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Collagenous colitis: The influence of inflammation and bile acids on intestinal barrier function
Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background and aims: Collagenous colitis (CC) is a diarrheal disorder with an incidence rate of 5-6/100000 inhabitants, affecting mainly middle-aged women. The diagnosis is made by histology of the colonic mucosa. Classical findings are a thickened subepithelial collagenous layer and chronic inflammation in the lamina propria. In inflammatory bowel disease (IBD) the mucosal barrier function is important in pathogenesis. The main purpose of the thesis was therefore to describe the barrier function in CC. The cause of CC is uncertain but the condition seems to be associated with bile acid malabsorption. Increased faecal bile acids are known to induce diarrhea. In functional studies the influence of bile acids on mucosal permeability in biopsies of healthy human individuals and in patients with CC was investigated.

Methods and patients: In the first paper a single patient with intractable CC was examined before surgery, with loop-ileostomy and after bowel reconstruction. For the other studies a total of 25 patients with CC were included (20 women, 5 men, mean age 66 years). There were three groups (14 patients in clinical remission without medical treatment, 11 with active disease, and 8 of these again after 6 weeks of budesonide treatment); 17 individuals with normal histology served as controls. Endoscopic biopsies from the sigmoid colon were mounted in modified Ussing chambers and assessed for short-circuit current (Isc), transepithelial resistance (TER), and transmucosal passage of chemically killed E. coli K12 after addition of chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA). The biopsies were further investigated with confocal microscopy to assess bacterial transepithelial passage.

Results: Para- and transcellular permeability was increased in active CC, but normalized with histological improvement due to faecal stream diversion. After bowel reconstruction, permeability to CrEDTA and HRP increased again.

In CC, bacterial uptake in colonic biopsies was significantly higher in all groups than in controls. Despite significant alleviation of symptoms, budesonide did not normalize the increased bacterial passage. Histology was unchanged after 6 weeks of budesonide treatment. DCA augmented mucosal permeability to CrEDTA in a dose-dependent manner and even such a low dose as 100 μmol/l DCA increased bacterial uptake significantly. The combination of bile acids and E.coli K12 had additive effects on TER.

100 μmol/l CDCA and DCA increased bacterial uptake in biopsies of CC patients in remission 4-fold, but had no additive effect on biopsies from patients with active disease. Furthermore, patients in clinical remission on budesonide treatment showed no bile acidinduced effects on E.coli K12 passage.

Conclusion: Collagenous colitis presents with increased para/transcellular permeability and bacterial uptake, irrespective of disease activity or budesonide treatment, signifying an underlying mucosal barrier defect. Faecal stream diversion can normalize the barrier dysfunction, but budesonide does not, despite its beneficial clinical effects which alleviate diarrhea or bowel symptoms. Bile acids in physiological concentrations have the potential to augment bacterial uptake, especially in mucosa from CC patients in remission. Budesonide treatment appears to counteract the bile acid induced mucosal impairment. These detrimental effects of bile acids on mucosal barrier function might facilitate initiation and perpetuation of mucosal inflammation in CC.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2010. , 78 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1180
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-56291ISBN: 978-91-7393-409-1 (print)OAI: oai:DiVA.org:liu-56291DiVA: diva2:318290
Public defence
2010-05-21, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2010-05-07 Created: 2010-05-07 Last updated: 2012-03-22Bibliographically approved
List of papers
1. Dynamics of mucosal permeability and inflammation in collagenous colitis before, during, and after loop ileostomy
Open this publication in new window or tab >>Dynamics of mucosal permeability and inflammation in collagenous colitis before, during, and after loop ileostomy
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2005 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 54, no 8, 1126-1128 p.Article in journal (Refereed) Published
Abstract [en]

