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Gut commensal metabolite rhamnose promotes macrophages phagocytosis by activating slc12a4 and protects against sepsis in mice

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3068-3085页

作者： Dongping Li Rongjuan Wei Xianglong Zhang Shenhai Gong Meijuan Wan Fangzhao Wang Jiaxin Li Meiling Chen Ruofan Liu Yantong Wan Yinghao Hong Zhenhua Zeng Peng Gu Zhang Wang Kutty Selva Nandakumar Yong Jiang Hongwei Zhou Peng Chen Department of Pathophysiology Guangdong Provincial Key Laboratory of ProteomicsSchool of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510000China Department of Critical Care Medicine Nanfang HospitalSouthern Medical UniversityGuangzhou 510000China Department of Gastroenterology Shenzhen HospitalSouthern Medical UniversityShenzhen 518000China Institute of Ecological Sciences School of Life SciencesSouth China Normal UniversityGuangzhou 510000China Department of Environmental and Biosciences School of BusinessInnovation and SustainabilityKristian IV’s vag 3Halmstad UniversityHalmstad 30004Sweden Microbiome Medicine Center Zhujiang HospitalSouthern Medical UniversityGuangzhou 510000China

Sepsis progression is significantly associated with the disruption of gut ***,the modulatory mechanisms of gut microbiota operating during sepsis are still ***,we investigated how gut commensals impact sepsis development in a pre-clinical *** ligation and puncture(CLP)surgery was used to establish polymicrobial sepsis in *** depleted of gut microbiota by an antibiotic cocktail(ABX)exhibited a significantly higher level of mortality than *** determined by metabolomics analysis,ABX treatment has depleted many metabolites,and subsequent supplementation with L-rhamnose(rhamnose,Rha),a bacterial carbohydrate metabolite,exerted profound immunomodulatory properties with a significant enhancement in macrophage phagocytosis,which in turn improved organ damage and ***,rhamnose binds directly to and activates the solute carrier family 12(potassium-chloride symporter),member 4(slc12a4)in macrophages and promotes phagocytosis by activating the small G-proteins,Ras-related C3 botulinum toxin substrate1(Rac1)and cell division control protein 42 homolog(Cdc42).Interestingly,rhamnose has enhanced the phagocytosis capacity of macrophages from sepsis *** conclusion,by identifying slc12a4 as the host interacting protein,we disclosed that the gut commensal metabolite rhamnose is a functional molecular that could promote the phagocytosis capacity of macrophages and protect the host against sepsis.

关键词： Gut microbiota Sepsis Rhamnose slc12a4 GTP-Rac1 GTP-Cdc42 Macrophage Phagocytosis

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