Mechanisms of Altered Gastrointestinal Dysfunction

摘要： 腹泻型肠易激综合征(IBS-D)是最常见的 胃肠道疾病表现为腹痛、水样大便疏松和 在没有可识别的炎症、结构或代谢异常的情况下的紧迫感。一 最常见和最难治疗的IBS-D组是那些感染肠道疾病的人 由食物中毒引起的感染，随后发展为感染后腹泻为主， 肠易激综合征(PI-IBS-D)。迁延性泄泻脏腑病机(S) 结肠炎缓解后的伤害性感觉尚不清楚，还需要进一步的工作来 了解它的病理生理学。它给卫生保健资源带来了巨大的财政负担 并降低生活质量。不幸的是，对于PI-IBS-D的药物治疗仍然存在 有限且不能令人满意。因此，我们正在专注于这一亚群的患者进行研究 结肠炎后胃肠功能障碍的基本机制(S)。 我们现在有了初步的数据，为儿茶酚-O-的作用提供了非常强有力的理论基础。 甲基转移酶(COMT)和miRNAs导致PI-IBS-D患者胃肠功能障碍 肠道感染改变了胃肠功能和内脏伤害性感觉，导致PI-IBS-D。 我们已经在PI-IBS-D患者中发现了受COMT信号通路调控的miRNAs 结肠肠道神经系统中控制炎症后反应的下游靶基因 胃肠功能和内脏伤害性感觉的调节。我们假设miRNAs 肠道感染后通过改变COMT信号调节下游靶点 小路。这些新的发现表明，PI-IBS-D涉及复合体的失调 MiRNAs通过下游靶标相互作用的调控途径。我们的实验室有 确定miRNAs在表观遗传学中的细胞内和细胞内作用的已建立的技术 调控其下游靶基因的表达。这些方法包括 MiRNAs的相互作用分析；miRNAs的体外转染；体内注射 寡核苷酸。这些发现可能有助于阐明细胞调节失调的机制。 PI-IBS-D患者的胃肠功能这将克服在以下方面取得进展的关键障碍 肠道感染和结肠炎患者的处理--缺乏有效的治疗 干预措施，并可能导致对PI-IBS-D患者采取预防和/或治疗策略 模仿或抑制特定miRNAs对靶基因表达的影响。

ABSTRACT: Diarrhea-predominant, irritable bowel syndrome (IBS-D) is one of the most frequent gastrointestinal disorders seen and is characterized by abdominal pain, loose watery stools, and urgency in the absence of an identifiable inflammatory, structural, or metabolic abnormality. One of the most common and difficult to treat IBS-D groups are those who contract an enteric infection from food poisoning and subsequently develop post-infectious, diarrhea-predominant, irritable bowel syndrome (PI-IBS-D). The mechanism(s) of persistent diarrhea and visceral nociception following resolution of the colitis are unclear and further work is needed to understand its pathophysiology. It puts an enormous financial burden on health care resources and decreases quality of life. Unfortunately, pharmacologic therapies for PI-IBS-D remain limited and unsatisfactory. Therefore, we are focusing on this subpopulation of patients to study the underling mechanism(s) of post-colitis gastrointestinal dysfunction. We now have preliminary data that provides a very strong rationale for the role of Catechol-O- Methyl-Transferase (COMT) and miRNAs leading to GI dysfunction in PI-IBS-D patients. Enteric infections alter gastrointestinal function and visceral nociception leading to PI-IBS-D. We have identified miRNAs in PI-IBS-D patients, modulated by COMT signaling pathways, that target downstream genes in the colonic enteric nervous system which control post-inflammatory regulation of gastrointestinal function and visceral nociception. We hypothesize that miRNAs dysregulate downstream targets following an enteric infection through altered COMT signaling pathways. These new findings suggest that PI-IBS-D involves dysregulation of complex regulatory pathways in which miRNAs interact through downstream targets. Our lab has established techniques to determine inter- and intra-cellular roles of miRNAs in the epigenetic regulation of the expression of their down-stream target genes. These methods include interaction analysis of miRNAs; in vitro transfection of miRNAs; and in vivo injection of miRNAs oligonucleotides. These findings may shed light on the mechanisms of dysregulation of gastrointestinal function in PI-IBS-D patients. This will overcome a critical barrier to progress in the management of patients following enteric infection and colitis–absence of effective treatment interventions and may lead to preventive and/or therapeutic strategies in PI-IBS-D patients that mimic or inhibit the effects of specific miRNAs on target gene expression.