    • , Lulu Ye
    • , Haofei Liu
    • , Lulu Huang
    • , Qian Yang
    •  & Qinghua Yu
  2. Department of Pathology, The University of Chicago, Chicago, IL, USA

    • JR Turner
  3. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    • JR Turner
  4. Department of Medicine,Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital, Boston, MA, USA

    • JR Turner

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The authors declare that they have no conflict of interest.

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Correspondence to Qinghua Yu.

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DOI

https://doi.org/10.1038/s41418-018-0070-2