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  • 1.
    Bouma, Gerd
    et al.
    Vrije University, Netherlands.
    Münch, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Microscopic Colitis2015In: Digestive Diseases, ISSN 0257-2753, E-ISSN 1421-9875, Vol. 33, no 2, p. 208-214Article in journal (Refereed)
    Abstract [en]

    Microscopic colitis (MC) is the common denominator for lymphocytic and collagenous colitis (CC). It is now recognized as a relatively frequent cause of diarrhea that equals the prevalence of inflammatory bowel disease. Patients are typically middle-aged women, but disease may occur at every age. Patients with MC report watery, non-bloody diarrhea in the absence of endoscopic and radiologic abnormalities. Lymphocytic colitis is characterized by an increased number of intraepithelial lymphocytes, and CC by a thickened subepithelial collagen band, whereas in both an increased mononuclear infiltration of the lamina propria is found. The pathogenesis of MC is largely unknown, but may relate to autoimmunity, adverse reactions to drugs or (bacterial) toxins, and abnormal collagen metabolism in the case of CC. Budesonide is so far the only drug that has proven efficacy in randomized controlled trials both for the induction and maintenance of remission. Patients who are nonresponsive, dependent or who experience side effects on budesonide may benefit from thiopurine or anti-TNF treatment, but these options are still experimental. The long-term prognosis of MC is good; it does not appear to predispose to malignancies and can in some cases be self-limiting. Further research and randomized clinical trials are required to expand our understanding of the natural course and the pathogenesis of MC.

  • 2.
    Daferera, Niki
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Kumar Kumawat, Ashok
    University of Örebro, Sweden.
    Hultgren-Hornquist, Elisabeth
    University of Örebro, Sweden.
    Ignatova, Simone
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology. Linköping University, Faculty of Medicine and Health Sciences.
    Münch, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Fecal stream diversion and mucosal cytokine levels in collagenous colitis: A case report2015In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 21, no 19, p. 6065-6071Article in journal (Refereed)
    Abstract [en]

    In this case report, we examined the levels of cytokines expressed before and during fecal stream diversion and after intestinal continuity was restored in a patient with collagenous colitis. We report the case of a 46-year-old woman with chronic, active collagenous colitis who either failed to achieve clinical remission or experienced adverse effects with the following drugs: loperamide, cholestyramine, budesonide, methotrexate and adalimumab. Due to the intractable nature of the disease and because the patient was having up to 15 watery bowel movements per day, she underwent a temporary ileostomy. Colonic biopsies were analyzed for mucosal cytokine protein levels before and during fecal stream diversion and after intestinal continuity was restored. Mucosal protein levels of interleukin (IL)-1 beta, IL-2, IL-6, IL-12, IL-17 A, IL-23, TNF, IFN-gamma, IL-4, IL-5, IL-10 and IL-13 were all higher during active disease and decreased to non-detectable or considerably lower levels during fecal stream diversion. One month after the restoration of bowel continuity, when the patient experienced a relapse of symptoms, IL-2, IL-23 and IL-21 levels were again increased. Our results indicate that fecal stream diversion in this patient suppressed the levels of all cytokines analyzed in colonic biopsies. With the recurrence of clinical symptoms and histological changes after bowel reconstruction, the levels of primarily proinflammatory cytokines increased. Our findings support the hypothesis that a luminal factor triggers the inflammation observed in collagenous colitis.

  • 3.
    Langner, Cord
    et al.
    Medical University of Graz, Austria.
    Aust, Daniela
    Technical University of Dresden, Germany.
    Ensari, Arzu
    Ankara University Medical School, Turkey.
    Villanacci, Vincenzo
    Institute of Pathology, Spedali Civili, Brescia, Italy .
    Becheanu, Gabriel
    Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
    Miehlke, Stephan
    Internal Medicine Eppendorf, Hamburg Germany.
    Geboes, Karel
    UZ Gent, Belgium .
    Münch, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Histology of Microscopic Colitis - Review with Practical Approach for Pathologists2015In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 66, no 5, p. 613-626Article, review/survey (Refereed)
    Abstract [en]

    Microscopic colitis has emerged as a major cause of chronic watery non-bloody diarrhoea, particularly in elderly females. The term is used as an umbrella term to categorize a subgroup of colitides with distinct clinicopathologic phenotypes and no significant endoscopic abnormalities: Lymphocytic colitis is defined by an increased number of surface intraepithelial lymphocytes, collagenous colitis by a thickened collagen band underneath the surface epithelium. There is increased inflammation in the lamina propria, but only little or no crypt architectural distortion. Incomplete and variant forms showing less characteristic features have been reported under different names. Differential diagnosis mainly includes resolving infectious colitis and changes related to the intake of drugs such as non-steroidal anti-inflammatory drugs. Substantial clinical and histological overlap between lymphocytic and collagenous colitis has been described, raising the suspicion that the conditions are two histological manifestations of the same entity, possibly representing different manifestations during the disease course or different stages of disease development. In this review we provide a practical approach for pathologists with focus on diagnostic criteria and differential diagnosis, discuss recent insights into the pathogenesis of disease and the relation to classical chronic inflammatory bowel disease, i.e. Crohn's disease and ulcerative colitis.

