2. Academic Validation
  3. Novel tripeptide RKH derived from Akkermansia muciniphila protects against lethal sepsis

Novel tripeptide RKH derived from Akkermansia muciniphila protects against lethal sepsis

  • Gut. 2023 Dec 7;73(1):78-91. doi: 10.1136/gutjnl-2023-329996.
Shihao Xie # 1 2,  Jiaxin Li # 1 2,  Fengyuan Lyu # 1,  Qingming Xiong # 3,  Peng Gu 1 4,  Yuqi Chen 1,  Meiling Chen 1,  Jingna Bao 2,  Xianglong Zhang 1,  Rongjuan Wei 1,  Youpeng Deng 5,  Hongzheng Wang 5,  Zhenhua Zeng 2,  Zhongqing Chen 2,  Yongqiang Deng 1,  Zhuoshi Lian 6,  Jie Zhao 6,  Wei Gong 4,  Ye Chen 4,  Ke-Xuan Liu 7,  Yi Duan 8,  Yong Jiang 9,  Hong-Wei Zhou 10,  Peng Chen 9
Affiliations

Affiliations

  • 1 Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
  • 2 Department of Critical Care Medicine, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China.
  • 3 Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, China.
  • 4 Department of Gastroenterology, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, China.
  • 5 Department 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 NMPA 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 Departmentof Anesthesiology, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China.
  • 8 Department 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 perchen@smu.edu.cn biodegradation@gmail.com jiang48231@163.com yduan@ustc.edu.cn.
  • 9 Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China perchen@smu.edu.cn biodegradation@gmail.com jiang48231@163.com yduan@ustc.edu.cn.
  • 10 Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China perchen@smu.edu.cn biodegradation@gmail.com jiang48231@163.com yduan@ustc.edu.cn.
  • # Contributed equally.
PMID: 37553229 DOI: 10.1136/gutjnl-2023-329996
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.

Keywords

inflammation; intestinal microbiology; macrophages; probiotics; sepsis.

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