Liu Yu-Feng, Niu Guo-Chao, Li Chen-Yang, Guo Jin-Bo, Song Jia, Li Hui, Zhang Xiao-Lan
Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
Department of Gastroenterology, Dingzhou People's Hospital of Hebei Province, Dingzhou, China.
Front Physiol. 2021 Sep 17;12:695019. doi: 10.3389/fphys.2021.695019. eCollection 2021.
The progression of liver disorders is frequently associated with inflammatory bowel disease through the gut-liver axis. However, no direct evidence showed the mechanisms of ulcerative colitis (UC) in the development of liver fibrosis . Thus, this study aimed to evaluate the effects of UC on liver fibrosis and its potential mechanism in the experimental model. Male C57BL/6 mice were allocated into five groups ( = 10 per group) to receive either drinking water (control), 2% dextran sulfate sodium (DSS), olive oil, carbon tetrachloride (CCl) or DSS + CCl for 4 cycles. Blood was collected for biochemical analysis. Colons were excised for the evaluation of colon length and morphological score. Liver, colon, and mesenteric lymph nodes (MLNs) were collected for histopathological staining, expression analysis, and bacterial translocation assay to evaluate the inflammation, fibrosis, the activation of hepatic stellate cells (HSCs), and gut barrier function. DSS caused severe colitis in mice treated or treated with CCl, as evident from the elevation of disease activity index (DAI), histological abnormalities, and increased pro-inflammatory cytokines (TNF-α, IFN-γ, and IL-17A). Histopathological staining revealed that DSS treatment aggravated the CCl-induced extracellular matrix deposition, liver fibrosis, and inflammation in mice. Additionally, biochemical and expression analysis indicated the DSS treatment caused the increase of hydroxyproline and pro-inflammatory cytokines, as well as the abnormal liver function indexes in CCl-induced mice. Gut barrier function was impaired in DSS- and DSS + CCl-treated mice, manifesting as the increase in bacterial translocation and lipopolysaccharide level, and the reduction in tight junction proteins (occluding, claudin-1 and ZO-1) expression. Further, the activations of HSCs and TLR4 signaling pathway were observed after DSS + CCl treatment, presenting with the increase in expression of α-SMA, vimentin, TGF-β, collagen type I, collagen type II, TIMP-2, TLR4, TRAF6, and NF-κB p65, and a decrease in GFAP and MMP-2 expression. The present study verified that UC aggravated CCl-induced liver injury, inflammation, and fibrosis in mice through the gut-liver axis. Gut barrier dysfunction in UC leads to bacterial translocation and elevated lipopolysaccharide, which may promote the activation of TLR4 signaling and HSCs in the liver.
肝脏疾病的进展通常通过肠-肝轴与炎症性肠病相关联。然而，尚无直接证据表明溃疡性结肠炎（UC）在肝纤维化发展中的机制。因此，本研究旨在评估UC对实验模型中肝纤维化的影响及其潜在机制。将雄性C57BL/6小鼠分为五组（每组n = 10），分别给予饮用水（对照组）、2%葡聚糖硫酸钠（DSS）、橄榄油、四氯化碳（CCl）或DSS + CCl，进行4个周期的处理。采集血液进行生化分析。切除结肠以评估结肠长度和形态学评分。收集肝脏、结肠和肠系膜淋巴结（MLN）进行组织病理学染色、表达分析和细菌易位测定，以评估炎症、纤维化、肝星状细胞（HSC）的激活和肠道屏障功能。DSS在接受CCl处理或未处理的小鼠中均引起严重结肠炎，疾病活动指数（DAI）升高、组织学异常以及促炎细胞因子（TNF-α、IFN-γ和IL-17A）增加均证明了这一点。组织病理学染色显示，DSS处理加剧了CCl诱导的小鼠细胞外基质沉积、肝纤维化和炎症。此外，生化和表达分析表明，DSS处理导致CCl诱导的小鼠中羟脯氨酸和促炎细胞因子增加，以及肝功能指标异常。DSS和DSS + CCl处理的小鼠肠道屏障功能受损，表现为细菌易位和脂多糖水平增加，以及紧密连接蛋白（闭合蛋白、claudin-1和ZO-1）表达降低。此外，DSS + CCl处理后观察到HSC和TLR4信号通路的激活，表现为α-SMA、波形蛋白、TGF-β、I型胶原、II型胶原（原文有误，应为III型胶原）、TIMP-2、TLR4、TRAF6和NF-κB p65表达增加，而GFAP和MMP-2表达降低。本研究证实，UC通过肠-肝轴加重了CCl诱导的小鼠肝损伤、炎症和纤维化。UC中的肠道屏障功能障碍导致细菌易位和脂多糖升高，这可能促进肝脏中TLR4信号和HSC的激活。
