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.
- 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 [email protected] [email protected] [email protected] [email protected].
- 9. Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China [email protected] [email protected] [email protected] [email protected].
- 10. Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China [email protected] [email protected] [email protected] [email protected].
- # Contributed equally.
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.
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Cat. No.Product NameDescriptionTargetResearch Area
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target: Toll-like Receptor (TLR)
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target: Toll-like Receptor (TLR)Research Areas: Infection