  • 4.
    Miehlke, Stephan
    et al.
    Internal Med Ctr Eppendorf, Germany.
    Aust, Daniela
    Tech Univ Dresden, Germany.
    Mihaly, Emese
    Semmelweis Univ, Hungary.
    Armerding, Peter
    Gastroenterology, Private Practice, Berlin, Germany.
    Boehm, Guenther
    Internal Medicine and Cardiology, Private Practice, Ludwigshafen am Rhein, Germany.
    Bonderup, Ole
    Reg Hosp Silkeborg, Denmark.
    Fernandez-Banares, Fernando
    Hosp Univ Mutua Terrassa, Spain.
    Kupcinskas, Juozas
    Lithuanian Univ Hlth Sci, Lithuania.
    Munck, Lars Kristian
    Zealand Univ Hosp, Denmark; Univ Copenhagen, Denmark.
    Rehbehn, Kai-Uwe
    Gastroenterology, Private Practice, Solingen, Germany.
    Nacak, Tanju
    Dr Falk Pharma GmbH, Germany.
    Greinwald, Roland
    Dr Falk Pharma GmbH, Germany.
    Münch, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Efficacy and Safety of Budesonide, vs Mesalazine or Placebo, as Induction Therapy for Lymphocytic Colitis2018In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 155, no 6, p. 1795-+Article in journal (Refereed)
    Abstract [en]

    BACKGROUND amp; AIMS: Lymphocytic colitis is a common cause of chronic, nonbloody diarrhea. However, the effects of treatment are unclear and randomized placebo-controlled trials were requested in a Cochrane review. We performed a randomized, placebo-controlled, multicenter study to evaluate budesonide and mesalazine as induction therapy for lymphocytic colitis. METHODS: Patients with active lymphocytic colitis were randomly assigned to groups given budesonide 9 mg once daily (Budenofalk granules), mesalazine 3 g once daily (Salofalk granules), or placebo for 8 weeks in a double-blind, double-dummy design. The primary endpoint was clinical remission, defined as amp;lt;= 21 stools (including amp;lt;= 6 watery stools), in the 7 days before week 8. RESULTS: The final analysis included 57 patients (19 per group). Most patients were female (72%) and the mean age was 59 years. The proportion of patients in clinical remission at week 8 was significantly higher in the budesonide group than in the placebo group (intention-to-treat analysis, 79% vs 42%; P=.01). The difference in proportions of patients in clinical remission at week 8 between the mesalazine (63%) and placebo groups was not significant (P=.09). The proportion of patients with histologic remission at week 8 was significantly higher in the budesonide group (68%) vs the mesalazine (26%; P=.02) or placebo (21%; P=.008) groups. The incidence of adverse events was 47.4% in the budesonide group, 68.4% in the mesalazine group, and 42.1% in the placebo group. CONCLUSIONS: In a randomized multicenter study, we found oral budesonide 9 mg once daily to be effective and safe for induction of clinical and histologic remission in patients with lymphocytic colitis, compared with placebo. Oral mesalazine 3 g once daily was not significantly better than placebo. ClinicalTrials.gov no: NCT01209208.

  • 5.
    Munch, A
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Fernandez-Banares, F
    University of Barcelona, Spain .
    Munck, L K.
    University of Copenhagen, Denmark .
    Azathioprine and mercaptopurine in the management of patients with chronic, active microscopic colitis2013In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 37, no 8, p. 795-798Article in journal (Refereed)
    Abstract [en]

    Background Microscopic colitis (MC) is a common chronic diarrhoeal disease, and remission can be induced with budesonide. However, diarrhoea relapses frequently when budesonide is tapered and a few patients become budesonide intolerant. Aim To examine retrospectively the effect of azathioprine (AZA) and mercaptopurine (MP) in patients with chronic, active MC. Methods/patients Data on all MC patients who received AZA or MP in the years 19972011 at three centres representing three countries were pooled for analysis. The indications for thiopurine therapy were frequent relapses after short-term treatment (N=26), budesonide dependency on 6mg (N=15) and budesonide intolerance (N=5). The response to thiopurine treatment was defined as clinical remission, intolerance or nonresponse. Results Forty-six MC patients (32 CC and 14 LC), 32 female; median age 59years (range: 3683) with a median disease duration of 3years (range: 0.518) were included. Thirteen patients (28%) achieved long-term clinical remission on AZA therapy. AZA failed in 31 patients (67%) due to intolerance and in 2 patients (4%) because of nonresponse. Thirteen of 31 AZA-intolerant patients were switched to MP and 6 patients (46%) obtained clinical remission. Thus, the overall response rate to thiopurines was 19/46 (41%). The main side effects were nausea/vomiting and abnormally elevated liver enzymes. Conclusions In this retrospective case series, the majority of chronic, active MC patients were intolerant to AZA leading to cessation of treatment. However, further studies are needed to explore the efficacy, acceptance, tolerance and safety of MP in patients with chronic, active MC refractory to budesonide.

