Mechanisms of Gastrointestinal Post-Inflammatory Disease

摘要： 腹泻为主的肠易激综合征（IBS-D）是最常见的 胃肠道疾病，表现为腹痛、稀水样便， 在没有可识别的炎症，结构或代谢异常的情况下的紧迫性。一 最常见和最难治疗的IBS-D组是那些患有肠易激综合征的人， 食物中毒感染，随后发展为感染后，以绦虫为主， 肠易激综合征（PI-IBS-D）。持续性腹泻与内脏器官损害的机制 结肠炎消退后的伤害感受尚不清楚，需要进一步的研究， 了解其病理生理学。这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，PI-IBS-D的药物治疗仍然存在， 有限且不令人满意。因此，我们正在集中对这一亚群患者进行研究 结肠炎后胃肠功能障碍的潜在机制。 我们现在有了初步的数据，为cAMP的作用提供了非常有力的理论基础- 反应元件转录因子（CREB）和miRNAs，导致阿片基因减少 在PI-IBS-D患者中表达。肠道感染改变胃肠道功能和内脏 伤害性感受导致PI-IBS-D。我们已经在PI-IBS-D患者中鉴定了miRNA， 由CREB信号通路调节，靶向结肠中的下游阿片基因， 肠神经系统与胃肠功能炎症后调控 和内脏伤害感受。我们假设miRNAs对下游靶点的调节异常 通过改变CREB信号通路引起肠道感染。这些新发现 表明PI-IBS-D涉及复杂调控途径的失调，其中miRNAs 通过下游目标相互作用。我们的实验室已经建立了创新的技术， 确定miRNA在表达的表观遗传调控中的细胞间和细胞内作用， 下游靶基因的表达。这些方法包括miRNA的相互作用分析; miRNA的体外转染;以及miRNA寡核苷酸的体内注射。这些发现 将（i）阐明PI-IBS-D中胃肠功能失调的机制 （ii）克服一个关键障碍，以取得进展，在病人的管理， 肠道感染和结肠炎-缺乏有效的治疗干预措施; ㈢导致预防性 和/或治疗策略，其模拟或抑制特异性免疫抑制剂的作用， miRNA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 mechanisms 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 underlying mechanisms of post-colitis gastrointestinal dysfunction. We now have preliminary data that provide a very strong rationale for a role for the cAMP- response element transcription factor (CREB) and miRNAs, leading to decreased opioid gene expression 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 that are modulated by CREB signaling pathways, that target downstream opioid genes in the colonic enteric nervous system and that control post-inflammatory regulation of gastrointestinal function and visceral nociception. We hypothesize that miRNAs dysregulate downstream targets following an enteric infection through altered CREB 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 innovative 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 will (i) shed light on the mechanisms of dysregulation of gastrointestinal function in PI-IBS-D patients; (ii) overcome a critical barrier to progress in the management of patients following enteric infection and colitis–absence of effective treatment interventions; (iii) 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.