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Gut microbiota
Original research
Novel tripeptide RKH derived from Akkermansia muciniphila protects against lethal sepsis
  1. Shihao Xie1,2,
  2. Jiaxin Li1,2,
  3. Fengyuan Lyu1,
  4. Qingming Xiong3,
  5. Peng Gu1,4,
  6. Yuqi Chen1,
  7. Meiling Chen1,
  8. Jingna Bao2,
  9. Xianglong Zhang1,
  10. Rongjuan Wei1,
  11. Youpeng Deng5,
  12. Hongzheng Wang5,
  13. Zhenhua Zeng2,
  14. Zhongqing Chen2,
  15. Yongqiang Deng1,
  16. Zhuoshi Lian6,
  17. Jie Zhao6,
  18. Wei Gong4,
  19. Ye Chen4,
  20. Ke-Xuan Liu7,
  21. Yi Duan5,
  22. Yong Jiang1,
  23. Hong-Wei Zhou8,
  24. Peng Chen1
  1. 1Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
  2. 2Department of Critical Care Medicine, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China
  3. 3Department of Anesthesiology, The First People’s Hospital of Foshan, Foshan, China
  4. 4Department of Gastroenterology, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, China
  5. 5Department of Infectious Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
  6. 6NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
  7. 7Departmentof Anesthesiology, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China
  8. 8Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
  1. Correspondence to Professor Peng Chen, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China; perchen{at}smu.edu.cn; Professor Hong-Wei Zhou, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China; biodegradation{at}gmail.com; Professor Yong Jiang, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China; jiang48231{at}163.com; Professor Yi Duan, Department of Infectious Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; yduan{at}ustc.edu.cn

Abstract

Objective The pathogenesis of sepsis is complex, and the sepsis-induced systemic proinflammatory phase is one of the key drivers of organ failure and consequent mortality. Akkermansia muciniphila (AKK) is recognised as a functional probiotic strain that exerts beneficial effects on the progression of many diseases; however, whether AKK participates in sepsis pathogenesis is still unclear. Here, we evaluated the potential contribution of AKK to lethal sepsis development.

Design Relative abundance of gut microbial AKK in septic patients was evaluated. Cecal ligation and puncture (CLP) surgery and lipopolysaccharide (LPS) injection were employed to establish sepsis in mice. Non-targeted and targeted metabolomics analysis were used for metabolites analysis.

Results We first found that the relative abundance of gut microbial AKK in septic patients was significantly reduced compared with that in non-septic controls. Live AKK supplementation, as well as supplementation with its culture supernatant, remarkably reduced sepsis-induced mortality in sepsis models. Metabolomics analysis and germ-free mouse validation experiments revealed that live AKK was able to generate a novel tripeptide Arg-Lys-His (RKH). RKH exerted protective effects against sepsis-induced death and organ damage. Furthermore, RKH markedly reduced sepsis-induced inflammatory cell activation and proinflammatory factor overproduction. A mechanistic study revealed that RKH could directly bind to Toll-like receptor 4 (TLR4) and block TLR4 signal transduction in immune cells. Finally, we validated the preventive effects of RKH against sepsis-induced systemic inflammation and organ damage in a piglet model.

Conclusion We revealed that a novel tripeptide, RKH, derived from live AKK, may act as a novel endogenous antagonist for TLR4. RKH may serve as a novel potential therapeutic approach to combat lethal sepsis after successfully translating its efficacy into clinical practice.

  • sepsis
  • probiotics
  • macrophages
  • inflammation
  • intestinal microbiology

Data availability statement

Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information. Transcriptome data and 2bRAD sequencing for the Microbiome of mice are available in the Genome Sequence Archive (GSA) database: Bioproject PRJCA017617 and PRJCA017573. Raw data not included therein can be obtained with the consent of the corresponding author.

http://dx.doi.org/10.1136/gutjnl-2023-329996

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    Data availability statement

    Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information. Transcriptome data and 2bRAD sequencing for the Microbiome of mice are available in the Genome Sequence Archive (GSA) database: Bioproject PRJCA017617 and PRJCA017573. Raw data not included therein can be obtained with the consent of the corresponding author.

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    Footnotes

    • SX, JL, FL and QX contributed equally.

    • Correction notice This article has been corrected since it published Online First. The third author affiliation has been updated.

    • Contributors SX, JL, FL, PG, YuC, MC, JB, RW, YouD, HW and YonD performed the experiments and analysed the data; XZ participated in the bioinformatics analysis; ZZ, ZC, K-XL, WG and QX collected clinical data; ZL and JZ participated in bacterial culture experiments; YeC, YiD, YJ, H-WZ and PC designed the study, interpreted the data, drafted and edited the manuscript, and supervised the study. PC is the guarantor for this paper. All authors read and approved the final manuscript.

    • Funding This study was supported by the National Key R&D Program of China (2022YFA0806400), and the National Natural Science Foundation of China (32071124, 32271230) to PC. National Natural Science Foundation of China (82130063), Special Support Plan for Outstanding Talents of Guangdong Province (2019JC05Y340) to YJ.

    • Competing interests None declared.

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

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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