Inflammatory Cells and the Regulation of Gut Motility (2004)

The intraluminal contents of the gastrointestinal tract are moved from one specialised region of the gut to another by the co-ordinated contraction of its smooth muscle layers. The pattern of motility is integrated with and related to the function of particular regions. For example, the oesophagus acts as a propulsive conduit for the delivery of food into the stomach, which is a mixing and storage organ. This integrated transit of nutrients requires a highly sophisticated control system, which acts upon the smooth muscle cells to produce the required effect. The control systems involve the intrinsic nervous system and the enteric nervous system modulated by extrinsic nerves, paracrine and endocrine polypeptide hormones and immune cells. In recent years it has become appreciated that there are clearly defined spatial relationships with some immune cells, particularly most cells and mucosal nerve fibres. Inflammatory cells are able to influence the function of the enteric neuromusculature. Experimental data in both animals and humans have shown that degranulation of mast cells such as occurs in stress and IgE mediated hypersensitivity responses results in activation of mucosal nerves via PAR-2 receptors and ultimately disturbed motor activity. Induction of mucosal inflammation by nematode parasitic infection in the experimental animal results in profound changes in enteric nerves and smooth muscle. These include changes in muscle contractility and phenotype, in neural reactivity and in the content of neurotransmitters. These changes occur at non-inflamed distal sites and with very superficial inflammation of the mucosa. The muscle cells exhibited hypercontractility generating more tension per unit of cross-sectional area than control tissue. This persisted and did not return to normal for about at least six weeks. The muscle cells also became involved in the inflammatory response with alteration of their phenotype to both synthesise cytokines and to express HLA-DR enabling them to act as amateur antigen presenting cells. Repetitive activation of intrinsic afferent neurons might occur with the release of 5 hydronxy-tryptanine from enteroendocrine cells repeatedly activates such neurons resulting in increased sensitivity of afferent mucosal nerve endings. Such sensitised nerves produce both an exaggerated and prolonged response to stimuli in the experimental animal. In these experimental animal models, steroid treatment attenuates this response. Similarly, studies in athymic mice that lack functional T cells showed a considerable diminution of the hyperreflexic response suggesting that T cells are somehow important for this hypercontractility neurotode infections generate a TH2 response with increased 1L-13 and IL-4 production. These cytokines appear to initiate the hyperflexiavia via the signal transducer and activator of transcription 6 pathway. Importantly, these changes persist after the resolution of the infection and they accompany mucosal inflammatory response. Increasingly, it is being recognised that irritable bowel syndrome symptoms occur following an enteric infection with Salmonella, Shigella and Campylobacter. Often evidence is found of a low-grade inflammatory response in the gut. Much less commonly, an enteric infection will induce a severe autoimmune response directed against either the enteric nerves where anti-Hu antibodies may both directly influence enteric nerve function and be a marker for a lymphocytic ganglionitis or against smooth-muscle cells causing a myositis. In both cases, immunosuppression may be life-saving. There is an increasing body of evidence suggesting important neuro-immune interactions as well as a myo-immune interaction. These interactions may have major implications for the intestinal dysmotility associated with food allergic responses, stress and post infectious irritable bowel syndrome.