Background and Aims: The activation of p38MAPK signaling pathway participates in inflammatory regulation, and its inhibitor, SB203580, can suppress the secretion of inflammation-related factors, which also has been proven to lessen the damage of gastrointestinal mucosal barrier in acute pancreatitis (AP). However, the role of p38MAPK signaling pathway in intestinal inflammation and microflora imbalance in hyperlipidemic acute pancreatitis (HLP) is unclear. Therefore, this study was conducted to observe the effect of SB203580 on gut inflammation and microbiota dysbiosis in HLP model of rats, so as to provide theoretical and experimental basis for the treatment of HLP.  
Methods: Twenty-four male SD rats were equally randomized into sham operation group, model group and SB203580 group. Rats in sham operation group were fed with normal standard diet, and those in model group and SB203580 group were fed with high-fat diet for 4 weeks. After that, rats in sham operation group underwent sham operation, and those in the latter two groups underwent taurocholic acid injection into the pancreaticobiliary duct to induce AP, and rats in SB203580 group were intraperitoneally injected with SB203580 (5 mg/kg) 1 h before the model creation. At 12 h after operation, rats in each group were sacrificed and the blood and fecal samples as well as the the specimens of distal ileum and pancreatic tissues were obtained. The histopathological changes of pancreas and ileum were observed by HE staining, the contents of D-lactate and diamine oxidase (DAO) in plasma and the levels of IL-1β, TNF-α and IL-6 in the intestinal tissue were measured by ELISA assay, the expressions of p38MAPK and p-p38MAPK protein in the intestinal tissue were determined by Western blot analysis, and the changes in gut microbiota were identified by16s rDNA gene sequencing.
Results:  In model group compared with sham operation group, the pancreas and ileum showed obvious pathological damage, the contents of D-lactate, DAO, IL-1β, TNF-α, and IL-6 as well as the expressions of p38MAPK and p-p38MAPK protein were significantly increased (all P<0.05); the abundance of Bacteroidetes and Lactobacillus increased and the abundance of Akkermansia decreased (all P<0.05). In SB203580 group compared with model group, the contents of DAO, IL-1β, TNF-α and IL-6 together with the expressions of p38MAPK and p-p38MAPK protein were significantly decreased (all P<0.05); the proportion of Bacteroidetes was decreased and the abundance of Firmicuts and Akkermansia were increased (all P<0.05).
Conclusion: The p38MAPK inhibitor SB203580 can reduce gut inflammation and regulate microbiota dysbiosis in HLP model of rats.