Collagenous colitis has become a more frequent diagnosis but the aetiology of this disease is still unknown. We describe a female patient with intractable collagenous colitis who was treated with a temporary loop ileostomy. She was followed clinically, histopathologically, and functionally by measuring mucosal permeability before surgery, after ileostomy, and after bowel reconstruction. In our case report, active collagenous colitis was combined with increased transcellular and paracellular mucosal permeability. Diversion of the faecal stream decreased inflammation of the mucosa and normalised epithelial degeneration and mucosal permeability. After restoration of bowel continuity, mucosal permeability was altered prior to the appearance of a collagenous layer.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-33212 (URN)10.1136/gut.2004.058750 (DOI)19199 (Local ID)19199 (Archive number)19199 (OAI)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2016-03-09
2. Dihydroxy bile acids increase mucosal permeability and bacterial uptake in human colon biopsies
Open this publication in new window or tab >>Dihydroxy bile acids increase mucosal permeability and bacterial uptake in human colon biopsies
2007 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 42, no 10, 1167-1174 p.Article in journal (Refereed) Published
Abstract [en]

Objective. Bile acids in mM concentrations are known to increase chloride secretion and alter mucosal permeability in animal colon. Increased mucosal permeability is believed to play an important role in the development of intestinal inflammation. The aim of this study was to investigate the influence of μM concentrations of dihydroxy bile acids on permeability and bacterial uptake in the normal human colon. Material and methods. Endoscopic biopsies from the sigmoid colon of 18 subjects with normal colonic histology were mounted in modified Ussing chambers. Chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) were added to the mucosal compartment. Short-circuit current (Isc) and transepithelial resistance (TER) were studied for 120 min. Cr-EDTA and horseradish peroxidase (HRP) were used to assess paracellular and transcellular permeability, respectively. The transmucosal passage of chemically killed Escherichia coli was quantified and investigated using confocal microscopy. Results. A significant decrease in TER was seen after 60 min of exposure to 1000 μmol/l CDCA and DCA. The combination of E. coli and 100 μmol/l CDCA gave a decrease in TER compared to controls (p=0.06). DCA showed a dose-related increase in Cr-EDTA permeability, which was most pronounced at 1000 μmol/l (p=0.02). Increased E. coli uptake was induced by 500 μmol/l (p=0.01) and 1000 μmol/l CDCA (p=0.04). Bacterial uptake was increased at 100 μmol/l by exposure to DCA (p=0.03). Confocal microscopy revealed the presence of E. coli bacteria in the lamina propria after 15 min of exposure to 1000 μmol/l CDCA and DCA. Conclusions. Our study suggests that dihydroxy bile acids in μM concentrations alter barrier function in normal human colon biopsies, causing increased antigen and bacterial uptake, thereby bile acids may contribute to the development of intestinal inflammation. © 2007 Taylor & Francis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-40148 (URN)10.1080/00365520701320463 (DOI)52434 (Local ID)52434 (Archive number)52434 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2016-03-09
3. Increased Transmucosal Uptake of E-coli K12 in Collagenous Colitis Persists After Budesonide Treatment
Open this publication in new window or tab >>Increased Transmucosal Uptake of E-coli K12 in Collagenous Colitis Persists After Budesonide Treatment
2009 (English)In: American Journal of Gastroenterology, ISSN 0002-9270, E-ISSN 1572-0241, Vol. 104, no 3, 679-685 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Collagenous colitis is increasingly recognized as a common diarrheal disorder of inflammatory origin. Intestinal inflammation is generally associated with increased mucosal permeability, but little is known about barrier function in microscopic colitis. Our aim was to investigate the mucosal barrier to nonpathogenic bacteria in collagenous colitis.

METHODS: The study included 33 individuals, 25 with collagenous colitis (14 in clinical remission, 11 with active disease, and 8 of these again after 6 weeks budesonide treatment) and 8 control patients. Bowel movements were registered for 1 week. Endoscopic biopsies from the sigmoid colon were mounted in modified Ussing chambers and assessed for short-circuit current (I-sc), transepithelial resistance (TER), and transmucosal passage of chemically killed Escherichia coli K12.

