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Protective Effects of Probiotics on Chronic Stress-Induced Intestinal Permeability in Rats are mediated via Mast Cells and PPARγ
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Gastrointestinal Research Unit, Department of Surgery, University Medical Center, Utrecht, The Netherlands.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
Gastrointestinal Research Unit, Department of Surgery, University Medical Center, Utrecht, The Netherlands.
Gastrointestinal Research Unit, Department of Surgery, University Medical Center, Utrecht, The Netherlands..
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2013 (English)Manuscript (preprint) (Other academic)
Abstract [en]

BACKGROUND: Chronic stress, which may affect in the clinical course of inflammatory and functional bowel diseases, disrupts intestinal barrier function by routes involving mast cells. Probiotics have been shown to ameliorate the deleterious effects of stress on intestinal function, but mechanisms remain to be elucidated. Peroxisome proliferator-activated receptor (PPAR)-γ signaling is activated as an endogenous defense mechanism during chronic stress and evidence suggests that probiotics reduce the degradation of PPAR-γ. As a source of the endogenous agonist for PPAR-γ, 15d-PGJ2, and as an important mediator of the stress response, mast cells may have both a beneficial and a deleterious role in the effects on intestinal function by probiotics.

AIM: Our aim was to study if mast cells contribute to the positive effects of probiotic therapy on intestinal function in a rat model of chronic stress.

METHODS: 32 Mast cell deficient (Ws/Ws) and 32 wild-type (+/+) rats were subjected to water avoidance stress (WAS) or sham stress (SS) 1hr/day for 10 days. Seven days prior to the onset of stress, probiotics (PB, multispecies combination of 10 different lactic acid bacteria) were added to the standard diet (St) in half of the animals. To determine dependence of PPAR-γ, 8 probiotic-fed wild-type rats subjected to WAS were injected daily with the specific PPAR-γ antagonist T0070907. The colonic mucosa was exposed to E. coli HB101 incorporated with green fluorescent protein and permeability was assessed in Ussing chambers. Mesenteric lymph nodes (MLN) were cultured to determine bacterial translocation.

RESULTS: Chronic stress induced a marked increase in ileal permeability to E.coli HB101 in +/+ rats (0.17±0.1 x106CFU/hr in SS/St/++ vs. 2.13±0.4 in WAS/St/++; P<0.001). This breach in barrier integrity was less pronounced in Ws/Ws rats (2.13±0.4 in WAS/St/++ vs. 1.19±0.3 in WAS/St/WsWs; P<0.01). Probiotics prevented stress-induced effects in E.coli HB101 passage only in wild-type rats (82% decrease in +/+ vs. 0% in Ws/Ws rats). Furthermore, only in the presence of mast cells did probiotics reduce the enhanced bacterial translocation to MLNs during chronic stress. In wild-type rats treated with a PPAR-γ antagonist, the barrier protective effects of probiotics were diminished.

CONCLUSIONS: Mast cells acting via a PPAR-γ dependent pathway contribute to the beneficial effects of probiotics on chronic stress-induced mucosal dysfunction in rats.

Place, publisher, year, edition, pages
2013.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-100767OAI: oai:DiVA.org:liu-100767DiVA: diva2:663513
Available from: 2013-11-12 Created: 2013-11-12 Last updated: 2014-03-25
In thesis
1. Role of mast cells and probiotics in the regulation of intestinal barrier function
Open this publication in new window or tab >>Role of mast cells and probiotics in the regulation of intestinal barrier function
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The intestinal mucosa is the largest contact area and one of the most important barriers to the outside environment. It is highly specialized in aiding us digest and absorb nutrients. It is daily exposed to several potentially dangerous substances and microorganisms, which if they were allowed to pass into the body, could give rise to diseases. Throughout the small intestine certain sites specialized in antigen sampling are found. These sites are named Peyer’s patches and are lymphoid follicles. The epithelium covering the Peyer’s patches is called follicle-associated epithelium and is specialized in antigen sampling and uptake. The special epithelium enables presentation of luminal antigen to immune cells in the underlying follicle.

Persistent life stress and stressful life events affect the course of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) through largely unknown mechanisms. Regulation of epithelial permeability to antigens is crucial for the balance between inflammation and immune-surveillance, and increased intestinal permeability has been shown in patients with ulcerative colitis and Crohns disease. Vasoactive intestinal polypeptide (VIP) and corticotropin-releasing factor have been implicated as important mediators of stress-induced abnormalities in intestinal mucosal functions in animal models. Both of these mediators have been reported to regulate bowel ion secretion in humans during stress and uptake of horseradish peroxidase in rodents. Probiotics have been shown to ameliorate the deleterious effects of stress on intestinal function, but mechanisms remain to be elucidated.

The aim of this thesis was to elucidate whether mast cells play an important role in intestinal barrier function during stress and inflammation. Moreover, we wanted to determine whether probiotics can ameliorate the mucosal barrier integrity during stress and inflammation.

To study the function of mast cells we conducted in vitro experiments on cell lines and ex vivo experiments in Ussing chambers on mouse, rat and human intestinal tissue. The Ussing chamber technique measures electrophysiological properties of the tissue and also gives the possibility to study transcellular and paracellular passage of markers and bacteria. Immunohistology and confocal microscopy have been used to identify mast cells and receptors of interest.

Our results show that stress affects the follicle-associated epithelium barrier by mechanisms involving VIP and mast cells. These findings were corroborated by the localization of VIP receptors on mucosal mast cells. Furthermore, pretreatment with probiotics was effective in protecting the gut against stress-induced intestinal barrier dysfunction and mucosal inflammation. This protection appeared to involve a mast cell and peroxisome proliferatoractivated receptor-γ dependent mechanism.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 62 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1363
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-100770 (URN)10.3384/diss.diva-100770 (DOI)978-91-7519-630-5 (ISBN)
Public defence
2013-12-12, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 13:15 (Swedish)
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Available from: 2013-11-12 Created: 2013-11-12 Last updated: 2013-11-12Bibliographically approved

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Lutgendorff, FemkeCarlsson, Anders H.Söderholm, Johan D.

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Department of Clinical and Experimental MedicineFaculty of Health SciencesDivision of Clinical SciencesDepartment of Surgery in Linköping
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