Gut microbiota-derived succinate aggravates acute lung injury after intestinal ischemia/reperfusion in mice
Gut microbiota-derived succinate aggravates acute lung injury after intestinal ischemia/reperfusion in mice
复制标题
肠道微生物群衍生的琥珀酸加重小鼠肠道缺血/再灌注后的急性肺损伤
DOI：
10.1183/13993003.00840-2022
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发表时间：
2022
影响因子：
24.3
通讯作者：
Ke-Xuan Liu
中科院分区：
文献类型：
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作者：
Yi-Heng Wang;Zheng-Zheng Yan;Si-Dan Luo;Jing-Juan Hu;Mei Wu;Jin Zhao;Wei-Feng Liu;Cai Li;Ke-Xuan Liu
急性肺损伤（acute lung injury，ALI）是肠缺血/再灌注（intestinal ischemia/reperfusion，I/R）后发病和死亡的主要原因。肠道微生物群及其代谢副产物作为肠-肺轴的重要调节剂。本研究旨在确定琥珀酸，一个关键的微生物群代谢产物，在肠道I/R诱导的ALI progression.MethodsGut和肺微生物群的小鼠肠I/R进行了分析，使用16 S rRNA基因测序的作用。在无菌（GF）小鼠或用抗生素治疗的常规小鼠中测量琥珀酸水平变化。琥珀酸诱导的肺泡巨噬细胞极化及其对肺泡上皮细胞凋亡的影响在琥珀酸受体1（Sucnr 1）缺陷小鼠和转染Sucnr 1-siRNA的小鼠肺泡巨噬细胞中进行了评价。琥珀酸水平进行测量，在接受心肺转流术，包括肠I/R.ResultsSuccinate积累在肺肠I/R后，这是与琥珀酸生产和琥珀酸消耗细菌在肠道中的不平衡，但不是肺。GF小鼠中不存在琥珀酸积累，并且通过用抗生素消耗肠道微生物群来逆转，表明肠道微生物群是肺琥珀酸的来源。此外，琥珀酸促进肺泡巨噬细胞极化，肺泡上皮细胞凋亡，并在肠I/R肺损伤。相反，在体外和体内敲低Sucnr 1或阻断SUCNR 1可通过调节PI 3 K-AKT/HIF-1α通路逆转琥珀酸的作用。血浆琥珀酸水平显着相关的肠I/R相关的肺injury after cardiopulmonarybypass.ConclusionGut微生物衍生的琥珀酸加剧肠I/R诱导的ALI通过SUCNR 1依赖的肺泡巨噬细胞极化，确定琥珀酸作为一个新的目标肠源性ALI在危重病人。
IntroductionAcute lung injury (ALI) is a major cause of morbidity and mortality after intestinal ischemia/reperfusion (I/R). Gut microbiota and their metabolic byproducts act as important modulators of the gut–lung axis. This study aimed to define the role of succinate, a key microbiota metabolite, in intestinal I/R-induced ALI progression.MethodsGut and lung microbiota of mice subjected to intestinal I/R were analysed using 16S rRNA gene sequencing. Succinate level alterations were measured in Germ-free (GF) mice or conventional mice treated with antibiotics. Succinate-induced alveolar macrophage polarisation and its effects on alveolar epithelial apoptosis were evaluated in succinate receptor1 (Sucnr1)-deficient mice and in murine alveolar macrophages transfected withSucnr1-siRNA. Succinate levels were measured in patients undergoing cardiopulmonary bypass, including intestinal I/R.ResultsSuccinate accumulated in lungs after intestinal I/R, and this was associated with an imbalance of succinate-producing and succinate-consuming bacteria in the gut, but not the lungs. Succinate accumulation was absent in GF mice and was reversed by gut microbiota depletion with antibiotics, indicating that gut microbiota are a source of lung succinate. Moreover, succinate promoted alveolar macrophage polarisation, alveolar epithelial apoptosis, and lung injury during intestinal I/R. Conversely, knockdown ofSucnr1or blockage of SUCNR1in vitroandin vivoreversed the effects of succinate by modulating PI3K-AKT/HIF-1α pathway. Plasma succinate levels significantly correlated with intestinal I/R-related lung injury after cardiopulmonary bypass.ConclusionGut microbiota-derived succinate exacerbates intestinal I/R–induced ALI through SUCNR1-dependent alveolar macrophage polarisation, identifying succinate as a novel target for gut-derived ALI in critically ill patients.