RESULTS: Bacterial uptake was increased in patients in remission, 1.6 U (1.1-3.0) and in those with active disease, 4.6 U (2.5-5.8; median (IQR)), compared to controls, 0.7 U (0.1-1.1; P=0.004 and P=0.001, respectively). Active disease also had significant decrease in transepithelial resistance (TER) after 120 min, -9.7 Omega cm(2) ((-13)-(-4.3)), compared to controls, -5.2 Omega cm(2) ((-7.2)-(-3.1)), P=0.03; or patients in remission, -4.8 Omega cm(2) ((-8.0)-(-1.2)), P=0.04. Budesonide decreased median stool frequency to 1.9 (1.3-2.2) compared to 3.8 (3.7-4.2) before treatment (P=0.01), but bacterial uptake was still increased after budesonide 2.9 U (1.5-3.8), (P=0.006 compared to controls), and there were no significant changes in histology.

CONCLUSIONS: Collagenous colitis presents with significantly increased uptake and altered mucosal reactivity to nonpathogenic bacteria. Budesonide induces clinical remission and restores mucosal reactivity but does not abolish the increased bacterial uptake. An underlying barrier dysfunction may explain the frequent and rapid relapses in CC.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17522 (URN)10.1038/ajg.2008.95 (DOI)
Available from: 2009-03-28 Created: 2009-03-27 Last updated: 2011-01-19
4. Physiological levels of bile acids increase bacterial uptake in colonic biopsies of collagenous colitis patients in remission
Open this publication in new window or tab >>Physiological levels of bile acids increase bacterial uptake in colonic biopsies of collagenous colitis patients in remission
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objective: Patients with collagenous colitis (CC) have an impaired mucosal barrier. Moreover CC is associated with bile acid malabsorption. Bile acids may increase bacterial mucosal uptake in humans. To elucidate the possible role of bile acids in CC pathophysiology, the mucosal barrier function was investigated by exposing colonic biopsies to physiological concentrations of chenodeoxycholic acid (CDCA) or deoxycholic acid (DCA) in Ussing chamber experiments.

Patients/Interventions: The study included 33 individuals; 25 with collagenous colitis (14 in clinical remission without treatment, 11 with active disease, and 8 of these again after 6 weeks budesonide treatment); 8 healthy individuals undergoing screening colonoscopy served as controls. Endoscopic biopsies from the sigmoid colon were mounted in modified Ussing chambers and assessed for short circuit current (Isc), transepithelial resistance (TER), and transmucosal passage of chemically killed E. coli K12 after addition of 100 μmol/l CDCA or DCA. The biopsies were further investigated with confocal microscopy to asses bacterial transepithelial passage routes.

Results: By adding 100μmol/l CDCA or DCA the bacterial uptake was increased by 4-fold in biopsies of patients in remission; CDCA 6.5 units [2.5-9.8] and DCA 6.2 units [2.1-22] (median [IQR]), compared with uptake in biopsies without added bile acids 1.6 units [1.1-3]; (p=0.004 and p=0.01, respectively). In active disease and in patients in remission on budesonide, bile acids had no effect on bacterial uptake. Isc and TER were unaffected by the bile acids at 100μmol/l in all groups. Confocal microscopy demonstrated transepithelial passage of E.coli K12 via the paracellular route.

Conclusions: Physiological concentrations of dihydroxy-bile acids augment mucosal barrier dysfunction in colonic biopsies of patients with CC in remission. This leads to a substantially increased bacterial uptake that may contribute to relapse of inflammation. Budesonide seems to counteract the bile acid-induced mucosal impairment.

Keyword
Microscopic colitis, permeability, intestinal mucosa, diffusion chamber, bile acids
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-56290 (URN)
Available from: 2010-05-07 Created: 2010-05-07 Last updated: 2010-05-07

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