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Role of Melatonin, Neuropeptide S and Short Chain Fatty Acids in Regulation of Duodenal Mucosal Barrier Function and Motility
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The duodenal epithelium is regularly exposed to HCl, digestive enzymes, bacteria and toxins, and sometimes also to ethanol and drugs. The imbalance of aggressive factors in the intestinal lumen and mucosal barrier function increases the risk of tissue injury and inflammation. The key components of the duodenal barrier function include mucosal permeability, bicarbonate transport and the secretion or absorption of fluids. This thesis aims to elucidate the role of melatonin, neuropeptide S (NPS) and short chain fatty acids (SCFAs) in the regulation of intestinal mucosal barrier function and motility in the anesthetized rat in vivo and in tissues of human origin in vitro.

Melatonin was found to reduce ethanol-induced increases in paracellular permeability and motility by a neural pathway within the enteric nervous system involving nicotinic receptors. In response to luminal exposure of ethanol, signs of mild mucosal edema and beginning of desquamation were observed in a few villi only, an effect that was not influenced by melatonin. Melatonin did not modify increases in paracellular permeability in response to luminal acid.

NPS decreased basal and ethanol-induced increases in duodenal motility as well as bethanechol stimulated colonic motility in a dose-dependent manner. Furthermore, NPS was shown to inhibit basal duodenal bicarbonate secretion, stimulate mucosal fluid absorption and increase mucosal paracellular permeability. In response to luminal exposure of acid, NPS increased bicarbonate secretion and mucosal paracellular permeability. All effects induced by the administration of NPS were dependent on nitrergic pathways. In rats, administration of NPS increased the tissue protein levels of the inflammatory biomarkers IL-1β and CXCL1. Immunohistochemistry showed that NPS was localized at myenteric nerve cell bodies and fibers, while NPSR1 and nNOS were only confined to the myenteric nerve cell bodies.

Perfusing the duodenal segment with the SCFAs acetate or propionate reduced the duodenal mucosal paracellular permeability, decreased transepithelial net fluid secretion and increased bicarbonate secretion. An i.v. infusion of SCFAs reduces mucosal paracellular permeability without any effects on mucosal net fluid flux. However, it significantly decreased bicarbonate secretion. Luminal SCFAs changed the duodenal motility pattern from fasting to feeding motility while i.v. SCFAs was without effect on motility. The systemic administration of glucagon-like peptide-2 (GLP-2) induced increases in mucosal bicarbonate secretion and fluid absorption. An i.v. GLP-2 infusion during a luminal perfusion of SCFAs significantly reduced the duodenal motility.

In conclusion, the results in the present thesis show that melatonin, NPS and SCFAs influence the neurohumoral regulation of intestinal mucosal barrier function and motility. Aberrant signaling in response to melatonin, NPS and to luminal fatty acids might be involved in the symptom or the onset of disease related to intestinal dysfunction in humans.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 89 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1144
Keyword [en]
51Cr-EDTA, rat, in vivo, duodenum, enteric nervous system, paralytic ileus, parecoxib, bicarbonate secretion, motility, ethanol, HCl, melatonin, neuropeptide S, short chain fatty acids, chemosensing
National Category
Physiology
Research subject
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-264405ISBN: 978-91-554-9369-1 (print)OAI: oai:DiVA.org:uu-264405DiVA: diva2:860240
Public defence
2015-11-26, C4:305, Husargatan 3, Biomedicinskt Centrum, Uppsala, 09:15 (English)
Opponent
Supervisors
Funder
Swedish Research Council, 7916The Swedish Medical Association, SLS-176671
Note

Research funders and strategic development areas:

- Bengt Ihre Foundation (grant SLS-177521)

- Socialstyrelsen(grant SLS-176671)

- Erik, Karin, and Gösta Selanders Foundation

- Emil and Ragna Börjesson Foundation

- Uppsala University 

- Ministry of Education of Malaysia

- Universiti Malaysia Sabah, Malaysia

Available from: 2015-11-04 Created: 2015-10-11 Last updated: 2016-01-27
List of papers
1. 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
2. Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide
Open this publication in new window or tab >>Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide
Show others...
2015 (English)In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 309, no 8, G625-G634 p.Article in journal (Refereed) Published
Abstract [en]

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 100-4000 pmol/kg·min had effects on the small intestine and colon. Low doses of NPS increased myoelectric spiking (p<0.05). Higher doses reduced spiking and prolonged the cycle length of the migrating myoelectric complex, reduced intraluminal pressures (p<0.05-0.01) and increased permeability (p<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 ~0.3 nmol/l dissociation constant (Kd) of NPSR1, with no difference between healthy and IBD subjects. In human intestinal muscle strips pre-contracted by bethanechol, NPS 1-1000 nmol/l induced NO-dependent muscle relaxation (p<0.05) that was sensitive also to tetrodotoxin (p<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 up-regulation of NPSR1 could potentially exacerbate dysmotility and hyperpermeability by local mechanisms in gastrointestinal functional and inflammatory reactions.

Keyword
inflammation; inflammatory bowel disease; migrating motor complex; NO; peristalsis
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-264766 (URN)10.1152/ajpgi.00104.2015 (DOI)000364068300002 ()26206857 (PubMedID)
Funder
The Swedish Medical Association, SLS-176671Swedish Research Council, 7916Swedish Society of Medicine, SLS-176671Swedish National Board of Health and Welfare, SLS-176671
Note

Shared first name: Wan Salman Wan Saudi and Md. Abdul Halim.