  • 6.
    Munch, Andreas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Bohr, Johan
    Örebro University Hospital, Örebro University, Sweden.
    Vigren, Linus
    Lund University, Sweden.
    Tysk, Curt
    Örebro University Hospital, Örebro University, Sweden.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Lack of effect of methotrexate in budesonide-refractory collagenous colitis2013In: Clinical and Experimental Gastroenterology, ISSN 1178-7023, E-ISSN 1178-7023, Vol. 6, p. 149-152Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    In most cases, collagenous colitis can be treated effectively with budesonide. However, some patients develop side effects or have chronic symptoms refractory to budesonide. This paper reports an open case series of patients intolerant or refractory to budesonide who were treated with methotrexate (MTX).

    METHODS AND PATIENTS:

    Nine patients (seven women) with a median (range) age of 62 (44-77) years were studied. Bowel movements were registered during 1 week prior to baseline and after 6 and 12 weeks' treatment, enabling calculation of the mean bowel movements/day. All patients underwent colonoscopy with biopsies before inclusion to confirm diagnosis. Open treatment with MTX was given 15 mg subcutaneously weekly for 6 weeks and was increased to 25 mg for a further 6 weeks if symptoms were unresponsive to the first 6 weeks' treatment. The endpoint was clinical remission, which was defined as a mean <3 stools/day and mean <1 watery stool/day/week at Week 12. The Short Health Scale was used at baseline and Week 12 to assess health-related quality of life.

    RESULTS:

    Five patients fulfilled the treatment according to the protocol and four patients discontinued the study after 3-6 weeks because of adverse events. No patient achieved clinical remission at Week 12. The mean stool frequency/day at baseline was 6.0 stools/day, thereof 5.4 watery stools/day and after 12 weeks treatment 6.4 stools/day, thereof 5.7 watery/day. No patient appreciated an improvement of health-related quality of life.

    CONCLUSION:

    Short-term treatment with MTX had no clinical effect in collagenous colitis patients intolerant or refractory to budesonide. Alternative therapies should be investigated in these patients.

  • 7.
    Munch, Andreas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Ost, A
    Medilab, Taby, Sweden .
    Carlsson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Low levels of bile acids increase bacterial uptake in colonic biopsies from patients with collagenous colitis in remission2011In: ALIMENTARY PHARMACOLOGY and THERAPEUTICS, ISSN 0269-2813, Vol. 33, no 8, p. 954-960Article in journal (Refereed)
    Abstract [en]

    Pandgt;Background Patients with collagenous colitis have an impaired mucosal barrier. Moreover, collagenous colitis is associated with bile acid malabsorption. Bile acids can increase bacterial mucosal uptake in humans. Mucosal barrier function was investigated by exposing colonic biopsies to chenodeoxycholic acid (CDCA) or deoxycholic acid (DCA) in Ussing chamber experiments. Aim To find if low levels of bile acids increase bacterial uptake in colonic biopsies from collagenous colitis patients. Methods The study comprised 33 individuals; 25 with collagenous colitis (14 in clinical remission without treatment, 11 with active disease and 10 examined in clinical remission resulting from treatment with 6 mg budesonide); eight 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), potential difference, trans-epithelial resistance and transmucosal passage of Escherichia coli K12 after adding 100 mu mol/L CDCA or DCA. Results When adding 100 mu mol/L CDCA or DCA, bacterial uptake increased fourfold 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 due to budesonide treatment, bile acids did not affect bacterial uptake. Confocal microscopy revealed trans-epithelial passage of E. coli K12 within 30 min. Conclusions Low concentrations of dihydroxy-bile acids exacerbate mucosal barrier dysfunction in colonic biopsies of patients with collagenous colitis in remission. This allows a substantially increased bacterial uptake, which may contribute to recurrence of inflammation.

  • 8.
    Munch, Andreas
    et al.
    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.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Ost, Åke
    Medilab, Taby, Sweden.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Increased Transmucosal Uptake of E-coli K12 in Collagenous Colitis Persists After Budesonide Treatment2009In: American Journal of Gastroenterology, ISSN 0002-9270, E-ISSN 1572-0241, Vol. 104, no 3, p. 679-685Article in journal (Refereed)
    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.

