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• W2012106488 abstract "Artificial distinctions between disciplines within the biological sciences are an impediment to progress. In contrast, research that pitches seemingly disparate disciplines together often yields unexpected results, expands traditional concepts of disease pathogenesis and generates new hypotheses to be tested. From this, exciting therapeutic strategies may emerge. Examples of successful, developing hybrid disciplines include neuroimmunophysiology, psychoneuroimmunology and cellular microbiology.1-4 By integrating information from traditional avenues of research, these hybrid disciplines provide a coherent and more complete understanding of disease pathogenesis. This is particularly true for complex disorders such as inflammatory bowel disease.5 Investigation of mucosal inflammatory cells and mediators outside the context of the regulatory influence of their local microenvironment is unlikely to yield a complete picture of what happens in vivo. Mucosal immune and inflammatory effector cells exchange regulatory signals with other resident cells within the mucosal microenvironment.1,6,7 Thus, enteric nerves, epithelium and stromal cells can no longer be considered innocent bystanders in inflammatory diseases. Rather, they may actively participate and modify the inflammatory process. Some of these interactions including lymphoepithelial and immunomyenteric molecular cross-talk have been reviewed elsewhere.1,6-8 Nerves may contribute to the pathophysiology of inflammatory bowel disease by at least three interrelated mechanisms. First, the amplification and healing phases of inflammation may disturb the functional interactions of enteric nerves with their target cells within the inflamed microenvironment. This may alter motor and secretory function of the gut, accounting for reported alterations in contractility and responsiveness to lumenal stimuli, and may contribute to symptoms such as diarrhoea and cramps. Some of these disturbances in motor function may be evident at sites distant from the area of disease activity and appear to be due to activation of neural circuits within the inflamed area of bowel.8 In this issue of Neurogastroenterology and Motility, Geboes and Collins present an overview of the structural abnormalities of the enteric nervous system in Crohn's disease and ulcerative colitis. Although central and peripheral nervous system abnormalities have been well described in both of these disorders, they are uncommon.9 In contrast, abnormalities of the enteric nervous system are frequently noted in patients with inflammatory bowel disease and were first postulated to have a role in pathogenesis almost 50 years ago.10 Morphological changes in enteric nerves are more characteristic of Crohn's disease than ulcerative colitis, but are not specific. They include both proliferative and degenerative changes, and are associated with alterations in neuropeptide content. Neuronal distortions are probably secondary to the inflammatory process. While axonal damage may be understood in terms of injurious effects of inflammatory mediators, it may actually involve local T lymphocyte activation within the nerve plexus itself. Thus, enteroglial cells can express major histocompatibility complex (MHC) class II antigens required for antigen presentation and, therefore, might be involved in the initiation of inflammatory responses.11 The proliferative changes in enteric nerves are more difficult to explain. Remodelling of nerves by intestinal inflammation has been described,12 but whether neuronal hyperplasia represents actual mitosis of neurones, or more likely the possible presence of stem cells with proliferative potential within enteric ganglia, is unclear. In this context, upregulation of nerve growth factor reported in neuronal fibres in intestinal inflammation may be have a role.13 A second mechanism by which nerves may contribute to the pathophysiology of inflammatory bowel disease involves the modulation of the mucosal immune system by the neuroendocrine system. Enteric nerves relay the systemic regulatory influence of the psyche and central nervous system on the mucosal immune response. This may contribute to the dysfunctional mucosal immune regulation thought to underlie Crohn's disease and ulcerative colitis.5 The concept of psychoneuroimmune regulation of inflammation is beyond our scope here but raises intriguing theoretical possibilities to account for clinical observations such as the role of stress and the marked placebo effect on inflammatory disease activity in patients with inflammatory bowel disease.14,15 A third related mechanism occurs at a more local level, where enteric nerves may release neurotransmitters which may prime, perpetuate or otherwise modify the mucosal inflammatory and healing processes. Most of the extrinsic innervation of the bowel consists of sensory afferents, and a single enteric neurone may contain more than one neuropeptide.16 Local release of neuropeptides, most notably substance P and calcitonin gene-related peptide (CGRP), from sensory nerve terminals, can modulate or initiate an inflammatory response in peripheral tissues – 'neurogenic inflammation'.1,6 This involves local vasodilatation, extravasation of plasma, mast cell degranulation and secondary effects of mast cell mediators on mucosal cell function. Mucosal levels of substance P tend to be normal or modestly elevated in inflammatory bowel disease, whereas marked upregulation of substance P binding sites has been found by autoradiography in mucosal vasculature and lymphoid tissue in Crohn's disease and ulcerative colitis,17 and increased binding sites on enteric neurones has been reported in Crohn's disease but not in ulcerative colitis.18 Results using molecular techniques including in situ hybridization have not confirmed the marked degree of this upregulation but clearly confirm the receptor distribution in inflamed mucosa.19 The proinflammatory and immunomodulatory effects of substance P are also well documented and are particularly evident in mucosal tissue.6,20 Experimental studies in animal models of inflammation treated with capsaicin have shown that sensory nerves may also have a protective effect on mucosal integrity during inflammation and contribute to the healing phase of inflammation. It appears that CGRP may be primarily responsible for these protective effects.20 In addition to symptoms such as pain and diarrhoea, can enteric neuropathology explain other clinical puzzles in patients with inflammatory bowel disease? Geboes and Collins comment on functional disturbances occurring at sites remote from the inflammatory activity due to excitation of neural circuits, and also allude to the possibility that enteric innervation might influence disease distribution. But, could enteric nerves explain why relapses of Crohn's disease usually occur proximal to a previous surgical anastomosis? Could nerves explain abrupt cut-off of inflammatory disease activity in patients with colitis limited to the left colon? What are the therapeutic implications of neuropathophysiology in inflammatory bowel disease? In an earlier era, vagotomy and pelvic nerve lesions were thought to have a favourable effect on the outcome of patients with inflammatory bowel disease.21 In modern times, trials of substance P receptor antagonists have been initiated and the influence of neuroactive compounds such as clonidine, nicotine and local anaesthetics are being investigated for their apparent therapeutic effects on mucosal inflammatory disease.21 Finally, can enteric neuropathophysiology in inflammatory disorders offer anything to our understanding of functional gastrointestinal disorders? Considerable effort has been expended in investigating the enteric nervous system in relation to alterations of motor and sensory function in patients with functional (perhaps better termed 'dysfunctional') disorders of the gut. This is hardly surprising given the high prevalence of these conditions in clinical practice. Unfortunately, progress has been limited by confounding variables including criteria of disease definition and the heterogeneity of functional disorders.22 However, much can be learned from the neuropathophysiology of diseases with a defined organic basis such as infectious and inflammatory bowel diseases. Perhaps information gleaned from studying such disorders may serve as a model for formulating concepts and testable hypotheses relating to less tangible functional gastrointestinal disorders. For example, the normal intestinal mucosa exists in a state of 'controlled inflammation'.1 Bidirectional communication between this regulated inflammatory infiltrate and enteric nerves is mediated by cytokines, neuropeptides and other factors. Whether this communication is disturbed or contributes to sensory and motor abnormalities in the dysfunctional (nonpathologically inflamed) bowel deserves consideration. The author is supported in part by the Health Research Board of Ireland." @default.
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• W2012106488 title "Enteric neuropathophysiology and inflammatory bowel disease" @default.
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