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Short-chain fatty acids augment rat duodenal mucosal barrier function
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 Neuroscience, Physiology.ORCID iD: 0000-0002-1406-9389
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.

Place, publisher, year, edition, pages
2017. Vol. 102, no 7, 791-803 p.
Keyword [en]
barrier function, motility, chemosensing, short chain fatty acids, GLP-2, enteroendocrine cells, functional dyspepsia
National Category
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-264402DOI: 10.1113/EP086110ISI: 000404648000005PubMedID: 28436589OAI: oai:DiVA.org:uu-264402DiVA: diva2:860218
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
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

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Wan Saudi, Wan SalmanSjöblom, Markus

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