Mechanisms Underlying the Therapeutic Efficacy of Exclusive Enteral Nutrition in Crohn s Disease
Abstract
Crohn’s disease (CD) is an inflammatory bowel disease (IBD), characterized by recurrent transmural inflammation (involving full-thickness of gut wall) in the colon or/and ileum. The main symptoms with CD include abdominal pain, diarrhea, and constipation. The mechanisms of CD-associated inflammation and bowel symptoms are not well understood. There is no cure for CD, and treatments aim to suppress inflammation and reduce symptoms. Among the therapeutic options, corticosteroids, immune modulators, and biologic agents all have substantial adverse effects or limitations, whereas exclusive enteral nutrition (EEN) is safe and effective, and now a first-line treatment for active CD especially in young patients. EEN involves oral or nasogastric tube feeding of a complete liquid diet with exclusion of normal foods for a defined period (usually 4 to 8 weeks). As a dietary therapy, EEN is found as equivalent as, or superior to corticosteroids in the induction of remission in children (with nearly 80% remission rate). Although EEN is widely used in Europe, Asia, and Australia, it is not well accepted in the US, partly because the exact mechanisms for its therapeutic benefits in CD are not clear. Although mechanical stress (MS), associated with inflammatory cell infiltration, edema, fibrosis, and stenosis, are commonly encountered in CD, the role of MS in the development of inflammation and gut dysfunction is largely unrecognized. In a well-established rodent model of CD, we found that intracolonic instillation of a hapten reagent TNBS induces a localized transmural inflammation (as in CD) in the distal colon, which is associated with mechanical tension in the local inflammation site and lumen distention in the bowel prior to inflammation. These changes represent significant MS in the colon. Our preliminary studies demonstrated that MS induces marked induction of certain pro-inflammatory mediators such as osteopontin (OPN) and COX-2 in the inflammation and pre-inflammation sites, which contribute significantly to the development of inflammation and bowel symptoms. We found that EEN treatment dramatically decreases feces production and prevents inflammation-associated MS. Our hypotheses are: (1) transmural inflammation in CD causes MS in the inflammation and pre-inflammation sites, and the MS induces expression of mechanosensitive genes OPN and COX-2 to contribute to the development of inflammation and bowel dysfunctions and (2) EEN treatment is beneficial in CD by preventing MS and blocking the effects of MS-induced gene expression. Accordingly, our specific aims are: (1) to determine if MS plays a role in the development of CD by evaluating the effects of EEN on mechanosensitive gene expression, inflammation and bowel dysfunction; (2) to investigate the mechanisms underlying the beneficial effect of EEN on gut inflammation in CD, by focusing on the role of mechanosensitive expression of OPN in Th1/Th17 immune response; and (3) to investigate the mechanisms underlying the beneficial effect of EEN on bowel dysfunctions in CD, by focusing on the role of mechanosensitive expression of COX-2 in motility dysfunction. To identify the role of MS in the development of CD, we will take novel approach to differentiate the effects of MS from that of inflammation by studying site-specific changes of gene expression, inflammation and motility function in tissues exposed to MS or/and inflammation. Further studies in animal models and mechanical stretch of cultured cells will be applied to confirm the role of MS. To uncover the mechanisms of EEN efficacy, we will investigate the site-specific changes and underlying mechanisms in the CD model treated with either regular chow or EEN. The significance and mechanisms of mechanosensitive expression of OPN and COX-2 in inflammation and motility dysfunction will be further determined in gene deficient animals and with pharmacological inhibitors. Upon completion of the study, we are expec
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010681
Entities
People
- Xuan-Zheng Shi
Organizations
- United States Army
- University of Texas Medical Branch