Institute of Health Sciences, China Medical University, Shenyang, Liaoning, China.
Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, Illinois.
Am J Physiol Gastrointest Liver Physiol. 2019 Oct 1;317(4):G453-G462. doi: 10.1152/ajpgi.00103.2019. Epub 2019 Aug 14.
Diets high in animal fats are associated with increased risks of inflammatory bowel disease, but the mechanism remains unclear. In this study, we investigated the effect of high-fat diet (HFD) on the development of experimental colitis in mice. Relative to mice fed low-fat diet (LFD), HFD feeding for 4 wk increased the levels of triglyceride, cholesterol, and free fatty acids in the plasma as well as within the colonic mucosa. In an experimental colitis model induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS), mice on 4-wk HFD exhibited more severe colonic inflammation and developed more severe colitis compared with the LFD counterparts. HFD feeding resulted in higher production of mucosal pro-inflammatory cytokines, greater activation of the myosin light chain kinase (MLCK) tight junction regulatory pathway, and greater increases in mucosal barrier permeability in mice following TNBS induction. HFD feeding also induced gp91, an NADPH oxidase subunit, and promoted reactive oxygen species (ROS) production in both colonic epithelial cells and lamina propria cells. In HCT116 cell culture, palmitic acid or palmitic acid and TNF-α combination markedly increased ROS production and induced the MLCK pathway, and these effects were markedly diminished in the presence of a ROS scavenger. Taken together, these data suggest that HFD promotes colitis by aggravating mucosal oxidative stress, which rapidly drives mucosal inflammation and increases intestinal mucosal barrier permeability. This study demonstrates high-fat diet feeding promotes colitis in a 2,4,6-trinitrobenzenesulfonic acid-induced experimental colitis model in mice. The underlying mechanism is that high-fat diet induces oxidative stress in the colonic mucosa, which increases colonic epithelial barrier permeability and drives colonic mucosal inflammation. These observations provide molecular evidence that diets high in saturated fats are detrimental to patients with inflammatory bowel diseases.
高脂肪饮食与炎症性肠病风险增加有关，但机制尚不清楚。在这项研究中，我们研究了高脂肪饮食（HFD）对小鼠实验性结肠炎发展的影响。与低脂饮食（LFD）喂养的小鼠相比，HFD 喂养 4 周会增加血浆和结肠黏膜内的甘油三酯、胆固醇和游离脂肪酸水平。在 2,4,6-三硝基苯磺酸（TNBS）诱导的实验性结肠炎模型中，与 LFD 对照组相比，HFD 喂养 4 周的小鼠表现出更严重的结肠炎症，并发展出更严重的结肠炎。HFD 喂养导致黏膜促炎细胞因子产生增加、肌球蛋白轻链激酶（MLCK）紧密连接调节途径更活跃以及 TNBS 诱导后小鼠黏膜屏障通透性增加。HFD 喂养还诱导 NADPH 氧化酶亚基 gp91，并促进结肠上皮细胞和固有层细胞中的活性氧（ROS）产生。在 HCT116 细胞培养中，棕榈酸或棕榈酸和 TNF-α 联合显著增加 ROS 产生并诱导 MLCK 途径，而在存在 ROS 清除剂的情况下，这些作用明显减弱。总之，这些数据表明 HFD 通过加重黏膜氧化应激来促进结肠炎，这迅速驱动黏膜炎症并增加肠道黏膜屏障通透性。本研究表明 HFD 促进了小鼠 2,4,6-三硝基苯磺酸诱导的实验性结肠炎模型中的结肠炎。其潜在机制是高脂肪饮食诱导结肠黏膜氧化应激，增加结肠上皮屏障通透性并驱动结肠黏膜炎症。这些观察结果为饮食中富含饱和脂肪对炎症性肠病患者有害提供了分子证据。