  • 9.
    Münch, Andreas
    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.
    Collagenous colitis: The influence of inflammation and bile acids on intestinal barrier function2010Doctoral 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.

    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
    Show others...
    2005 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 54, no 8, p. 1126-1128Article 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: 2017-12-13
    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, p. 1167-1174Article 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: 2017-12-13
    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, p. 679-685Article 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: 2017-12-13
    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.

    Keywords
    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
  • 10.
    Münch, Andreas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Aust, D.
    University Hospital, Dresden, Germany.
    Bohr, J.
    Örebro University Hospital, Sweden and University of Örebro, Sweden .
    Bonderup, O.
    Regional Hospital Silkeborg, Denmark .
    Fernandez Banares, F.
    University of Barcelona, Spain .
    Hjortswang, Henrik
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Madisch, A.
    Academic Teaching Hospital Siloah, Hannover, Germany.
    Munck, L. K.
    Koege University Hospital, Denmark.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Tysk, C.
    Örebro University Hospital, Sweden and University of Örebro, Sweden .
    Miehlke, S.
    Centre Digest Disease, Hamburg, Germany.
    Microscopic colitis: Current status, present and future challenges Statements of the European Microscopic Colitis Group2012In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 6, no 9, p. 932-945Article in journal (Refereed)
    Abstract [en]

    Microscopic colitis (MC) is an inflammatory bowel disease presenting with chronic, non-bloody watery diarrhoea and few or no endoscopic abnormalities. The histological examination reveals mainly two subtypes of MC, lymphocytic or collagenous colitis. Despite the fact that the incidence in MC has been rising over the last decades, research has been sparse and our knowledge about MC remains limited. Specialists in the field have initiated the European Microscopic Colitis Group (EMCG) with the primary goal to create awareness on MC. The EMCG is furthermore a forum with the intention to promote clinical and basic research. In this article statements and comments are given that all members of the EMCG have considered being of importance for a better understanding of MC. The paper focuses on the newest updates in epidemiology, symptoms and diagnostic criteria, pathophysiology and highlights some unsolved problems. Moreover, a new treatment algorithm is proposed on the basis of new evidence from well-designed, randomized control trials.

  • 11.
    Münch, Andreas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Bohr, Johan
    Örebro University Hospital, and School of Health and Medical Sciences, Örebro University, Sweden .
    Miehlke, Stephan
    Centre for Digestive Disease, Hamburg, Germany .
    Benoni, Cecilia
    University Hospital, Malmö, Sweden .
    Olesen, Martin
    University Hospital, Malmö, Sweden .
    Ost, Ake
    Aleris Medilab, Täby, Sweden.
    Strandberg, Lars
    Region Hospital, Falun, Sweden.
    Hellström, Per M
    Uppsala University, Sweden.
    Hertervig, Erik
    University Hospital, Lund, Sweden.
    Armerding, Peter
    Gastroenterology, Private Practice, Berlin, Germany .
    Stehlik, Jiri
    Region Hospital, Usti nad Labem, Czech Repbulic.
    Lindberg, Greger
    Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Björk, Jan
    Karolinska University Hospital Solna, Stockholm, Sweden .
    Lapidus, Annika
    Ersta Hospital, Stockholm, Sweden .
    Löfberg, Robert
    Sophiahemmet, Stockholm, Sweden .
    Bonderup, Ole
    Regional Hospital, Silkeborg, Danmark .
    Avnström, Sören
    Amager Hospital, Copenhagen, Denmark .
    Rössle, Martin
    Gastroeneterology, Priva Practice, Freiburg, Germany.
    Dilger, Karin
    Dr Falk, Pharma GmBH, Freiburg, Germany.
    Mueller, Ralph
    Dr Falk, Pharma GmBH, Freiburg, Germany.
    Greinwald, Roland
    Dr Falk, Pharma GmBH, Freiburg, Germany.
    Tysk, Curt
    Örebro University Hospital, and School of Health and Medical Sciences, Örebro University, Sweden.
    Ström, Magnus
    Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Low-dose budesonide for maintenance of clinical remission in collagenous colitis: a randomised, placebo-controlled, 12-month trial2016In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 65, no 1, p. 47-56Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: This 1-year study aimed to assess low-dose budesonide therapy for maintenance of clinical remission in patients with collagenous colitis.

    DESIGN: A prospective, randomised, placebo-controlled study beginning with an 8-week open-label induction phase in which patients with histologically confirmed active collagenous colitis received budesonide (Budenofalk, 9 mg/day initially, tapered to 4.5 mg/day), after which 92 patients in clinical remission were randomised to budesonide (mean dose 4.5 mg/day; Budenofalk 3 mg capsules, two or one capsule on alternate days) or placebo in a 12-month double-blind phase with 6 months treatment-free follow-up. Primary endpoint was clinical remission throughout the double-blind phase.

