Mechanisms of Gastrointestinal Post-Inflammatory Disease

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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.