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Alterations of Neuropeptide Levels among the Gut-brain Axis in Experimental Colitis and the Impact of Dipeptidyl Peptidase IV Deficiency

INTRODUCTION: Peptidases are considered to exert a crucial role in the etiopathology of inflammatory bowel diseases (IBD, including Crohn’s disease and ulcerative colitis). Increasing scientific evidence confirms a causal connection between the central and enteric nervous system where peptidases play a fundamental role in maintaining the homeostasis of their biologically important substrates. Dipeptidyl-peptidase IV (DPP IV/CD26) is an intrinsic membrane-bound and soluble glycoprotein showing a pleiotropic role in the organism. We hypothesized that DPP IV/CD26 contributes to IBD pathogenesis by influencing circulating and tissue levels of neuropeptides among the gut-brain axis. MATERIAL AND METHODS: A trinitrobenzenesulfonic acid (TNBS)-induced (Crohn-like, chemically induced) model of colitis has been induced in CD26 deficient and wild type (C57BL/6) mice. Control animals received the same volume of 50% ethanol and saline solution. Animals were monitored daily for evaluating the disease activity index and were sacrificed 2, 7, 10, 15 and 30 days after TNBS application, representing the whole range of colitis development and tissue healing. Histomorphometrical and pathohistological analyses of colon tissues were performed. Neuropeptides concentrations and protein expressions as well as DPP IV/CD26 enzymatic activity among the gut-brain axis have been determined at both systemic and local levels by ELISA and Western blot techniques. RESULTS: Our study revealed that CD26 deficient mice constitutionally have significantly (p<0.05) higher serum vasoactive intestinal peptide (VIP) concentrations compared to their wild-type counterpairs. VIP concentrations in serum of both mice strains reach their maximum values in the acute phase of colitis. This increase is significantly more accentuated in CD26 deficient mice. Neuropeptide concentrations in colon were increased in both mice strains in acute inflammation as well, with significantly (p<0.05) higher values in CD26 deficient mice. Likewise, VIP levels in the brain showed increased concentrations in both mice strains in acute inflammation with significantly (p<0.05) higher values in CD26 deficient mice. CONCLUSION: The results of our study indicate that mechanisms activated locally in the gut mucosa upon inflammatory events induce changes in neuropeptides in the brain, confirming the importance of the gut-brain axis in IBD. Moreover, DPP IV/CD26 has been confirmed to play an important neuroimmunomodulative role in IBD pathogenesis, which should further be evaluated.

neuropeptides, gut-brain axis, experimental colitis

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