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 -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.

中文翻译：

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肠道共生代谢物鼠李糖通过激活 SLC12A4 促进巨噬细胞吞噬作用并预防小鼠败血症

脓毒症的进展与肠道生态平衡的破坏显着相关。然而，脓毒症期间肠道微生物群的调节机制仍不清楚。在此，我们研究了临床前模型中肠道共生体如何影响脓毒症的发展。盲肠结扎穿刺（CLP）手术用于在小鼠中建立多种微生物败血症。通过抗生素混合物（ABX）耗尽肠道微生物群的小鼠表现出比对照组显着更高的死亡率。代谢组学分析表明，ABX 治疗耗尽了许多代谢物，随后补充细菌碳水化合物代谢物 -鼠李糖 (rhamnose, Rha)，发挥了深远的免疫调节特性，显着增强了巨噬细胞的吞噬作用，从而改善了器官损伤和死亡率。从机制上讲，鼠李糖直接结合并激活巨噬细胞中的溶质载体家族 12（氯化钾同向转运蛋白）成员 4 (SLC12A4)，并通过激活小 G 蛋白、Ras 相关的 C3 肉毒毒素底物 1 (Rac1) 和细胞来促进吞噬作用分裂控制蛋白 42 同源物 (Cdc42)。有趣的是，鼠李糖增强了脓毒症患者巨噬细胞的吞噬能力。总之，通过将SLC12A4确定为宿主相互作用蛋白，我们揭示了肠道共生代谢物鼠李糖是一种功能分子，可以促进巨噬细胞的吞噬能力并保护宿主免受脓毒症的侵害。