Shared last name: Dominic-Luc Webb, Markus Sjöblom and Per M. Hellström.

Available from: 2015-10-16 Created: 2015-10-16 Last updated: 2017-12-01Bibliographically approved
3. Neuropeptide S reduces duodenal bicarbonate secretion and ethanol-induced increases in duodenal motility in rats
Open this publication in new window or tab >>Neuropeptide S reduces duodenal bicarbonate secretion and ethanol-induced increases in duodenal motility in rats
2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 4, e0175312Article in journal (Refereed) Published
Abstract [en]

Alcohol disrupts the intestinal mucosal barrier by inducing metabolic and functional changes in epithelial cells. Recently, we showed that neuropeptide S (NPS) decreases duodenal motility and increases mucosal paracellular permeability, suggesting a role of NPS in the pathogenesis of disorders and dysfunctions in the small intestine. The aim of the present study was to investigate the effects of NPS on ethanol- and HCl-induced changes of duodenal mucosal barrier function and motility. Rats were anaesthetized with thiobarbiturate, and a 30-mm segment of the proximal duodenum with an intact blood supply was perfused in situ. The effects on duodenal bicarbonate secretion, the blood-to-lumen clearance of 51Cr-EDTA, motility and transepithelial net fluid flux were investigated.

Intravenous (i.v.) administration of NPS significantly reduced duodenal mucosal bicarbonate secretion and stimulated mucosal transepithelial fluid absorption, mechanisms dependent on nitrergic signaling. NPS dose-dependently reduced ethanol-induced increases in duodenal motility. NPS (83 pmol·kg-1·min-1, i.v.) reduced the bicarbonate and fluid secretory response to luminal ethanol, whereas a 10-fold higher dose stimulated fluid secretion but did not influence bicarbonate secretion. In NPS-treated animals, duodenal perfusion of acid (pH 3) induced greater bicarbonate secretory rates than in controls. Pre-treating animals with Nω-nitro-L-arginine methyl ester (L-NAME) inhibited the effect of NPS on bicarbonate secretion. In response to luminal acid, NPS-treated animals had significantly higher paracellular permeability compared to controls, an effect that was abolished by L-NAME.

Our findings demonstrate that NPS reduces basal and ethanol-induced increases in duodenal motility. In addition, NPS increases luminal alkalinization and mucosal permeability in response to luminal acid via mechanisms that are dependent on nitric oxide signaling. The data support a role for NPS in neurohumoral regulation of duodenal mucosal barrier function and motility.

Keyword
barrier function, motility, neuropeptide S, enteroendocrine cells, ethanol, post-prandial acid, inflammatory bowel disease
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:uu:diva-264426 (URN)10.1371/journal.pone.0175312 (DOI)000399371900153 ()
Note

Research funders and strategic development areas:

- Emil and Ragna Börjesson Foundation

- Uppsala University

- Ministry of Education of Malaysia

- Universiti Malaysia Sabah, Malaysia

Available from: 2015-10-12 Created: 2015-10-12 Last updated: 2017-12-01Bibliographically approved
4. Short-chain fatty acids augment rat duodenal mucosal barrier function
Open this publication in new window or tab >>Short-chain fatty acids augment rat duodenal mucosal barrier function
2017 (English)In: Experimental Physiology, ISSN 0958-0670, E-ISSN 1469-445X, Vol. 102, no 7, 791-803 p.Article in journal (Refereed) Published
Abstract [en]

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 to SCFAs derived mainly from oral bacteria or 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 the effects of acetate and propionate on duodenal mucosal barrier function and motility. Rats were anaesthetized with thiobarbiturate, and a 30 mm segment of proximal duodenum with an intact blood supply was perfused. The effects on duodenal bicarbonate secretion, blood-to-lumen clearance of Cr-51-EDTA, motility and transepithelial net fluid flux were investigated. Perfusion of the duodenum with acetate or propionate significantly decreased mucosal paracellular permeability and transepithelial net fluid flux and significantly increased bicarbonate secretion. Acetate or propionate administered as an I.V. infusion decreased the mucosal paracellular permeability, but significantly decreased bicarbonate secretion. Luminal SCFAs changed the duodenal motility pattern from migrating motor complexes to fed patterns. Systemic administration of glucagon-like peptide-2 induced increases in both bicarbonate secretion and net fluid absorption, but did not change motility. Glucagon-like peptide-2 infusion during luminal perfusion of SCFAs significantly reduced the motility. In conclusion, SCFAs decreased duodenal paracellular permeability and net fluid flux. Short-chain fatty acids induced opposite effects on bicarbonate secretion after luminal and i.v. administration. Presence of SCFAs in the lumen induces fed motility patterns. Altered luminal chemosensing and aberrant signalling in response to SCFAs might contribute to symptoms observed in patients with suppressed barrier function.

Keyword
barrier function, motility, chemosensing, short chain fatty acids, GLP-2, enteroendocrine cells, functional dyspepsia
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-264402 (URN)10.1113/EP086110 (DOI)000404648000005 ()28436589 (PubMedID)
Note

Research funders and strategic development areas:

- Emil and Ragna Börjesson Foundation

- Uppsala University 

- Ministry of Education of Malaysia

- University Malaysia Sabah, Malaysia

Available from: 2015-10-12 Created: 2015-10-11 Last updated: 2017-10-05Bibliographically approved

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