Gut commensal metabolite rhamnose promotes macrophages phagocytosis by activating SLC12A4 and protects against sepsis in mice  

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 

机构地区：[1]Department of Pathophysiology,Guangdong Provincial Key Laboratory of Proteomics,School of Basic Medical Sciences,Southern Medical University,Guangzhou 510000,China [2]Department of Critical Care Medicine,Nanfang Hospital,Southern Medical University,Guangzhou 510000,China [3]Department of Gastroenterology,Shenzhen Hospital,Southern Medical University,Shenzhen 518000,China [4]Institute of Ecological Sciences,School of Life Sciences,South China Normal University,Guangzhou 510000,China [5]Department of Environmental and Biosciences,School of Business,Innovation and Sustainability,Kristian IV’s vag 3,Halmstad University,Halmstad 30004,Sweden [6]Microbiome Medicine Center,Zhujiang Hospital,Southern Medical University,Guangzhou 510000,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第7期3068-3085,共18页药学学报（英文版）

基　　金：supported by the National Key R&D Program of China(2022YFA0806400);the National Natural Science Foundation of China(32071124,32271230)to Peng Chen;National Natural Science Foundation of China(82130063);Special Support Plan for Outstanding Talents of Guangdong Province(2019JC05Y340,China)to Yong Jiang.

摘　　要：Sepsis progression is significantly associated with the disruption of gut eubiosis.However,the modulatory mechanisms of gut microbiota operating during sepsis are still unclear.Herein,we investigated how gut commensals impact sepsis development in a pre-clinical model.Cecal ligation and puncture(CLP)surgery was used to establish polymicrobial sepsis in mice.Mice depleted of gut microbiota by an antibiotic cocktail(ABX)exhibited a significantly higher level of mortality than controls.As 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 mortality.Mechanistically,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 patients.In 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 

分 类 号：R515.3[医药卫生—内科学]