Gut Microbial Metabolite Pravastatin Attenuates Intestinal Ischemia/Reperfusion Injury Through Promoting IL-13 Release From Type II Innate Lymphoid Cells via IL-33/ST2 Signaling.
Gut Microbial Metabolite Pravastatin Attenuates Intestinal Ischemia/Reperfusion Injury Through Promoting IL-13 Release From Type II Innate Lymphoid Cells via IL-33/ST2 Signaling.
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肠道微生物代谢物普伐他汀通过 IL-33/ST2 信号传导促进 II 型先天淋巴细胞释放 IL-13，从而减轻肠道缺血/再灌注损伤
DOI：
10.3389/fimmu.2021.704836
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发表时间：
2021
影响因子：
7.3
通讯作者：
Liu KX
中科院分区：
文献类型：
--
作者：
Deng F;Hu JJ;Yang X;Sun QS;Lin ZB;Zhao BC;Yao ZW;Luo SD;Chen ZL;Liu Y;Yan ZZ;Li C;Liu WF;Liu KX
肠缺血/再灌注（I/R）损伤是一种严重的疾病，发病率和死亡率都很高。我们先前证实了肠I/R诱导肠道植物群紊乱和代谢物的变化，但不同代谢物在肠I/R损伤中的作用目前尚不清楚。基于靶向代谢测序，普伐他汀（PA）被确定为肠道微生物群的代谢产物。采用上级肠系膜动脉阻塞法建立小鼠肠I/R模型。此外，对小肠类器官和II型先天淋巴样细胞（ILC 2）的共培养模型进行缺氧/复氧（H/R）以模拟肠I/R模型。并对体外循环患者术前粪便PA水平与术后肠I/R损伤指标进行相关性分析。IL-33缺陷型小鼠、ILC 2缺失型小鼠和抗IL-13中和抗体也用于探索PA减轻肠I/R损伤的潜在机制。我们证明，在接受体外循环的患者术前粪便中的PA水平与术后肠I/R损伤的指数呈负相关。PA还能减轻肠I/R损伤，提高小鼠存活率。我们进一步表明，PA通过激活IL-33/ST 2信号通路促进IL-13从ILC 2释放，从而减轻肠I/R损伤。此外，IL-13通过激活Notch 1和Wnt信号促进肠干细胞的自我更新。总之，结果表明，肠道微生物代谢产物PA可以通过促进IL-33/ST 2信号转导从ILC 2s释放IL-13来减轻肠I/R损伤，揭示了肠I/R损伤的新机制和治疗策略。
Intestinal ischemia/reperfusion (I/R) injury is a grave condition with high morbidity and mortality. We previously confirmed that intestinal I/R induces intestinal flora disorders and changes in metabolites, but the role of different metabolites in intestinal I/R injury is currently unclear. Based on targeted metabolic sequencing, pravastatin (PA) was determined to be a metabolite of the gut microbiota. Further, intestinal I/R model mice were established through superior mesenteric artery obstruction. In addition, a co-culture model of small intestinal organoids and type II innate lymphoid cells (ILC2s) was subjected to hypoxia/reoxygenation (H/R) to simulate an intestinal I/R model. Moreover, correlation analysis between the PA level in preoperative feces of patients undergoing cardiopulmonary bypass and the indices of postoperative intestinal I/R injury was carried out. IL-33-deficient mice, ILC2-deleted mice, and anti-IL-13 neutralizing antibodies were also used to explore the potential mechanism through which PA attenuates intestinal I/R injury. We demonstrated that PA levels in the preoperative stool of patients undergoing cardiopulmonary bypass were negatively correlated with the indices of postoperative intestinal I/R injury. Furthermore, PA alleviated intestinal I/R injury and improved the survival of mice. We further showed that PA promotes IL-13 release from ILC2s by activating IL-33/ST2 signaling to attenuate intestinal I/R injury. In addition, IL-13 promoted the self-renewal of intestinal stem cells by activating Notch1 and Wnt signals. Overall, results indicated that the gut microbial metabolite PA can attenuate intestinal I/R injury by promoting the release of IL-13 from ILC2s via IL-33/ST2 signaling, revealing a novel mechanism of and therapeutic strategy for intestinal I/R injury.
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