Abstract: Objective To explore the effects and underlying molecular mechanisms of high fat diet (HFD) on intestinal barrier damage and inflammatory reaction in mice with irritable bowel syndrome (IBS) induced by sodium dextran sulfate (DSS). Methods C57BL/6 mice were randomly divided into four groups (n=6): Normal group, DSS group (1.5% DSS solution for one week), HFD+DSS group, and HFD+DSS+WY14643 group(intraperitoneally injected daily with PPARα agonist WY14643 6 mg/kg). The body weight and liver weight of mice were measured. Colon pathology was observed by HE staining. The protein expression of zonula occludens-1(ZO-1) and occludin was detected by immunohistochemistry. The mRNA expression of tumor necrosis factor-α (TNF-α), interleukin-β (IL-1β), and interleukin-17 (IL-17) were determined by qRT-PCR. PPARα protein expression was determined by Western blot. Results The body weight and liver weight of mice in the HFD+DSS group were significantly higher than those in the DSS group (P＜0.001).HE staining showed normal colonic tissue structure in Normal group, while other three groups exhibited varying degrees of mucosal damage with a small amount of inflammatory cell infiltration and epithelial cell shedding. Among these, the HFD+DSS group displayed the most severe intestinal mucosal damage and inflammatory infiltration. Compared with the DSS group, the HFD+DSS group showed decreased ZO-1 and Occludin protein expression (P＜0.001), elevated TNF-α, IL-1 β, and IL-17 mRNA levels(all P＜0.001), and downregulated PPARα protein expression(P＜0.01).Compared with the HFD+DSS group, mice in HFD+DSS+WY14643 group showed improvement in intestinal mucosal damage and reduced infiltration of inflammatory cells. The protein expression of ZO-1 and occludin in colon of mice in the HFD+DSS+WY14643 was increased (all P＜0.05), while the expression of TNF-α, IL-1 β, and IL-17 mRNA was downregulated (P＜0.01 or P＜0.05), and the protein expression of PPAR α was upregulated(P＜0.05). Conclusions HFD-induced obesity aggravates intestinal mucosal damage, intestinal barrier destruction and inflammatory response in IBS mice, and its molecular mechanism is potentially related to downregulation of PPARα expression in intestinal tissues.

Key words: irritable bowel syndrome, obesity, peroxisome proliferator-activated receptor-α, intestinal barrier damage, inflammatory factors