    RESULTS: Clinical remission during open-label treatment was achieved by 84.5% (93/110 patients). The median time to remission was 10.5 days (95% CI (9.0 to 14.0 days)). The maintenance of clinical remission at 1 year was achieved by 61.4% (27/44 patients) in the budesonide group versus 16.7% (8/48 patients) receiving placebo (treatment difference 44.5% in favour of budesonide; 95% CI (26.9% to 62.7%), p<0.001). Health-related quality of life was maintained during the 12-month double-blind phase in budesonide-treated patients. During treatment-free follow-up, 82.1% (23/28 patients) formerly receiving budesonide relapsed after study drug discontinuation. Low-dose budesonide over 1 year resulted in few suspected adverse drug reactions (7/44 patients), all non-serious.

    CONCLUSIONS: Budesonide at a mean dose of 4.5 mg/day maintained clinical remission for at least 1 year in the majority of patients with collagenous colitis and preserved health-related quality of life without safety concerns. Treatment extension with low-dose budesonide beyond 1 year may be beneficial given the high relapse rate after budesonide discontinuation.

    TRIAL REGISTRATION NUMBERS: http://www.clinicaltrials.gov (NCT01278082) and http://www.clinicaltrialsregister.eu (EudraCT: 2007-001315-31).

  • 12.
    Münch, Andreas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Ignatova, Simone
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Adalimumab in budesonide and methotrexate refractory collagenous colitis2012In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, ISSN 0036-5521, Vol. 47, no 1, p. 59-63Article in journal (Refereed)
    Abstract [en]

    Background. We described three patients with collagenous colitis (CC) who developed side effects or were refractory to both budesonide and methotrexate and were given adalimumab (ADA) as a third-line treatment. Method/Patients. Three patients (two women, mean age 45 years and one man, 74 years old) were included. Mean bowel movements per day per week were calculated and stool weight/24 h registered prior to and following ADA treatment. ADA was given in doses 160 mg s.c. (baseline), 80 mg (week 2) and 40 mg (week 4). Sigmoidoscopies with biopsies were performed at baseline and after 6 weeks to examine changes in histology. The Psychological General Well-Being Index (PGWBI) and Short Health Scale (SHS) were used at baseline and after 6 weeks. Results. The two female patients tolerated the treatment well. The male patient developed, despite clinical response, side effects (vomiting, abdominal pain) after 80 mg of ADA and the treatment was stopped as side effects reoccurred after rechallenge. The two women were in clinical remission at week 6 and the mean stool frequency per day decreased from mean 11 to 2. Mean stool weight/24 h changed from 600 to 185 g. The quality of life improved drastically in all patients. There were no consistent changes in histology. Conclusion. ADA seems effective in budesonide and methotrexate refractory CC and can be administrated to selected patients to achieve clinical remission, improve quality of life and possibly avoid colectomy. Further studies for induction and maintenance treatment should be conducted to confirm efficacy and examine safety issues, even in long term

  • 13.
    Münch, Andreas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Langner, Cord
    Medical University of Graz, Austria .
    Microscopic Colitis: Clinical and Pathologic Perspectives2015In: Clinical Gastroenterology and Hepatology, ISSN 1542-3565, E-ISSN 1542-7714, Vol. 13, no 2, p. 228-236Article, review/survey (Refereed)
    Abstract [en]

    Microscopic colitis is a chronic inflammatory bowel disease characterized by chronic nonbloody diarrhea and specific histopathology features. Active disease, defined as 3 or more stools or 1 or more watery stools per day, significantly reduces quality of life. Epidemiologic studies have found the incidence and prevalence of microscopic colitis to be comparable with those of Crohn's disease and ulcerative colitis. Nevertheless, microscopic colitis is still under-recognized in clinical practice-most health care workers know little about its etiology and pathophysiology. Furthermore, there are many challenges to the diagnosis and treatment of patients. We review the epidemiologic and clinical features of this disorder and discuss its pathogenesis. We also outline the criteria for histopathologic evaluation of microscopic colitis, recently published by the European Consensus on Inflammatory Bowel Disease, and discuss a treatment algorithm created by the European Microscopic Colitis Group. Treatment options for patients with budesonide-refractory disease are discussed.

  • 14.
    Münch, Andreas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology.
    Ström, Magnus
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Dihydroxy bile acids increase mucosal permeability and bacterial uptake in human colon biopsies2007In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 42, no 10, p. 1167-1174Article in journal (Refereed)
    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.

  • 15.
    Münch, Andreas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences.
    Söderholm, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology.
    Carlsson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Öst, Åke
    Medilab, Täby, Sweden.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland.
    Physiological levels of bile acids increase bacterial uptake in colonic biopsies of collagenous colitis patients in remissionManuscript (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.

