Sommansson A, Saudi WSW, Nylander O, Sjöblom M. Melatonin inhibits alcohol-induced increases in duodenal mucosal permeability in rats in vivo. Am J Physiol Gastrointest Liver Physiol 305: G95-G105, 2013. First published May 2, 2013; doi:10.1152/ajpgi.00074.2013.-Increased intestinal permeability is often associated with epithelial inflammation, leaky gut, or other pathological conditions in the gastrointestinal tract. We recently found that melatonin decreases basal duodenal mucosal permeability, suggesting a mucosal protective mode of action of this agent. The aim of the present study was to elucidate the effects of melatonin on ethanol-, wine-, and HCl-induced changes of duodenal mucosal paracellular permeability and motility. Rats were anesthetized with thiobarbiturate and a ϳ30-mm segment of the proximal duodenum was perfused in situ. Effects on duodenal mucosal paracellular permeability, assessed by measuring the blood-to-lumen clearance of 51 Cr-EDTA, motility, and morphology, were investigated. Perfusing the duodenal segment with ethanol (10 or 15% alcohol by volume), red wine, or HCl (25-100 mM) induced concentration-dependent increases in paracellular permeability. Luminal ethanol and wine increased, whereas HCl transiently decreased duodenal motility. Administration of melatonin significantly reduced ethanol-and wine-induced increases in permeability by a mechanism abolished by the nicotinic receptor antagonists hexamethonium (iv) or mecamylamine (luminally). Signs of mucosal injury (edema and beginning of desquamation of the epithelium) in response to ethanol exposure were seen only in a few villi, an effect that was histologically not changed by melatonin. Melatonin did not affect HClinduced increases in mucosal permeability or decreases in motility. Our results show that melatonin reduces ethanol-and wine-induced increases in duodenal paracellular permeability partly via an enteric inhibitory nicotinic-receptor dependent neural pathway. In addition, melatonin inhibits ethanol-induced increases in duodenal motor activity. These results suggest that melatonin may serve important gastrointestinal barrier functions.

Short-chain fatty acids (SCFAs) are produced by bacterial fermentation in the large intestine, particularly from diets containing fibres and carbohydrates. The small intestinal epithelium is exposed toSCFAsderivedmainly fromoral bacteriaor food supplementation. Although luminal nutrients are important in regulation of intestinal functions, the role of SCFAs in regulation of small intestinal mucosal barrier function and motility has not been fully described. The aim of the present study was to elucidate

Wan Saudi WS, Halim MA, Rudholm-Feldreich T, Gillberg L, Rosenqvist E, Tengholm A, Sundbom M, Karlbom U, Näslund E, Webb DL, Sjöblom M, Hellström PM. Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide. Am J Physiol Gastrointest Liver Physiol 309: G625-G634, 2015. First published July 23, 2015; doi:10.1152/ajpgi.00104.2015.-Neuropeptide S (NPS) receptor (NPSR1) polymorphisms are associated with enteral dysmotility and inflammatory bowel disease (IBD). This study investigated the role of NPS in conjunction with nitrergic mechanisms in the regulation of intestinal motility and mucosal permeability. In rats, small intestinal myoelectric activity and luminal pressure changes in small intestine and colon, along with duodenal permeability, were studied. In human intestine, NPS and NPSR1 were localized by immunostaining. Pre-and postprandial plasma NPS was measured by ELISA in healthy and active IBD humans. Effects and mechanisms of NPS were studied in human intestinal muscle strips. In rats, NPS 100-4,000 pmol·kg Ϫ1 ·min Ϫ1 had effects on the small intestine and colon. Low doses of NPS increased myoelectric spiking (P Ͻ 0.05). Higher doses reduced spiking and prolonged the cycle length of the migrating myoelectric complex, reduced intraluminal pressures (P Ͻ 0.05-0.01), and increased permeability (P Ͻ 0.01) through NO-dependent mechanisms. In human intestine, NPS localized at myenteric nerve cell bodies and fibers. NPSR1 was confined to nerve cell bodies. Circulating NPS in humans was tenfold below the ϳ0.3 nmol/l dissociation constant (K d) of NPSR1, with no difference between healthy and IBD subjects. In human intestinal muscle strips precontracted by bethanechol, NPS 1-1,000 nmol/l induced NO-dependent muscle relaxation (P Ͻ 0.05) that was sensitive also to tetrodotoxin (P Ͻ 0.01). In conclusion, NPS inhibits motility and increases permeability in neurocrine fashion acting through NO in the myenteric plexus in rats and humans. Aberrant signaling and upregulation of NPSR1 could potentially exacerbate dysmotility and hyperpermeability by local mechanisms in gastrointestinal functional and inflammatory reactions.inflammation; inflammatory bowel disease; migrating motor complex; NO; peristalsis NEUROPEPTIDE S (NPS) is localized to the brain stem and gastrointestinal tract. NPS activates the G protein-coupled receptor NPSR1 (also named GPR154) and activates adenylate cyclase to increase cAMP (17). NPS is regarded as an excitatory neurotransmitter and is involved in stress responses with regulation of arousal, wakefulness, and anxiety in mammals (4,5,22). The presence of an Asn-Gly (NG) sequence is a defining feature of a phylogenetically ancient family of neuropeptides called "NG peptides" (4). Rodent and human NPS possesses this NG sequence (18).NPS and NPSR1 exist in gastrointestinal mucosal epithelial cells (3,9,21). An NPSR1 polymorphism was reported along with higher mucosal epithelial immunoreactivity of NPSR1 in inflammatory bowel disease (IBD) with expression...

