Department of Pathophysiology, Institute of Digestive Disease, Tongji University School of Medicine, Shanghai, China.
Department of Immunology and Pathogenic Biology, Tongji University School of Medicine, Shanghai, China.
Neurogastroenterol Motil. 2018 Jun;30(6):e13286. doi: 10.1111/nmo.13286. Epub 2018 Jan 4.
The changes in the gut barrier (GB) and associated mechanisms in postoperative ileus (POI) are still unclear. Toll-like receptor 4 (TLR4) is involved in inflammation, which may cause GB dysfunction and POI. Here, the roles of the GB in POI in relation to TLR4-dependent signaling pathways were explored.
POI was induced by small bowel manipulation in wild-type (WT) and TLR4-knockout (TLR4-/-) mice. Twenty-four hours after manipulation, indices of gastrointestinal (GI) transit, GB structure and function, inflammation, and related signaling pathways were analyzed.
Normal GI motility and GB function were not affected by TLR4 knockout. Compared with WT POI mice, TLR4-/-POI mice showed milder GI transit retardation, GB dysfunction, and inflammatory responses. In WT mice, GB disorder was characterized by colonic goblet cells depletion, increased gut claudin-2 expression, and decreased CD4+/CD8+ ratios in intestinal Peyer's patches. Green fluorescent protein-tagged Escherichia coli in the gut was detected in plasma and extraintestinal organs, followed with increased plasma lipopolysaccharide. These changes displayed in WT POI mice were less severe in TLR4-/-POI mice. Furthermore, the mRNA and protein expression of interleukin-6, monocyte chemotactic protein-1, pp38 and pJNK in the intestine, and TNF-α level in plasma were significantly increased in WT, but not TLR4-/-POI mice.
CONCLUSIONS & INFERENCES: These results indicate that GB is impaired in the experimental POI, with inflammation being involved in this pathological process. TLR4 deficiency alleviated GB dysfunction and suppressed inflammation by disrupting the activation of mitogen-activated protein kinase signaling pathways, thereby ameliorating POI.
术后肠梗阻（POI）时肠道屏障（GB）的变化及其相关机制尚不清楚。Toll 样受体 4（TLR4）参与炎症反应，可能导致 GB 功能障碍和 POI。本研究旨在探讨 TLR4 依赖性信号通路在 POI 中 GB 变化中的作用。
通过小肠操作诱导野生型（WT）和 TLR4 敲除（TLR4-/-）小鼠发生 POI。操作 24 小时后，分析胃肠道（GI）转运、GB 结构和功能、炎症和相关信号通路的指标。
TLR4 敲除不影响正常 GI 蠕动和 GB 功能。与 WT POI 小鼠相比，TLR4-/-POI 小鼠的 GI 转运延迟、GB 功能障碍和炎症反应较轻。在 WT 小鼠中，GB 紊乱表现为结肠杯状细胞耗竭、肠道紧密连接蛋白-2 表达增加和肠道派尔集合淋巴结中 CD4+/CD8+比值降低。肠道内绿色荧光蛋白标记的大肠杆菌可检测到血浆和肠外器官中，并伴有血浆内毒素增加。这些变化在 TLR4-/-POI 小鼠中较轻。此外，WT 但不是 TLR4-/-POI 小鼠的肠道中白细胞介素-6、单核细胞趋化蛋白-1、pp38 和 pJNK 的 mRNA 和蛋白表达以及血浆中 TNF-α水平显著增加。
这些结果表明，实验性 POI 时 GB 受损，炎症参与了这一病理过程。TLR4 缺失通过破坏丝裂原活化蛋白激酶信号通路的激活，减轻了 GB 功能障碍和炎症反应，从而改善了 POI。
