Neuro-immune interactions in inflammatory bowel disease and irritable bowel syndrome: future therapeutic targets.
ABSTRACT The gastro-intestinal tract is well known for its largest neural network outside the central nervous system and for the most extensive immune system in the body. Research in neurogastroenterology implicates the involvement of both enteric nervous system and immune system in symptoms of inflammatory bowel disease and irritable bowel syndrome. Since both disorders are associated with increased immune cell numbers, nerve growth and activation of both immune cells and nerves, we focus in this review on the involvement of immune cell-nerve interactions in inflammatory bowel disease and irritable bowel syndrome. Firstly, the possible effects of enteric nerves, especially of the nonadrenergic and noncholinergic nerves, on the intestinal immune system and their possible role in the pathogenesis of chronic intestinal inflammatory diseases are described. Secondly, the possible effects of immunological factors, from the innate (chemokines and Toll-like receptors) as well as the adaptive (cytokines and immunoglobulins) immune system, on gastro-intestinal nerves and its potential role in the development of inflammatory bowel disease and irritable bowel syndrome are reviewed. Investigations of receptor-mediated and intracellular signal pathways in neuro-immune interactions might help to develop more effective therapeutic approaches for chronic inflammatory intestinal diseases.
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ABSTRACT: : Treatments for inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), functional dyspepsia, or motility disorders are not adequate, and purinergic drugs offer exciting new possibilities. Gastrointestinal symptoms that could be targeted for therapy include visceral pain, inflammatory pain, dysmotility, constipation, and diarrhea. The focus of this review is on the potential for developing purinergic drugs for clinical trials to treat gastrointestinal symptoms. Purinergic receptors are divided into adenosine P1 (A1, A2A, A2B, A3), ionotropic ATP-gated P2X ion channel (P2X1-7), or metabotropic P2Y1,2,4,6,11-14 receptors. There is good experimental evidence for targeting A2A, A2B, A3, P2X7, and P2X3 receptors or increasing endogenous adenosine levels to treat IBD, inflammatory pain, IBS/visceral pain, inflammatory diarrhea, and motility disorders. Purine genes are also potential biomarkers of disease. Advances in medicinal chemistry have an accelerated pace toward clinical trials: Methotrexate and sulfasalazine, used to treat IBD, act by stimulating CD73-dependent adenosine production. ATP protects against NSAID-induced enteropathy and has pain-relieving properties in humans. A P2X7R antagonist AZD9056 is in clinical trials for Crohn's disease. A3 adenosine receptor drugs target inflammatory diseases (e.g., CF101, CF102). Dipyridamole, a nucleoside uptake inhibitor, is in trials for endotoxemia. Drugs for pain in clinical trials include P2X3/P2X2/3 (AF-219) and P2X7 (GSK1482160) antagonists and A1 (GW493838) or A2A (BVT.115959) agonists. Iberogast is a phytopharmacon targeting purine mechanisms with efficacy in IBS and functional dyspepsia. Purinergic drugs have excellent safety/efficacy profile for prospective clinical trials in IBD, IBS, functional dyspepsia, and inflammatory diarrhea. Genetic polymorphisms and caffeine consumption may affect susceptibility to treatment. Further studies in animals can clarify mechanisms and test new generation drugs. Finally, there is still a huge gap in our knowledge of human pathophysiology of purinergic signaling.Inflammatory Bowel Diseases 05/2014; DOI:10.1097/MIB.0000000000000047 · 5.48 Impact Factor
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ABSTRACT: Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), which affect 5% people in the U.S. and northern European countries, result in chronic visceral pain of unknown etiology. Pharmacological treatments are thus often palliative or not very effective. This review summarizes the current knowledge on peripheral and central mechanisms of colonic pain in IBS and IBD. The role of the commensal microflora and the enteric nervous system in peripheral inflammation and sensitization of intestinal nociceptors is emphasized. Moreover, supraspinal modulatory influences (descending pathways, stress, hypervigilance) on spinal cord activity and gut physiology are presented. These data highlight the critical role of the brain–gut axis in the pathophysiology of IBS and IBD through neuro-immune and neuro-enteric interactions.Douleurs Evaluation - Diagnostic - Traitement 04/2010; 11(2):65-74. DOI:10.1016/j.douler.2010.02.006
- Brain Behavior and Immunity 08/2011; 25. DOI:10.1016/j.bbi.2011.07.107 · 6.13 Impact Factor