The gut as a sensory organ.

TLDR: A major therapeutic opportunity exists to develop agents that target the receptors facing the gut lumen, and a major challenge is to develop a comprehensive understanding of the integrated responses of the gut to the sensory information it receives.

Abstract: The gastrointestinal tract presents the largest and most vulnerable surface to the outside world. Simultaneously, it must be accessible and permeable to nutrients and must defend against pathogens and potentially injurious chemicals. Integrated responses to these challenges require the gut to sense its environment, which it does through a range of detection systems for specific chemical entities, pathogenic organisms and their products (including toxins), as well as physicochemical properties of its contents. Sensory information is then communicated to four major effector systems: the enteroendocrine hormonal signalling system; the innervation of the gut, both intrinsic and extrinsic; the gut immune system; and the local tissue defence system. Extensive endocrine-neuro-immune-organ-defence interactions are demonstrable, but under-investigated. A major challenge is to develop a comprehensive understanding of the integrated responses of the gut to the sensory information it receives. A major therapeutic opportunity exists to develop agents that target the receptors facing the gut lumen.

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Figure 3 | Multiple sensors and multiple downstream effectors of gut sensory systems, using the L cell as an example. The L cell has exteroceptors for free fatty acids, sugars, protein fragments (peptone) and bile acids. These receptors face the contents of the intestine. L cells release the hormones GLP-1, GLP-2, PYY and oxyntomodulin. These hormones have actions on a range of effectors, including enterocytes, enteric neurons, vagal sensory neurons (vagus; the effect of PYY probably being indirect) and IPANs, blood vessels, lymphocytes, myofibroblasts and the hypothalamus. Downstream effects of GLP-1 on vagal afferents include slowed gastric emptying, inhibition of gastric acid secretion, stimulation of insulin release and satiety. In addition, vagal efferent pathways increase hormone release. L cells have processes that run adjacent to the basal surfaces of enterocytes. L cells also express interoceptors that receive signals from the internal milieu, including from

Figure 2 | Sensory systems at the lumenal interface. The intestinal lining epithelium is exposed to nutrients, which are primarily detected by receptors, most of which are GPCRs, on enteroendocrine cells. These cells release hormones that signal to the epithelium, lymphocytes, arteries and neurons locally, and which enter the circulation to act at remote sites. Presentation of antigen to Peyer’s patches is mediated by M cells121 that sample the lumen and transfer antigen to dendritic cells. M cells probably do not process antigens themselves as they do not express MHC class II molecules,122 although they do express PRRs, including TLR4.123 Apart from M cells, the epithelium is not completely impervious to bacteria; some cross it and can be found in the wall of the intestine, in the liver and in mesenteric lymph nodes. Bacterial antigens also cross the mucosal epithelium, where they can be sampled by antigen presenting cells and exhibited to T cells. A small proportion of dendritic cells extend processes between enterocytes and probably sample the luminal contents directly.3 Products of microorganisms are also detected by PRRs, including TLRs on Paneth cells and enterocytes. Foreign molecules, including toxins and pharmaceuticals, are recognised by FCTs, transported across the epithelium and metabolised by detoxifying enzymes in the gut wall and liver. Abbreviations: EEC, enteroendocrine cell; FCTs, foreign compound transporters; GPCRs, G protein-coupled receptors; PRRs, pattern-recognition receptors; TLRs, Toll-like receptors.

Table 1 | Enteroendocrine cells of the mammalian gastrointestinal tract Cell Products Luminal receptors Locations Principal effects A (X-like) cells and subtypes Ghrelin,

Figure 1 | Summary of sensory inputs to the gut and the effector systems that they influence. A complex mix of nutrients and their breakdown products, salts, pathogens, pathogen-derived antigens, digestive tract secretions, desquamated enterocytes, toxins and pharmaceuticals bathes the mucosa. Luminal contents activate four major effectors: the enteroendocrine system, the nervous system, the gut immune system, and the nonimmune defence system of the gut. Enteroendocrine cells (purple) in the mucosal epithelium sense luminal chemicals and release hormones that act locally on nerve endings, on enteric neurons, on the epithelium and on cells of the immune system. Hormones that enter the circulation act at remote sites. Lymphocytes are activated by antigens presented to them from the lumen. Immune cells and cells of tissue defence, such as mast cells and macrophages, also release substances that act locally within the gut wall. Some afferent neurons have cell bodies in the gut wall (intrinsic primary afferent neuron and intestinofugal neurons) and the cell bodies of others are in extrinsic ganglia (extrinsic primary afferent neurons). Bacterial products are detected by pattern-recognition receptors to activate local defence mechanisms, including secretion of antimicrobials from Paneth cells (red). Reproduced with permission from Furness, J. B. The Enteric Nervous System (Blackwell, Oxford, 2006).