Xie Shihao, Li Jiaxin, Lyu Fengyuan, Xiong Qingming, Gu Peng, Chen Yuqi, Chen Meiling, Bao Jingna, Zhang Xianglong, Wei Rongjuan, Deng Youpeng, Wang Hongzheng, Zeng Zhenhua, Chen Zhongqing, Deng Yongqiang, Lian Zhuoshi, Zhao Jie, Gong Wei, Chen Ye, Liu Ke-Xuan, Duan Yi, Jiang Yong, Zhou Hong-Wei, Chen Peng
Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Department of Critical Care Medicine, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China.
Gut. 2023 Dec 7;73(1):78-91. doi: 10.1136/gutjnl-2023-329996.
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. (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.
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.
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.
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.
脓毒症的发病机制复杂，脓毒症诱导的全身促炎期是器官衰竭及随之而来的死亡的关键驱动因素之一。嗜黏蛋白阿克曼氏菌（AKK）被认为是一种功能性益生菌菌株，对多种疾病的进展具有有益作用；然而，AKK是否参与脓毒症发病机制仍不清楚。在此，我们评估了AKK对致死性脓毒症发展的潜在作用。
评估脓毒症患者肠道微生物AKK的相对丰度。采用盲肠结扎和穿刺（CLP）手术及脂多糖（LPS）注射在小鼠中建立脓毒症模型。使用非靶向和靶向代谢组学分析进行代谢物分析。
我们首先发现，与非脓毒症对照组相比，脓毒症患者肠道微生物AKK的相对丰度显著降低。补充活的AKK及其培养上清液，可显著降低脓毒症模型中脓毒症诱导的死亡率。代谢组学分析和无菌小鼠验证实验表明，活的AKK能够产生一种新的三肽精氨酸-赖氨酸-组氨酸（RKH）。RKH对脓毒症诱导的死亡和器官损伤具有保护作用。此外，RKH显著降低了脓毒症诱导的炎症细胞活化和促炎因子过量产生。一项机制研究表明，RKH可直接结合Toll样受体4（TLR4）并阻断免疫细胞中TLR4信号转导。最后，我们在仔猪模型中验证了RKH对脓毒症诱导的全身炎症和器官损伤的预防作用。
我们发现，源自活的AKK的一种新的三肽RKH可能作为TLR4的一种新的内源性拮抗剂。在将其疗效成功转化为临床实践后，RKH可能成为对抗致死性脓毒症的一种新的潜在治疗方法。
