Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China.
Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
Gut Microbes. 2022 Jan-Dec;14(1):2112882. doi: 10.1080/19490976.2022.2112882.
Toll-like receptor 4 (TLR4) has been identified as a potentially promising therapeutic target in acute pancreatitis (AP). However, the role of intestinal TLR4 in AP and AP-associated gut injury remains unclear. This study aimed to explore the relationship between intestinal TLR4 and gut microbiota during AP. A mouse AP model was establish by intraperitoneal injection of L-arginine. Pancreatic injury and intestinal barrier function were evaluated in wild-type and intestinal epithelial TLR4 knockout (TLR4ΔIEC) mice. Gut microbiota was analyzed by 16S rRNA sequencing. Quadruple antibiotics were applied to induce microbiota-depleted mice. Differentially expressed genes in gut were detected by RNA sequencing. treatment was carried out in and study. Compared with wild-type mice, AP and AP-associated gut injury were exacerbated in TLR4ΔIEC mice in a gut microbiota-dependent manner. The relative abundance of and number of Paneth cells remarkably decreased in TLR4ΔIEC mice. The KEGG pathway analysis derived from RNA sequencing suggested that genes affected by intestinal TLR4 deletion were related to the activation of nod-like receptor pathway. Furthermore, treatment could significantly improve the pancreatic and intestinal injury in TLR4ΔIEC mice through promoting Paneth cells in a NOD2-dependent manner. Loss of intestinal epithelial TLR4 exacerbated pancreatic and intestinal damage during AP, which might be attributed to the gut microbiota dysbiosis especially the exhausted might maintain intestinal homeostasis and alleviate AP via Paneth cells modulation. AP Acute pancreatitis, TLR4 Toll-like receptor 4, IL-1β Interleukin-1β, IL-6 Interleukin-6, TNF-α Tumor necrosis factor-α, SIRS Systematic inflammatory response syndrome, LPS Lipopolysaccharides, SPF Specific pathogen-free, ZO-1 Zonula occludens-1, CON Control, H&E Hematoxylin and eosin, FISH Fluorescence in situ hybridization, DAPI 4',6-diamidino-2-phenylindole, PCoA Principal co-ordinates analysis, SCFA Short chain fatty acid, LEfSe Linear discriminant analysis Effect Size, ANOVA Analysis of variance, F/B Firmicutes/Bacteroidetes, PCA Principal component analysis, NOD2 Nod-like receptor 2, ABX antibiotics, PCNA proliferating cell nuclear antigen.
Toll 样受体 4（TLR4）已被确定为急性胰腺炎（AP）潜在的有前途的治疗靶点。然而，肠道 TLR4 在 AP 和 AP 相关的肠道损伤中的作用尚不清楚。本研究旨在探讨 AP 期间肠道 TLR4 与肠道微生物群之间的关系。通过腹腔内注射 L-精氨酸建立小鼠 AP 模型。在野生型和肠上皮 TLR4 敲除（TLR4ΔIEC）小鼠中评估胰腺损伤和肠道屏障功能。通过 16S rRNA 测序分析肠道微生物群。应用四重抗生素诱导微生物群耗竭小鼠。通过 RNA 测序检测肠道中差异表达的基因。在 和 研究中进行了 治疗。与野生型小鼠相比，TLR4ΔIEC 小鼠的 AP 和 AP 相关的肠道损伤在肠道微生物群依赖性方式下加重。TLR4ΔIEC 小鼠中的 相对丰度和潘氏细胞数量明显减少。RNA 测序得出的 KEGG 途径分析表明，肠道 TLR4 缺失影响的基因与 Nod 样受体途径的激活有关。此外，通过 NOD2 依赖性方式促进潘氏细胞， 治疗可显著改善 TLR4ΔIEC 小鼠的胰腺和肠道损伤。AP 急性胰腺炎，TLR4 Toll 样受体 4，IL-1β 白细胞介素-1β，IL-6 白细胞介素-6，TNF-α 肿瘤坏死因子-α，SIRS 全身炎症反应综合征，LPS 脂多糖，SPF 特定病原体-自由，ZO-1 封闭蛋白-1，CON 对照，H&E 苏木精和伊红，FISH 荧光原位杂交，DAPI 4'，6-二脒基-2-苯基吲哚，PCoA 主坐标分析，SCFA 短链脂肪酸，LEfSe 线性判别分析效应大小，ANOVA 方差分析，F/B 厚壁菌门/拟杆菌门，PCA 主成分分析，NOD2 Nod 样受体 2，ABX 抗生素，PCNA 增殖细胞核抗原。
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