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Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
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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.

Place, publisher, year, edition, pages
2015. Vol. 309, no 8, G625-G634 p.
Keyword [en]
inflammation; inflammatory bowel disease; migrating motor complex; NO; peristalsis
National Category
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-264766DOI: 10.1152/ajpgi.00104.2015ISI: 000364068300002PubMedID: 26206857OAI: oai:DiVA.org:uu-264766DiVA: diva2:861477
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
In thesis
1. Role of Melatonin, Neuropeptide S and Short Chain Fatty Acids in Regulation of Duodenal Mucosal Barrier Function and Motility
Open this publication in new window or tab >>Role of Melatonin, Neuropeptide S and Short Chain Fatty Acids in Regulation of Duodenal Mucosal Barrier Function and Motility
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
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:nbn:se:uu:diva-264405 (URN)978-91-554-9369-1 (ISBN)
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
2. Gut peptides in gastrointestinal motility and mucosal permeability
Open this publication in new window or tab >>Gut peptides in gastrointestinal motility and mucosal permeability
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Gut regulatory peptides, such as neuropeptides and incretins, play important roles in hunger, satiety and gastrointestinal motility, and possibly mucosal permeability. Many peptides secreted by myenteric nerves that regulate motor control are also produced in mucosal epithelial cells. Derangements in motility and mucosal permeability occur in many diseases. Current knowledge is fragmentary regarding gut peptide actions and mechanisms in motility and permeability.

This thesis aimed to 1) develop probes and methods for gut permeability testing, 2) elucidate the role of neuropeptide S (NPS) in motility and permeability, 3) characterize nitrergic muscle relaxation and 4) characterize mechanisms of glucagon-like peptide 1 (GLP-1) and the drug ROSE-010 (GLP-1 analog) in motility inhibition.

A rapid fluorescent permeability test was developed using riboflavin as a transcellular transport probe and the bisboronic acid 4,4'oBBV coupled to the fluorophore HPTS as a sensor for lactulose, a paracellular permeability probe. This yielded a lactulose:riboflavin ratio test.

NPS induced muscle relaxation and increased permeability through NO-dependent mechanisms. Organ bath studies revealed that NPS induced NO-dependent muscle relaxation that was tetrodotoxin (TTX) sensitive. In addition to the epithelium, NPS and its receptor NPSR1 localized at myenteric nerves. Circulating NPS was too low to activate NPSR1, indicating NPS uses local autocrine/paracrine mechanisms.

Nitrergic signaling inhibition by nitric oxide synthase inhibitor L-NMMA elicited premature duodenojejunal phase III contractions in migrating motility complex (MMC) in humans. L-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. Intestinal contractions were stimulated by L-NMMA, but not TTX. NOS immunoreactivity was detected in the myenteric plexus but not smooth muscle.

Food-intake increased motility of human antrum, duodenum and jejunum. GLP-1 and ROSE-010 relaxed bethanechol-induced contractions in muscle strips. Relaxation was blocked by GLP-1 receptor antagonist exendin(9-39) amide, L-NMMA, adenylate cyclase inhibitor 2´5´-dideoxyadenosine or TTX. GLP-1R and GLP-2R were expressed in myenteric neurons, but not muscle.

In conclusion, rapid chemistries for permeability were developed while physiological mechanisms of NPS, nitrergic and GLP-1 and ROSE-010 signaling were revealed. In the case of NPS, a tight synchrony between motility and permeability was found.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 58 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1233
Keyword
Gut regulatory peptides, Neuropeptides, Gastrointestinal mucosal permeability, Gastrointestinal motility, GLP-1, NPS, ROSE-010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-294390 (URN)978-91-554-9607-4 (ISBN)
Public defence
2016-06-14, Enghoffsalen, Entrance 50, Uppsala University Hospital, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2016-05-24 Created: 2016-05-19 Last updated: 2016-06-15

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Wan Saudi, Wan SalmanHalim, Mohammed AbdulTengholm, AndersSundbom, MagnusKarlbom, UrbanWebb, Dominic-LucSjöblom, MarkusHellström, Per M

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