Zhang Cheng, Chen Shiyin, Wang Zhien, Zhang Jian, Yu Wenqiao, Wang Yanshuai, Si Weiwei, Zhang Yuwei, Zhang Yun, Liang Tingbo
Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, Zhejiang Province, China.
Gut Microbes. 2025 Dec;17(1):2489768. doi: 10.1080/19490976.2025.2489768. Epub 2025 Apr 6.
Severe acute pancreatitis (SAP)-induced intestinal bacterial translocation and enterogenic infection are among the leading causes of mortality in patients. However, the mechanisms by which SAP disrupted the intestinal barrier and led to bacterial translocation remained unclear. Therefore, we employed multi-omics analysis including microbiome, metabolome, epigenome, transcriptome, and mass cytometry (CyTOF) to identify potential targets, followed by functional validation using transgenic mice. The integrated multi-omics analysis primarily indicated overgrowth of intestinal flagellated bacteria, upregulation of intestinal Toll-like receptor 5 (TLR5) and acute inflammatory response, and increased infiltration of intestinal high-expressing TLR5 lamina propria dendritic cells (TLR5 LPDC) after SAP. Subsequently, intestinal flagellin-TLR5 signaling was activated after SAP. Intestinal barrier disruption, bacterial translocation, and helper T cells (Th) differentiation imbalance caused by SAP were alleviated in TLR5 knocked out () or conditionally knocked out on LPDC () mice. However, TLR5 conditional knockout on intestinal epithelial cells () failed to improve SAP-induced bacterial translocation. Moreover, depletion of LPDC and regulatory T cells (Treg) ameliorated bacterial translocation after SAP. Our findings identify TLR5 on LPDC as a potential novel target for preventing or treating intestinal bacterial translocation caused by SAP.
重症急性胰腺炎（SAP）诱导的肠道细菌易位和肠源性感染是患者死亡的主要原因之一。然而，SAP破坏肠道屏障并导致细菌易位的机制仍不清楚。因此，我们采用了包括微生物组、代谢组、表观基因组、转录组和质谱流式细胞术（CyTOF）在内的多组学分析来确定潜在靶点，随后使用转基因小鼠进行功能验证。综合多组学分析主要表明，SAP后肠道鞭毛菌过度生长、肠道Toll样受体5（TLR5）上调和急性炎症反应，以及肠道高表达TLR5的固有层树突状细胞（TLR5 LPDC）浸润增加。随后，SAP后肠道鞭毛蛋白-TLR5信号被激活。在TLR5基因敲除（）或LPDC条件性敲除（）小鼠中，SAP引起的肠道屏障破坏、细菌易位和辅助性T细胞（Th）分化失衡得到缓解。然而，肠道上皮细胞条件性敲除TLR5（）未能改善SAP诱导的细菌易位。此外，LPDC和调节性T细胞（Treg）的耗竭改善了SAP后的细菌易位。我们的研究结果确定LPDC上的TLR5是预防或治疗SAP引起的肠道细菌易位的潜在新靶点。
