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Luminal sensing in the gut: an overview

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The wall of the gut responds to an impressive array of signals originating in the lumen, including nutrient and non-nutrient chemicals, mechanical factors, and micro-organisms. The idea that the gut wall exhibits luminal chemo-sensitivity is implied in the original discovery of secretin by Bayliss and Starling, and has become an integral part of models of neurohumoral control of gastrointestinal function. Entero-endocrine cells are specialised for luminal nutrient sensing but sub-epithelial nerve fibres may also respond to luminal chemicals that freely diffuse across the epithelium eg short chain fatty acids. The molecular recognition mechanisms include G-protein coupled receptors (GPCRs) eg the extracellular Ca2+ sensing receptor which also responds to aromatic amino acids. There are also GPCRs sensing fatty acids, as well as bitter or noxious compounds. In addition, though, gating of ion channels including events secondary to energy availability eg ATP, may be involved in sensing some luminal chemicals. There is likely to be integration of luminal signals at several levels including at the level of entero-endocrine cells and at sub-epithelial nerve fibers. For example, the intestinal hormone CCK acts on primary afferent nerve fibers of the vagal trunk. The same fibers also express leptin receptors that are thought to respond to leptin released from gastric chief cells, orexin receptors (activation of which inhibits CCK) and possibly ghrelin receptors. Multiple signalling mechanisms allow specific responses to be matched to meals of differing content.
Rats were fasted 48 h and then injected once with either saline, pentagastrin, EGF, secretin or combinations of secretin and pentagastrin or EGF. Another group of rats was fasted and refed. Animals were killed 4 h later and ODC assayed in mucosa of the cecum, proximal colon, and distal colon. EGF significantly increased ODC activity in all 3 tissues. Secretin had no effect by itself on ODC or ODC stimulated by EGF. Pentagastrin significantly increased ODC of the cecum, and secretin completely inhibited the effect of pentagastrin. Refeeding fasted rats significantly induced activity in all three tissues. Immunocytochemistry using a highly specific polyclonal ODC antibody showed that ODC was confined to the crypt cells of the proximal colon. Antibody dilution techniques demonstrated that gastrin, EGF and refeeding increased the level of enzyme in these cells. Refeeding in addition caused the appearance of enzyme in surface epithelial cells. These results showed that colonic mucosal ODC is present in proliferative cells and is regulated by the same peptides known to regulate growth in this tissue. Colonic mucosal ODC also responds the same way as it does in the oxyntic gland and small bowel mucosa.
At the turn of XIX and XX century, the principal concept explaining the mechanism of secretory activity of the digestive glands was nervism proposed by I. P. Pavlov at Russian physiological school in St Petersburg, and this dogma was widely recognized for several years in other countries. The discovery of secretin in 1902 by W.B. Bayliss and E.H. Starling, and then of gastrin in 1906 by J.S. Edkins, emphasized the hormonal regulation of pancreatic and gastric secretion, respectively. In 1943, A.C. Ivy and E. Olberg discovered a hormone, which contracts the gallbladder - cholecystokinin (CCK), while A. Harper and H.S. Raper described another hormone, pancreozymin, which stimulated pancreatic enzymes. It required over twenty years, however, for these and many other hormones to be identified, purified and synthesized due to the extensive work of several teams including R. Gregory, G. Dockray and Kenner of the UK; J. Rehfeld of Denmark and E. Wunsch of Germany for their work on gastrin; E. Jorpes and V. Mutt of Sweden and N. Yahaihara of Japan for their work on secretin and other GI hormones including, CCK, vasoactive intestinal peptide (VIP), gastric inhibitory peptide (GIP), motilin, gastrin-releasing peptide (GRP) and others peptides. CCK and pancreaozymin were found by E. Jorpes and V. Mutt to represent structurally a common messenger for pancreatico-biliary secretion. This rapid development of GI endocrinology in the 1960s and 1970s could be attributed to the application of peptide biochemistry in characterizing various peptide hormones. The technique of radioimmunoassay by S.A. Berson and R.S. Yalow in 1959 measured minute amounts of hormones in the circulation and tissue, and the technique of immunocytochemistry detected the cellular origin of these hormones. Further progress in molecular biology led to sequencing GI hormones and their prohormones, and opened a new area of investigation for the physiological role of these hormones in the mechanism of digestive gland secretion, motility of gastrointestinal tract, visceral blood flow, tissue growth and integrity in health, as well as in various digestive diseases. Overall, apparent divergent concepts, the nervous control (Pavlov) and hormonal control (Bayliss and Starling), greatly facilitated the elucidation of the interacting neuro-hormones during the cephalic, gastric, and intestinal phases of gastric and pancreatic secretion in health and digestive diseases. Although Polish contributions in the early phase of GI endocrinology concerned mostly gastric inhibitory hormones such as enterogastrone and urogastrone, major Polish traces can be detected in the elucidation of origin and physiological role and pathological involvement of gastrin, CCK, secretin, motilin, gastric inhibitory peptide and the most recent additions of enterohormones such as epidermal growth factor, somatostatin, leptin or ghrelin. Major achievements have been obtained in gastric and colorectal cancerogenesis involving gastrin and its precursor, progastrin.
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Brain-gut axis in pancreatic secretion and appetite control

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The stimulation of exocrine pancreatic secretion that has been attributed by Pavlov exclusively to various reflexes (nervism), was then found that it depend also on numerous enterohormones, especially cholecystokinin (CCK) and secretin, released by duodeno-jejunal mucosa and originally believed to act via an endocrine pathway. Recently, CCK and other enterohormones were found to stimulate the pancreas by excitation of sensory nerves and triggering vago-vagal and entero-pancreatic reflexes. Numerous neurotransmitters and neuropeptides released by enteric nervous system (ENS) of gut and pancreas have been also implicated in the regulation of exocrine pancreas. This article was designed to review the contribution of vagal nerves and entero-hormones, especially CCK and other enterohormones, involved in the control of appetitive behavior such as leptin and ghrelin and pancreatic polypeptide family (peptide YY and neuropeptide Y). Basal secretion shows periodic fluctuations with peals controlled by ENS and by motilin and Ach. Plasma ghrelin, that is considered as hunger hormone, increases under basal conditions, while plasma leptin falls to the lowest level. Postprandial pancreatic secretion, classically divided into cephalic, gastric and intestinal phases, involves predominantly CCK, which under physiological conditions acts almost entirely by activation of vago-vagal reflexes to stimulate the exocrine pancreas, being accompanied by the fall in plasma ghrelin and increase of plasma leptin, reflecting feeding behavior. We conclude that the major role in postprandial pancreatic secretion is played by vagus and gastrin in cephalic and gastric phases and by vagus in conjunction with CCK and secretin in intestinal phase. PP, PYY somatostatin, leptin and ghrelin that affect food intake appear to participate in the feedback control of postprandial pancreatic secretion via hypothalamic centers.
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