Alcohol may induce metabolic and functional changes in gastrointestinal epithelial cells, contributing to impaired mucosal barrier function. Duodenal mucosal bicarbonate secretion (DBS) is a primary epithelial defense against gastric acid and also has an important function in maintaining the homeostasis of the juxtamucosal microenvironment. The aim in this study was to investigate the effects of the luminal perfusion of moderate concentrations of ethanol in vivo on epithelial DBS, fluid secretion and paracellular permeability. Under thiobarbiturate anesthesia, a ∼30-mm segment of the proximal duodenum with an intact blood supply was perfused in situ in rats. The effects on DBS, duodenal transepithelial net fluid flux and the blood-to-lumen clearance of 51Cr-EDTA were investigated. Perfusing the duodenum with isotonic solutions of 10% or 15% ethanol-by-volume for 30 min increased DBS in a concentration-dependent manner, while the net fluid flux did not change. Pre-treatment with the CFTR inhibitor CFTRinh172 (i.p. or i.v.) did not change the secretory response to ethanol, while removing Cl− from the luminal perfusate abolished the ethanol-induced increase in DBS. The administration of hexamethonium (i.v.) but not capsazepine significantly reduced the basal net fluid flux and the ethanol-induced increase in DBS. Perfusing the duodenum with a combination of 1.0 mM HCl and 15% ethanol induced significantly greater increases in DBS than 15% ethanol or 1.0 mM HCl alone but did not influence fluid flux. Our data demonstrate that ethanol induces increases in DBS through a mechanism that is critically dependent on luminal Cl− and partly dependent on enteric neural pathways involving nicotinic receptors. Ethanol and HCl appears to stimulate DBS via the activation of different bicarbonate transporting mechanisms.

Neurogenesis involves cell proliferation, cell cycle arrest, differentiation, migration and the natural developmental death of the neural precursors. These processes are highly co-ordinated and governed by cell-cycle genes and neural transcription factors. Zn plays a crucial role as a functional and structural component of enzymes and transcription factors and components of the intracellular signaling pathway associated with the regulation of cell proliferation. The influence of additional Zn intake during pregnancy on the neuronal proliferation at ventricular zone of the developing fetus has been studied. Pups delivered by the group of mice provided with drinking water with 4.0 mM Zn supplement throughout pregnancy contained an increased number of proliferating neurons in the ventricular zone at P0 compared to those delivered by the mice provided with drinking water without any Zn supplement. This finding provides direct evidence to support the notion that maternal Zn levels influence the development of the nervous system of the offspring.