肠道微生态改变在胰腺炎发病中的作用及其机制研究

High fat diet is one of important reasons of obesity. Meanwhile, obesity is a high risk factor for acute pancreatitis. Recent studies have found that high fat diet can induce gut microbiota changes in obesity. Especially SRB(Sulfate Reducing Bacteria) in the gut microbiota were significantly enriched. Our previous study found that clearnce of Gram-negative bacteria in the gut(especially SRB inhibition)can significantly reduce the damage degree of pancreatitis. When mice were injected of LPS, this aggravated the damage degree of pancreatitis and increased moartality. These result suggested that SRB may play an important role in the onset of pancreatitis, but its mechanism is still not clear. In our project, based on our previous data, we try to address the relation between SRB and pancreatitis. Using cell model and molecular biotechnology, we try to find out the pathogenesis of its metabolites H2S, LPS influened the pancreatitis. This project can preliminary figure out the mechanism about the relation between SRB and pancreatitis, and provide theoretical basis for the treatment and prevention of pancreatitis.

高脂高热量饮食是肥胖的重要原因之一，同时肥胖是胰腺炎的高危因素。近年来研究发现高脂饮食导致的肥胖患者肠道微生态发生改变，以硫酸还原菌比例升高最为显著。我们前期研究发现清除肠道内革兰氏阴性菌（硫酸还原菌抑制更为明显）可显著减轻胰腺炎损伤程度，给予正常菌群小鼠注射LPS后加重胰腺炎损伤程度，死亡率上升，提示作为肠道菌群中之一的硫酸盐还原菌对胰腺炎发病具有重要作用，然而其机制尚不清楚。本课题旨在通过前期研究的基础之上：1.利用动物实验以及临床研究进一步证实肠道微生态中硫酸盐还原菌改变与胰腺炎的发病关系；2.通过细胞模型及分子生物学技术研究肠道硫酸还原菌及其代谢产物H2S、LPS影响胰腺炎发病的分子机制。通过本研究可进一步阐明肠道硫酸盐还原菌与胰腺炎的发病关系及分子机制，为胰腺炎治疗及预防提供新的思路。

肥胖是胰腺炎的独立危险因素之一，肥胖人群其胰腺炎的发生率和严重程度都明显升高。近几年研究表明高脂饮食诱导的肥胖患者肠道菌群发生严重紊乱，以硬壁菌门增加，拟杆菌门减少为主，那么肥胖患者紊乱的肠道菌群是否参与胰腺炎的发生和进展呢？基于此，我们完成了一系列实验，结果表明：（1）肥胖小鼠急性胰腺炎（AP）严重程度明显加重；（2）肥胖小鼠AP其肠道菌群严重紊乱；（3）肥胖AP小鼠血清中肠道菌群的代谢产物LPS、LBP等以及炎症因子IL-6、IL-1b等显著升高；（4）结合文献采用氨苄西林、新霉素、甲硝唑、万古霉素四联抗生素干预肥胖AP小鼠肠道菌群，胰腺炎严重程度减轻；万古霉素单独干预结果类似（5）肥胖人群内脏脂肪会分泌多种有活性的脂肪因子，我们通过对前期收集的临床不同严重程度胰腺炎血清样本，针对主要的脂肪因子及镁离子进行了检测，初步结果显示抵抗素可能作为一个胰腺炎患者合并持续器官衰竭的预测指标。结果提示肥胖胰腺炎患者的严重程度与肠道菌群的紊乱密切相关，本研究可为肥胖胰腺炎患者的发病和进展提供全新的认识，并为胰腺炎的治疗和预防提供新思路。