Autophagy Improves Inflammatory Response in Sepsis Accompanied by Changes in Gut Microbiota.

IF 4.4 3区 医学 Q2 CELL BIOLOGY Mediators of Inflammation Pub Date : 2024-10-18 eCollection Date: 2024-01-01 DOI:10.1155/2024/9550301
La Wang, WenJia Wang, GuiTong Jiang, ZunLi Ke, RuiXi Luo, WeiYi Tian
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Abstract

Background: Sepsis is defined as a life-threatening disease. Autophagy and the microbiome are increasingly connected with sepsis. The aim of this study was to investigate the protective effect of autophagy and the possible mechanisms. Methods: The septic rat model was established by cecal ligation perforation (CLP). Rapamycin (Rap), 3-methyladenine (3-MA), and chloroquine (CQ) were administered to interfere autophagy. Western blot (WB) was used to detect the expression of key proteins in autophagy. Hematoxylin and eosin (H&E) staining and enzyme-linked immunosorbent assays (ELISAs) were used to identify the effect of autophagy on various organs. 16S ribosomal RNA gene sequencing was used to analyze the changes of the gut microbiota. Results: Rap significantly upregulated the expression of key autophagy proteins, and 3-MA reduced the relative expression compared to the CLP group. The autophagic flux showed a corresponding trend. Interestingly, the autophagy inducer significantly decreased the mortality and the lipopolysaccharide (LPS) level in serum compared with the CLP group. Autophagy activation significantly improves the inflammatory response in sepsis. Histopathological sections showed that CLP destroyed the tight junctions between ileal epithelial cells, while autophagy induction reversed the damage. The sequencing results showed that autophagy activation increased the alpha diversity and alterted the composition and structure of gut microbiota. The abundance of Proteobacteria was markedly decreased in the Rap group, whereas Bacteroidetes was notably increased compared with the CLP group. Additionally, the protective effect of autophagy further changed the biomarkers in the microbial community. The top 35 functions in each sample were analyzed to obtain 18 genes including RNA synthesis, ATP binding and transport, chromosome assignment, osmotic polysaccharide transport, transcytosis, and methylation. Conclusion: Autophagy is able to improve inflammation and may directly or indirectly regulate the microbiota of septic rats. Autophagy may be an important target for future clinical interventions in the treatment of sepsis.

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自噬改善败血症中的炎症反应,同时伴随着肠道微生物群的变化
背景:败血症是一种危及生命的疾病。自噬和微生物组与败血症的关系日益密切。本研究旨在探讨自噬的保护作用及其可能的机制。研究方法通过盲肠结扎术(CLP)建立败血症大鼠模型。给予雷帕霉素(Rap)、3-甲基腺嘌呤(3-MA)和氯喹(CQ)以干扰自噬。用 Western 印迹(WB)检测自噬过程中关键蛋白的表达。采用血红素和伊红(H&E)染色法和酶联免疫吸附试验(ELISA)来确定自噬对各器官的影响。16S 核糖体 RNA 基因测序用于分析肠道微生物群的变化。结果发现与中电解质组相比,Rap能明显上调关键自噬蛋白的表达,而3-MA能降低其相对表达。自噬通量也呈现出相应的趋势。有趣的是,与CLP组相比,自噬诱导剂能显著降低死亡率和血清中脂多糖(LPS)的水平。自噬激活能明显改善败血症的炎症反应。组织病理学切片显示,CLP破坏了回肠上皮细胞之间的紧密连接,而自噬诱导则逆转了这种破坏。测序结果显示,自噬激活增加了肠道微生物群的α多样性,并改变了其组成和结构。与中电组相比较,Rap组中变形菌的丰度明显下降,而拟杆菌则明显增加。此外,自噬的保护作用进一步改变了微生物群落的生物标志物。通过分析每个样本中排名前 35 位的功能,获得了 18 个基因,包括 RNA 合成、ATP 结合和转运、染色体分配、渗透多糖转运、转胞作用和甲基化。结论自噬能改善炎症,并可能直接或间接调节脓毒症大鼠的微生物群。自噬可能是未来临床干预治疗败血症的一个重要靶点。
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来源期刊
Mediators of Inflammation
Mediators of Inflammation 医学-免疫学
CiteScore
8.70
自引率
0.00%
发文量
202
审稿时长
4 months
期刊介绍: Mediators of Inflammation is a peer-reviewed, Open Access journal that publishes original research and review articles on all types of inflammatory mediators, including cytokines, histamine, bradykinin, prostaglandins, leukotrienes, PAF, biological response modifiers and the family of cell adhesion-promoting molecules.
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