酪酸梭菌调节IRAK-4通路治疗腹泻型肠易激综合征的机制研究

Abstract: Diarrhea predominant irritable bowel syndrome involves the dysbiosis of gut microbiota and disruption of intestinal barrier. However, the mechanism of interaction between host and the disturbed microbiota remains unclear. Recent bioinformatic studies indicated that Clostridium plays an important role in gut microbial dysbiosis. The interleukin-1 receptor associated kinase 4 (IRAK-4) is an important mediator linking the host intestine and microbiota. Our preliminary work found that Clostridium butyricum was significantly associated with the improvement of IBS-D symptoms. But its mechanism remains unclear. Here we will integrate multiple-omics analysis, gene knockdown and RNA interfering technique to study how Clostridium butyricum modulates IRAK-4 expression and restores the intestinal epithelial barrier function. This study will establish a comprehensive signal pathway form Clostridium butyricum administration, through IRAK-4 regulation and intestinal epithelial barrier recovery, to symptom improvement. The result of this study may hopefully elucidate how Clostridium talks with the intestinal epithelial cells, and new targets for IBS-D management will be identified.

腹泻型肠易激综合征（IBS-D）患者存在肠道菌群失调与肠屏障功能破坏，但宿主与失调菌群的相互作用机制仍不清楚。新近生物信息学研究发现梭菌在肠道菌群失调中起重要作用，而宿主肠道白介素-1受体相关激酶4（IRAK-4）是调控宿主肠道菌群与肠道功能的重要信号。我们的前期研究发现，肠道酪酸梭菌含量与IBS-D的症状改善显著相关，而具体机制并不清楚。本课题拟在前期工作的基础上，利用多组学联合检测分析、基因敲除和干扰表达技术，对酪酸梭菌调节IRAK-4 继而恢复肠黏膜屏障的机制进行深入研究，建立梭菌调节IRAK-4，恢复肠上皮屏障功能，从而改善临床症状的完整信号通路。其结果将有助于阐明梭菌与肠上皮细胞的对话机制，为IBS-D的治疗提供新的靶点。

肠易激综合征（Irritable Bowel Syndrome, IBS）是常见的消化系统疾病，主要表现为腹痛和腹部不适，排便后症状减轻或消失，严重影响患者生活质量并加重经济负担。前期研究发现酪酸梭菌可以缓解肠易激综合征患者腹痛，其机制不清楚。本研究中，我们发现肠易激综合征肠上皮IRAK1与患者腹程度及频率成正相关；动物实验中发现TNBS模型鼠中IRAK1蛋白水平与疼痛阈值负相关；酪酸梭菌代谢产物丁酸钠可下调TNBS模型鼠肠粘膜IRAK1表达进而改善模型鼠的内脏敏感性；细胞实验表明丁酸可通过抑制引起的IRAK1和p-IRAK1表达上调发挥抑制内脏高敏感的作用。在此基础上，我们还发现IBS患者及TNBS模型鼠血清中靶向IRAK1的miR-146a-5p下调，mir-146a-5p agomir灌肠处理可显著提高结肠组织microRNA-146a-5p表达量，并可降低模型鼠的内脏敏感性，进一步研究发现mir-146a-5p agomir灌肠可抑制IRAK1的升高，进而治疗肠易激综合征的内脏高敏感。本研究为肠易激综合征内脏高敏感的治疗提供了新的靶点及干预策略。