中国普通外科杂志 ›› 2021, Vol. 30 ›› Issue (3): 286-293.doi: 10.7659/j.issn.1005-6947.2021.03.006

• 基础研究 • 上一篇    下一篇

p38MAPK抑制剂对高脂血症性急性胰腺炎大鼠肠道微生物区系的影响

李臻1,张晓英1,杨国栋2   

  1. (1. 川北医学院基础医学院,四川 南充 637000;2. 川北医学院附属医院 消化内科,四川 南充 637000)
  • 收稿日期:2020-12-10 修回日期:2021-02-17 出版日期:2021-03-25 发布日期:2021-04-06
  • 通讯作者: 张晓英, Email: zxy_ld2006@163.com
  • 作者简介:李臻,川北医学院基础医学院硕士生研究生,主要从事病原生物学方面的研究。
  • 基金资助:
    四川省教育厅重点基金资助项目(14ZA0194);四川省南充市校科技战略合作专项基金资助项目(18SXHZ0371)。

Effects of p38MAPK inhibitor on intestinal microbiota in rats with hyperlipidemic acute pancreatitis

LI Zhen1, ZHANG Xiaoying1, YANG Guodong2   

  1. (1. School of Basic Medicine, North Sichuan Medical College, Nanchong, Sichuan 637000, China; 2. Department of Gastroenterology, the Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China)
  • Received:2020-12-10 Revised:2021-02-17 Online:2021-03-25 Published:2021-04-06

摘要: 背景与目的:p38MAPK信号通路的激活参与了炎症的调节,其抑制剂SB203580能抑制炎症相关因子的分泌,已被证明可以减轻急性胰腺炎(AP)患者肠黏膜屏障的损伤。而p38MAPK信号通路在高脂血症性急性胰腺炎(HLP)肠道炎症和微生物区系失调中的作用仍不清楚,故本研究探讨SB203580对HLP模型大鼠肠道炎症和微生物区系失调的影响,为HLP的治疗提供理论和实验依据。
方法:将24只雄性SD大鼠随机均分为假手术组、模型组和SB203580组。假手术组大鼠用普通饲料喂养,模型组与SB203580组大鼠用高脂饲料喂养,4周后,假手术组行假手术,后两组采用5%牛磺胆酸溶液逆行胰胆管注射诱导AP模型,SB203580组大鼠造模前1 h腹腔注射SB203580(5 mg/kg)。术后12 h,取各组大鼠血液与粪便样本以及远端回肠和胰腺组织标本,HE染色观察胰腺和回肠组织病理学变化,ELISA检测血浆D-乳酸、二胺氧化酶(DAO)含量及肠道组织IL-1β、TNF-α和IL-6水平,Western blot分析肠道组织中p38MAPK和p-p38MAPK蛋白表达,16S rDNA基因测序研究肠道微生物区系变化。
结果:与假手术组比较,模型组大鼠胰腺和回肠组织有明显病理损伤,D-乳酸、DAO、IL-1β、TNF-α、IL-6含量及p38MAPK、p-p38MAPK蛋白表达明显增加(均P<0.05);拟杆菌门及乳酸杆菌丰度增加,阿克曼氏菌丰度降低(均P<0.05)。与模型组比较,SB203580组DAO、IL-1β、TNF-α、IL-6含量及p38MAPK、p-p38MAPK蛋白表达明显降低(均P<0.05);拟杆菌门比例降低,厚壁菌门及阿克曼氏菌丰度增加(均P<0.05)。
结论:p38MAPK抑制剂SB203580可减轻HLP模型大鼠肠道炎症反应,调节微生物区系失调。

关键词: 胰腺炎, 高脂血症, 胃肠道微生物组, 炎症, 丝裂原激活蛋白激酶激酶类

Abstract: 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.

Key words: Pancreatitis, Hyperlipidemias, Gastrointestinal Microbiome, Inflammation, Mitogen-Activated Protein Kinase Kinases

中图分类号: 

  • R576
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