  • 16.
    Münch, Andreas
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology.
    Söderholm, Johan D
    Linköping University, Department of Biomedicine and Surgery, Division of surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Wallon, Conny
    Linköping University, Department of Biomedicine and Surgery, Division of surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Öst, Åke
    Medilab, Täby, Sweden.
    Olaison, Gunnar
    Linköping University, Department of Biomedicine and Surgery, Division of surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Ström, Magnus
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Dynamics of mucosal permeability and inflammation in collagenous colitis before, during, and after loop ileostomy2005In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 54, no 8, p. 1126-1128Article in journal (Refereed)
    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.

  • 17.
    Münch, Andreas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Tysk, Curt
    Faculty of Medicine and Health, School of Health and Medical Sciences, Örebro University and Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Bohr, Johan
    Faculty of Medicine and Health, School of Health and Medical Sciences, Örebro University and Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Madisch, Ahmed
    Medical Department I, Siloah Hospital, Hannover, Germany.
    Bonderup, Ole K
    Diagnostic Center, Silkeborg Hospital, Silkeborg, Denmark.
    Mohrbacher, Ralf
    Research & Development, Dr Falk Pharma GmbH, Freiburg, Germany.
    Mueller, Ralph
    Research & Development, Dr Falk Pharma GmbH, Freiburg, Germany.
    Greinwald, Roland
    Research & Development, Dr Falk Pharma GmbH, Freiburg, Germany.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Miehlke, Stephan
    Center for Digestive Diseases, Cooperation of Internal Medicine, Hamburg, Germany.
    Smoking Status Influences Clinical Outcome in Collagenous Colitis.2016In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 10, no 4, p. 449-454Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The relationship between clinical and histological parameters in collagenous colitis (CC) is poorly understood. Smoking is a risk factor for CC, whereas its impact on clinical activity and outcome is not well known.

    METHODS: In a post hoc analysis of pooled data from two randomized controlled trials we assessed the association between demographic data (gender, age, smoking habits, family history of inflammatory bowel disease), clinical variables (duration of symptoms, mean number of stools/watery stools per day, abdominal pain, clinical remission) and histological data (thickness of the collagen band, inflammation of the lamina propria, total numbers of intraepithelial lymphocytes, degeneration). Moreover, we analysed the predictive value of baseline parameters for clinical outcome in a logistic regression model.

    RESULTS: Pooled data were available from 202 patients with active CC, of whom 36% were current smokers, 29% former smokers and 35% non-smokers. Smoking status was associated with decreased ability to achieve clinical remission (current smokers vs non-smokers: odds ratio [OR] 0.31, 95% confidence interval [CI] 0.10-0.98, p = 0.045; former smokers vs non-smokers: OR 0.19, 95% CI 0.05-0.73, p = 0.016). Current smokers had an increased mean number of watery stools at baseline compared with non-smokers (p = 0.051) and increased mean number of watery stools per se was associated with decreased likelihood of obtaining clinical remission (OR 0.63, 95% CI 0.47-0.86, p = 0.003). Patient characteristics and histology at baseline had no association with clinical parameters and no predictive value for clinical outcome.

    CONCLUSION: Smoking worsens clinical symptoms in CC and is associated with an increased number of watery stools and decreased likelihood of achieving clinical remission. There is no significant association between histology and clinical data.

  • 18.
    Münch, Andreas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Endocrinology. Linköping University, Faculty of Medicine and Health Sciences.
    Verhaegh, Bas
    Maastricht University, Netherlands.
    Cross-border scientific projects run by UEG national member societies reduce health inequalities across Europe2016In: United European Gastroenterology journal, ISSN 2050-6406, E-ISSN 2050-6414, Vol. 4, no 3, p. 478-478Article in journal (Other academic)
    Abstract [en]

    n/a

  • 19.
    Riviere, Pauline
    et al.
    Katholieke Univ Leuven, Belgium.
    Münch, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Michetti, Pierre
    Gastroenterol La Source Beaulieu, Switzerland.
    Chande, Nilesh
    Western Univ, Canada.
    de Hertogh, Gert
    Katholieke Univ Leuven, Belgium.
    Schoeters, Patrick
    AZA Herentals, Belgium.
    Ferrante, Marc
    Katholieke Univ Leuven, Belgium.
    Vermeire, Severine
    Katholieke Univ Leuven, Belgium.
    Van Assche, Gert
    Katholieke Univ Leuven, Belgium.
    Vedolizumab in Refractory Microscopic Colitis: An International Case Series2019In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 13, no 3, p. 337-340Article in journal (Refereed)
    Abstract [en]

