Enteric neural pathways mediate the anti-inflammatory actions of glucagon-like peptide 2

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David L Sigalet, Laurie E Wallace, Jens Juul Holst, Gary R Martin, Tatsuru Kaji, Hiroaki Tanaka, Keith A Sharkey

Glucagon-like peptide-2 (GLP-2) is an important regulator of nutritional absorptive capacity with anti-inflammatory actions. We hypothesized that GLP-2 reduces intestinal mucosal inflammation by activation of vasoactive intestinal polypeptide (VIP) neurons of the submucosal plexus. Ileitis or colitis was induced in rats by injection of trinitrobenzene sulfonic acid (TNBS), or colitis was induced by administration of dextran sodium sulfate (DSS) in drinking water. Subsets of animals received (1-33)-GLP-2 (50 mug/kg sc bid) either immediately or 2 days after the establishment of inflammation and were followed for 3-5 days. The involvement of VIP neurons was assessed by concomitant administration of GLP-2 and the VIP antagonist [Lys(1)-Pro(2,5)-Arg(3,4)-Tyr(6)]VIP and by immunohistochemical labeling of GLP-2-activated neurons. In all models, GLP-2 treatment, whether given immediately or delayed until inflammation was established, resulted in significant improvements in animal weights, mucosal inflammation indices (myeloperoxidase levels, histological mucosal scores), and reduced levels of inflammatory cytokines (IFN-gamma, TNF-alpha, IL-1beta) and inducible nitric oxide synthase, with increased levels of IL-10 in TNBS ileitis and DSS colitis. Reduced rates of crypt cell proliferation and of apoptosis within crypts in inflamed tissues were also noted with GLP-2 treatment. These effects were abolished with coadministration of GLP-2 and the VIP antagonist. GLP-2 was shown to activate neurons and to increase the number of cells expressing VIP in the submucosal plexus of the ileum. These findings suggest that GLP-2 acts as an anti-inflammatory agent through activation of enteric VIP neurons, independent of proliferative effects. They support further studies to examine the role of neural signaling in the regulation of intestinal inflammation.

Original languageEnglish
JournalAmerican Journal of Physiology: Gastrointestinal and Liver Physiology
Volume293
Issue number1
Pages (from-to)G211-21
ISSN0193-1857
DOIs
Publication statusPublished - Jul 2007

    Research areas

  • Animals, Anti-Inflammatory Agents, Colitis, Ulcerative, Dextran Sulfate, Disease Models, Animal, Enteric Nervous System, Glucagon-Like Peptide 2, Ileitis, Male, Neurotensin, Rats, Rats, Sprague-Dawley, Recombinant Fusion Proteins, Trinitrobenzenesulfonic Acid, Vasoactive Intestinal Peptide

ID: 132050246