Inflammatory bowel disease (IBD) is a complex multifactorial disease of unknown etiology. It is wide accepted that interplay of environmental, genetic, luminal and immune mechanisms culminate in this disease in predisposed subjects. Dextran sulphate sodium (DSS) model of colitis is considered as essential tool to investigate pathophysiological mechanisms and immunological processes of acute colitis and ulcerative colitis (UC). T helper (Th) cells are traditionally divided into 2 distinct subsets, Th1 and Th2. Recently, an additional Th cell subset was found and designated Th17. Regulatory T (Treg) cells expressing the transcription factor forkhead box p3 (Foxp3) are indispensable for the maintenance of immune homeostasis. The proper balance of a dynamic cross-regulation between Th1, Th2, Th17 and Treg pathways is critical for optimizing defenses to microbes and voiding chronic tissue inflammation. Glutamine (GLN) is the most abundant free amino acid in plasma and tissue pool. It is a critical substrate for enterocytes and rapidly proliferating immune cells. Numerous studies showed that GLN supplementation attenuated pro-inflammatory cytokine release, protected against organ damage, and decreased mortality in an infected animal model. Our study also found that GLN exerts a more balanced Th1/Th2 response in a septic condition. However, studies concerning the effect of GLN on T cell polarization in IBD are rare. At present, no study has investigated the role of GLN on Th1/Th2/Th17 and Treg pathways in IBD. According to previous studies, acute DSS colitis was found to be characterized by a polarization toward Th1/Th17, while UC is primarily associated with Th2 type response. In order to investigate the role of GLN on regulating the homeostasis of T cells in acute colitis and UC, we propose to carry out this study in 3 consecutive years. In the 1st year, a DSS-induced acute colitis and in the second year a UC-like colitis will be established to investigate the effects of GLN on inflammatory mediator expressing and the cross-regulation between Th1, Th2, Th17, and Treg pathways. In the 3rd year, an in vitro study will be performed to evaluate the effect of different concentrations of GLN on the expression of nuclear factor-κB and downstream inflammatory mediators by intestinal epithelial cell stimulated by cytokines. This study will be the first one to investigate the effects of GLN on T cell polarization and inflammatory response in IBD. The results may provide useful information for the clinical application in GLN-supplemented nutrition for patients with IBD.
|Effective start/end date||8/1/11 → 7/31/12|