    Background Evidence for second-line therapy in patients with microscopic colitis [MC] failing budesonide is scarce, although anti-tumour necrosis factors [anti-TNFs], methotrexate and azathioprine have been reported to be effective in small cohort studies. Vedolizumab, a monoclonal antibody targeting 47-integrin, prevents homing of T-cells to the gut. We evaluated clinical remission with vedolizumab in budesonide-refractory MC patients. Methods We solicited gastroenterologists in Europe and Canada for cases of MC treated with vedolizumab. Vedolizumab 300 mg IV was administered at weeks 0, 2 and 6, and then every 8 weeks. Clinical remission and histological remission were defined as less than three stools per day and normalization of histology, respectively, after induction treatment. Results Eleven cases were retrieved (nine females, lymphocytic colitis [LC] n = 5, collagenous colitis [CC] n = 6). Median [interquartile range] disease duration at vedolizumab initiation was 51 [29-70] months. Nine of 11 patients had failed one immunosuppressant and ten of 11 at least one anti-TNF agent. After three infusions of vedolizumab, clinical remission was observed in 5/11 patients [two LC and three CC] of whom three remained well with maintenance therapy [median duration of 13 months]. Biopsies were obtained from 9/11 patients. Histological remission was observed in 3/4 patients with clinical remission [2/3 CC, 1/1 LC] and 0/5 patients without clinical improvement. Conclusion In a series of highly refractory MC patients, vedolizumab induced clinical remission in 5/11 subjects, of whom 75% showed normalized histology. Larger randomized trials are needed to assess the efficacy of vedolizumab in patients with MC.

  • 20.
    Sänger, Andreas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Langner, Cord
    Medical University of Graz, Austria.
    Letter: Diagnosing Microscopic Colitis: Is Flexible Sigmoidoscopy a Reliable Alternative to Colonoscopy? Reply in CLINICAL GASTROENTEROLOGY AND HEPATOLOGY, vol 13, issue 3, pp 618-6192015In: Clinical Gastroenterology and Hepatology, ISSN 1542-3565, E-ISSN 1542-7714, Vol. 13, no 3, p. 618-619Article in journal (Other academic)
    Abstract [en]

    n/a

  • 21.
    Walter, Susanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Münch, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Ost, A
    Karolinska Institute.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Anorectal function in patients with collagenous colitis in active and clinically quiescent phase, in comparison with healthy controls2010In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 22, no 5, p. 534-+Article in journal (Refereed)
    Abstract [en]

    Background Collagenous colitis (CC) is characterized by chronic watery diarrhea, a macroscopically normal colonic mucosa but typical microscopic inflammation. Chronic mucosal inflammation of the colon and rectum has earlier been associated with altered visceral sensitivity, but anorectal function has never been reported in cases of CC. Methods Fifteen patients with CC in active phase recorded their symptoms. The severity of inflammation was determined in mucosal biopsies. Anorectal function was assessed and compared with that of 15 healthy volunteers of corresponding age and matched for gender. After 6 weeks of budesonide treatment when the patients were in clinical remission anorectal function was re-assessed. Key Results All patients had inflammation also in rectum. Patients in active phase had, during rectal balloon distension a higher rectal sensory threshold for the feeling of first sensation, compared with controls (P = 0.02). There were no differences in rectal sensory threshold for the feeling of urgency or maximum distension, between patients with CC in active phase and healthy controls. Rectal volume at first sensation was significantly greater in patients than in controls (P = 0.02), but there were no differences at urgency or maximum distension. Twelve of 15 patients completed 6 weeks of budesonide treatment and all went into clinical remission. No differences in anorectal function were measured when patients had active disease, compared with clinical remission. Conclusions andamp; Inferences Collagenous colitis was not associated with rectal hypersensitivity or disturbed anal function despite rectal inflammation. On the contrary, the sensation threshold for light rectal pressure was elevated in patients with active CC.

