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Regulation of Duodenal Mucosal Barrier Function and Motility: The Impact of Melatonin
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The duodenal mucosa is regularly exposed to acid, digestive enzymes and ingested noxious agents. It is thus critical to maintain a protective barrier to prevent the development of mucosal injury and inflammation, which are often observed in situations when barrier function is impaired. The rate of mucosal bicarbonate secretion, the regulation of epithelial paracellular permeability and motility are each key components of duodenal barrier function. The hormone melatonin is present in high levels in the gastrointestinal tract and it has been hypothesized that melatonin exerts protective properties. This thesis aims to investigate the impact of exogenous melatonin on the regulation of duodenal barrier function and motility in anesthetized rats in vivo. In addition, duodenal tissue was examined histologically and the expression levels of tight junction proteins and melatonin receptors were assessed with qRT-PCR.

It was found that melatonin stimulated mucosal bicarbonate secretion and decreased basal paracellular permeability. Exposing the duodenal mucosa to the well-characterized barrier breaker ethanol increased mucosal bicarbonate secretion, paracellular permeability and motility. Omission of luminal Clˉ abolished, while pretreatment with a nicotinic receptor antagonist reduced, the ethanol-induced bicarbonate secretion suggesting that the secretory response to ethanol is meditated via Clˉ/HCO3ˉexchangers and enteric neural pathways.

Melatonin reduced the ethanol-induced increases in paracellular permeability and motility either when injected intravenously or when administered in drinking water for two weeks. The actions of melatonin were abolished by the melatonin receptor antagonist luzindole and by nicotinic acetylcholine receptor inhibition.

Two weeks oral administration of melatonin up-regulated the expression levels of melatonin receptors, down-regulated the expression of ZO-3 while the expression of ZO-1, ZO-2, claudin 2-4, occludin and myosin light chain kinase were unaffected. Superficial epithelial changes in a few villi were seen in response to ethanol exposure, an effect that was histologically unchanged by melatonin pretreatment.

In conclusion, the results suggest that melatonin plays an important role in the neurohumoral regulation of gastrointestinal mucosal barrier function and motility via receptor- and enteric neural-dependent pathways in vivo in rats. Melatonin might be a candidate for treatment of barrier dysfunction in humans.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 74 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 944
Keyword [en]
51Cr-EDTA, bicarbonate secretion, duodenum, enteric nervous system, enterochromaffin cell, ethanol, hexamethonium, in vivo, mecamylamine, motility, mucosal permeability, parecoxib, rat
National Category
Physiology
Research subject
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-209669ISBN: 978-91-554-8790-4 (print)OAI: oai:DiVA.org:uu-209669DiVA: diva2:658984
Public defence
2013-12-06, B21, Biomedicinskt centrum, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2013-11-14 Created: 2013-10-23 Last updated: 2014-01-23
List of papers
1. Melatonin decreases duodenal epithelial paracellular permeability via a nicotinic receptor-dependent pathway in rats in vivo
Open this publication in new window or tab >>Melatonin decreases duodenal epithelial paracellular permeability via a nicotinic receptor-dependent pathway in rats in vivo
2013 (English)In: Journal of Pineal Research, ISSN 0742-3098, E-ISSN 1600-079X, Vol. 54, no 3, 282-291 p.Article in journal (Refereed) Published
Abstract [en]

Intestinal epithelial intercellular tight junctions (TJs) provide a rate-limiting barrier restricting passive transepithelial movement of solutes. TJs are highly dynamic areas, and their permeability is changed in response to various stimuli. Defects in the intestinal epithelial TJ barrier may contribute to intestinal inflammation or leaky gut. The gastrointestinal tract may be the largest extrapineal source of endogenous melatonin. Melatonin released from the duodenal mucosa is a potent stimulant of duodenal mucosal bicarbonate secretion (DBS). The aim of this study was to elucidate the role of melatonin in regulating duodenal mucosal barrier functions, including mucosal permeability, DBS, net fluid flux, and duodenal motor activity, in the living animal. Rats were anesthetized with thiobarbiturate, and a ~30-mm segment of the proximal duodenum with an intact blood supply was perfused in situ. Melatonin and the selective melatonin receptor antagonist luzindole were perfused luminally or given intravenously. Effects on permeability (blood-to-lumen clearance of (51) Cr-EDTA), DBS, mucosal net fluid flux, and duodenal motility were monitored. Luminal melatonin caused a rapid decrease in paracellular permeability and an increase in DBS, but had no effect on duodenal motor activity or net fluid flux. Luzindole did not influence any of the basal parameters studied, but significantly inhibited the effects of melatonin. The nonselective and noncompetitive nicotinic acetylcholine receptor antagonist mecamylamine abolished the effect of melatonin on duodenal permeability and reduced that on DBS. In conclusion, these findings provide evidence that melatonin significantly decreases duodenal mucosal paracellular permeability and increases DBS. The data support the important role of melatonin in the neurohumoral regulation of duodenal mucosal barrier.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-190280 (URN)10.1111/jpi.12013 (DOI)000315969100005 ()23009576 (PubMedID)
Available from: 2013-01-07 Created: 2013-01-07 Last updated: 2017-12-06Bibliographically approved
2. Melatonin inhibits alcohol-induced increases in duodenal mucosal permeability in rats in vivo
Open this publication in new window or tab >>Melatonin inhibits alcohol-induced increases in duodenal mucosal permeability in rats in vivo
2013 (English)In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 305, no 1, G95-G105 p.Article in journal (Refereed) Published
Abstract [en]

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 similar to 30-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 Cr-51-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 HCl-induced 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.

Keyword
duodenal barrier, intestinal barrier dysfunction, alcoholic liver disease, leaky gut syndrome, duodenal bicarbonate secretion
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-204777 (URN)10.1152/ajpgi.00074.2013 (DOI)000321198500009 ()
Available from: 2013-08-15 Created: 2013-08-12 Last updated: 2017-12-06Bibliographically approved
3. The Ethanol-Induced Stimulation of Rat Duodenal Mucosal Bicarbonate Secretion In Vivo Is Critically Dependent on Luminal Cl-
Open this publication in new window or tab >>The Ethanol-Induced Stimulation of Rat Duodenal Mucosal Bicarbonate Secretion In Vivo Is Critically Dependent on Luminal Cl-
2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, e102654- p.Article in journal (Refereed) Published
Abstract [en]

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 similar to 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 Cr-51-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.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-209667 (URN)10.1371/journal.pone.0102654 (DOI)000339418300075 ()25033198 (PubMedID)
Available from: 2013-10-23 Created: 2013-10-23 Last updated: 2017-12-06Bibliographically approved
4. Long-term oral melatonin administration reduces ethanol-induced increases in duodenal mucosal permeability and motility
Open this publication in new window or tab >>Long-term oral melatonin administration reduces ethanol-induced increases in duodenal mucosal permeability and motility
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-209668 (URN)
Available from: 2013-10-23 Created: 2013-10-23 Last updated: 2014-01-23

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