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  • A purified membrane protein from Akkermansia muciniphila or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8+ T cells in mice

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Gut microbiota
Original research
A purified membrane protein from Akkermansia muciniphila or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8+ T cells in mice
  1. Lijuan Wang1,
  2. Lei Tang1,
  3. Yiming Feng1,
  4. Suying Zhao2,
  5. Mei Han2,
  6. Chuan Zhang3,
  7. Gehui Yuan1,
  8. Jun Zhu1,
  9. Shuyuan Cao1,
  10. Qian Wu1,
  11. Lei Li1,
  12. Zhan Zhang1
  1. 1 Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu, China
  2. 2 Department of laboratory medicine, The Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, China
  3. 3 Department of General Surgery, Jiangsu Province People's Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, Jiangsu, China
  1. Correspondence to Dr Zhan Zhang, Center for Global Health, Nanjing Medical University, Nanjing 211166, China; zhanzhang{at}njmu.edu.cn; Professor Lei Li, Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu, China; lilei{at}njmu.edu.cn

Abstract

Objective Gut microbiota have been linked to inflammatory bowel disease (IBD) and colorectal cancer (CRC). Akkermansia muciniphila (A. muciniphila) is a gram-negative anaerobic bacterium that is selectively decreased in the faecal microbiota of patients with IBD, but its causative role and molecular mechanism in blunting colitis-associated colorectal cancer (CAC) remain inconclusive. This study investigates how A. muciniphila engages the immune response in CAC.

Design Mice were given dextran sulfate sodium to induce colitis, followed by azoxymethane to establish CAC with or without pasteurised A. muciniphila or a specific outer membrane protein (Amuc_1100) treatment. Faeces from mice and patients with IBD or CRC were collected for 16S rRNA sequencing. The effects of A. muciniphila or Amuc_1100 on the immune response in acute colitis and CAC were investigated.

Results A. muciniphila was significantly reduced in patients with IBD and mice with colitis or CAC. A. muciniphila or Amuc_1100 could improve colitis, with a reduction in infiltrating macrophages and CD8+ cytotoxic T lymphocytes (CTLs) in the colon. Their treatment also decreased CD16/32+ macrophages in the spleen and mesenteric lymph nodes (MLN) of colitis mice. Amuc_1100 elevated PD-1+ CTLs in the spleen. Moreover, A. muciniphila and Amuc_1100 blunted tumourigenesis by expanding CTLs in the colon and MLN. Remarkably, they activated CTLs in the MLN, as indicated by TNF-α induction and PD-1downregulation. Amuc_1100 could stimulate and activate CTLs from splenocytes in CT26 cell conditioned medium.

Conclusions These data indicate that pasteurised A. muciniphila or Amuc_1100 can blunt colitis and CAC through the modulation of CTLs.

  • colonic microflora
  • colorectal cancer
  • gut immunology
  • nutritional supplementation
  • experimental colitis
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/gutjnl-2019-320105

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    Footnotes

    • LW, LT and YF contributed equally.

    • Contributors LW, LT and YF carried out most experiments and analysed the data. SZ, MH and CZ provided clinical sample and performed data analyses. GY and JZ helped with animal experiments and analysis. SC, QW, ZZ and LL designed the experiments and analysed data. ZZ and LL directed the research and wrote the manuscript with input from coauthors.

    • Funding This project was supported by the National Natural Science Foundations of China (81973096 and 81502801) and Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX18_1513).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Patient consent for publication Not required.

    • Ethics approval All animal procedures were approved by the Animal Ethical and Welfare Committee of Nanjing Medical University (IACUC-1812031).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information. The 16S sequencing data from human and mice faeces had been submitted to NCBI (Sequence Read Archive, SRA). This BioProject accession number is PRJNA596333 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA596333).