  • 22.
    Westerlind, Helga
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Mellander, Marie-Rose
    Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Bresso, Francesca
    Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Munch, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Health Sciences.
    Bonfiglio, Ferdinando
    Karolinska Institutet, Stockholm, Sweden.
    Assadi, Ghazaleh
    Karolinska Institutet, Stockholm, Sweden.
    Rafter, Joseph
    Karolinska Institutet, Stockholm, Sweden.
    Hübenthal, Matthias
    Christian-Albrechts-University of Kiel, Kiel, Germany.
    Lieb, Wolfgang
    Christian-Albrechts-University of Kiel, Kiel, Germany.
    Källberg, Henrik
    Karolinska Institutet, Stockholm, Sweden.
    Brynedal, Boel
    Karolinska Institutet, Stockholm, Sweden.
    Padyukov, Leonid
    Karolinska Institutet, Stockholm, Sweden.
    Halfvarson, Jonas
    Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Törkvist, Leif
    Karolinska University Hospital, Stockholm, Sweden.
    Bjork, Jan
    Karolinska University Hospital, Stockholm, Sweden.
    Andreasson, Anna
    Karolinska Institutet, Stockholm, Sweden.
    Agreus, Lars
    Karolinska Institutet, Stockholm, Sweden.
    Almer, Sven
    arolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Miehlke, Stephan
    Internal Medicine Center Eppendorf, Hamburg, Germany.
    Madisch, Ahmed
    Siloah Hospital, Hannover, Germany.
    Ohlsson, Bodil
    Skåne University Hospital, Lund University, Lund, Sweden.
    Löfberg, Robert
    Karolinska Institutet, Stockholm, Sweden Sophiahemmet Hospital, Stockholm, Sweden.
    Hultcrantz, Rolf
    Karolinska Institutet, Stockholm, Sweden.
    Franke, Andre
    D'Amato, Mauro
    Karolinska Institutet, Stockholm, Sweden BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, Bilbao, Spain..
    Dense genotyping of immune-related loci identifies HLA variants associated with increased risk of collagenous colitis.2017In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 66, no 3, p. 421-428Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Collagenous colitis (CC) is a major cause of chronic non-bloody diarrhoea, particularly in the elderly female population. The aetiology of CC is unknown, and still poor is the understanding of its pathogenesis. This possibly involves dysregulated inflammation and immune-mediated reactions in genetically predisposed individuals, but the contribution of genetic factors to CC is underinvestigated. We systematically tested immune-related genes known to impact the risk of several autoimmune diseases for their potential CC-predisposing role.

    DESIGN: Three independent cohorts of histologically confirmed CC cases (N=314) and controls (N=4299) from Sweden and Germany were included in a 2-step association analysis. Immunochip and targeted single nucleotide polymorphism (SNP) genotype data were produced, respectively, for discovery and replication purposes. Classical human leucocyte antigen (HLA) variants at 2-digit and 4-digit resolution were obtained via imputation from single marker genotypes. SNPs and HLA variants passing quality control filters were tested for association with CC with logistic regression adjusting for age, sex and country of origin.

    RESULTS: Forty-two markers gave rise to genome-wide significant association signals, all contained within the HLA region on chromosome 6 (best p=4.2×10(-10) for SNP rs4143332). Among the HLA variants, most pronounced risk effects were observed for 8.1 haplotype alleles including DQ2.5, which was targeted and confirmed in the replication data set (p=2.3×10(-11); OR=2.06; 95% CI (1.67 to 2.55) in the combined analysis).

    CONCLUSIONS: HLA genotype associates with CC, thus implicating HLA-related immune mechanisms in its pathogenesis.

  • 23.
    Wickbom, Anna
    et al.
    Orebro Univ, Sweden.
    Bohr, Johan
    Orebro Univ, Sweden.
    Nyhlin, Nils
    Orebro Univ, Sweden.
    Eriksson, Anders
    East Hosp, Sweden.
    Lapidus, Annika
    Ersta Hosp, Sweden.
    Münch, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Ung, Kjell-Arne
    Sahlgrenska Univ Hosp Mölndal, Sweden.
    Vigren, Lina
    Trelleborg Hosp, Sweden.
    Öst, Åke
    Aleris Medilab, Sweden.
    Tysk, Curt
    Orebro Univ, Sweden.
    Microscopic colitis in patients with ulcerative colitis or Crohns disease: a retrospective observational study and review of the literature2018In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 53, no 4, p. 410-416Article in journal (Refereed)
    Abstract [en]

    Objectives: Onset of microscopic colitis (MC) in patients with ulcerative colitis (UC) or Crohns disease (CD), or vice versa, has been reported occasionally but the subject is not well described. We therefore report a retrospective observational study of such patients and review the literature.Methods: Forty-six Swedish gastroenterology clinics were contacted about patients with diagnoses of both inflammatory bowel disease (IBD) and MC. Publications were searched on PubMed.Results: We identified 31 patients with onset of MC after a median (range) of 20 (2-52) years after diagnosis of IBD, or vice versa; 21 UC patients developed collagenous colitis (CC) (n=16) or lymphocytic colitis (LC) (n=5); nine CD patients developed CC (n=5) or LC (n=4); one CC patient developed CD. Of the 21 UC patients, 18 had extensive disease, whereas no consistent phenotype occurred in CD. Literature review revealed 27 comprehensive case reports of patients with diagnoses of both IBD and MC. Thirteen MC patients developed IBD, of which four required colectomy. Fourteen IBD patients later developed MC. There were incomplete clinical data in 115 additional reported patients.Conclusions: Altogether 173 patients with occurrence of both IBD and MC were found. The most common finding in our patients was onset of CC in a patient with UC. Although these are likely random associations of two different disorders, MC should be considered in the patient with UC or CD if there is onset of chronic watery diarrhoea without endoscopic relapse of IBD.

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