Signe Wildt

Probiotic treatment of collagenous colitis: A randomized, double-blind, placebo-controlled trial with lactobacillus acidophilus and bifidobacterium animalis subsp. lactis

Background Probiotic treatment may be effective in diseases involving gut microflora and intestinal inflammation. In collagenous colitis (CC), a potential pathogenic role of the gut microflora has been proposed. The effect of probiotic treatment in CC is unknown. Our aim was to investigate the clinical effect of treatment with Lactobacillus acidophilus LA‐5 and Bifidobacterium animalis subsp. lactis BB‐12 (AB‐Cap‐10) in patients with CC. Materials and Methods Patients with CC and diarrhea were in a double‐blind placebo‐controlled study randomized (2:1) to AB‐Cap‐10 or placebo for 12 weeks. The primary end point was reduction in bowel frequency per week of ≥50%. Secondary end points were changes in bowel frequencies, stool consistency, stool weight, histopathology, and abdominal bloating and pain. Results Twenty‐nine patients were randomized: 21 to probiotics and 8 to placebo. Reduction in bowel frequency per week of ≥50% occurred in 6 of 21 (29%) and in 1 of 8 (13%) patients receiving probiotic and placebo, respectively (P = 0.635). No differences between treatments were observed regarding the secondary end points. Post hoc analysis showed a median reduction in bowel frequency per week from 32 (range 18–84) to 23 (range 11–56; P < 0.005), a reduction in number of days with liquid stools per week from 6 days (range 0–7 days) to 1 day (range 0–7 days; P < 0.005), and an increase in number of days with solid stools per week (P < 0.05) in the AB‐Cap‐10 group. Conclusions AB‐Cap‐10 had no significant effect on the chosen end points. Post hoc analysis demonstrated amelioration of clinical symptoms in the AB‐Cap‐10 group, indicating that probiotic treatment may potentially influence the disease course of CC.

Metabolic and inflammatory faecal markers in collagenous colitis.

Objectives To evaluate the excretion of the inflammatory and metabolic faecal markers calprotectin, lactoferrin, and short-chain fatty acids in symptomatic and quiescent collagenous colitis. Methods Faecal samples from 21 patients with active collagenous colitis, 12 patients retested in remission, and 13 controls were analysed. Calprotectin was determined using an enzyme-linked immunosorbent assay. Lactoferrin was estimated by a latex agglutination test. Short-chain fatty acids were determined by steam distillation followed by gas–liquid chromatography. Results Calprotectin was increased in patients with active collagenous colitis [80 μg/g (6.25–1899)] (median and range) compared with patients with quiescent collagenous colitis [26 μg/g (6.25–340)], P=0.025 and controls [6.25 μg/g (6.25–99)], P=0.002. Eight patients (38%) with active collagenous colitis had normal levels of calprotectin. Lactoferrin was detected in one patient only. Concentrations of total short-chain fatty acids did not differ in patients with active collagenous colitis compared with quiescent collagenous colitis or controls (P=0.75), whereas concentrations of the branched-chain fatty acids were decreased in patients with active collagenous colitis versus controls (P<0.005). In-vitro incubations demonstrated increased ratios of acetate in patients with active and quiescent collagenous colitis compared with controls (P<0.05), with a corresponding decrease in branched-chain fatty acids ratios (P<0.05). Conclusion Faecal calprotectin was increased in collagenous colitis; however, increased excretion was not a universal finding limiting the use of calprotectin as an inflammatory marker in collagenous colitis. Faecal lactoferrin was almost undetectable. Luminal fermentative conditions are altered in collagenous colitis. Fermentative alterations could be secondary to changes in substrate availability and intestinal transit time.

The Temporal Evolution of Histological Abnormalities in Microscopic Colitis.

BACKGROUND AND AIMS Microscopic colitis (MC) is a common cause of chronic watery diarrhoea but long-term follow-up data are sparse. METHODS We performed a retrospective review of health records and all pathology reports in a regional cohort of patients with MC to describe the change in pre- and post-diagnostic colon biopsies. RESULTS MC was diagnosed in 468 patients with collagenous colitis (CC), 361 with lymphocytic colitis (LC) and 226 with incomplete MC (MCi). The 2014 incidence of CC, LC and MCi was 14.5, 14.9 and 5 per 10(5). Biopsies from both right and left colon were obtained in 237 (51%) patients with CC, 200 (55%) with LC and 107 (47%) with MCi. The diagnostic sensitivities of both left- and right-sided biopsies for MC were high and did not differ. Pre-diagnostic biopsies were obtained in 150 patients and lamina propria inflammation was described in 59, 47 and 43% of patients with a diagnosis of CC, LC and MCi respectively within 1 year, while histology was normal in 16, 13 and 21%. Post-diagnostic biopsies were obtained in 283 patients. MC persisted for up to one year in 77% with CC, 64% with LC and 45% with MCi, of whom 6, 9 and 18% respectively changed to a different MC subgroup. CONCLUSIONS Colonic biopsies obtained prior to the MC diagnosis often revealed increased lamina propria inflammation. The pathological changes of CC and LC are more persistent than those of MCi. Biopsies from the descending or sigmoid colon are sufficient to elucidate whether a patient with chronic watery diarrhoea has MC.

Small-bowel permeability in collagenous colitis.

Objective. Collagenous colitis (CC) is a chronic inflammatory bowel disease that affects the colon. However, some patients with CC present with accompanying pathologic small-bowel manifestations such as coeliac disease, defects in bile acid absorption and histopathologic changes in small-intestinal biopsies, indicating that CC is a pan-intestinal disease. In small-intestinal disease, the intestinal barrier function may be impaired, and the permeability of the small intestine altered. The purpose of this research was to study small-bowel function in patients with CC as expressed by intestinal permeability. Material andmethods. Ten patients with CC and chronic diarrhoea participated in the study. Coeliac disease was excluded by small-bowel biopsy and/or serology. Intestinal permeability was assessed as urinary excretion (ratios) 2, 4 and 6 h after ingestion of 14C-labelled mannitol (14C-mannitol) and 99mTc-labelled diethylenetriamine-pentaacetic acid (99mTc-DTPA). Data were compared with the results from healthy controls. Results. No difference was found between groups in urinary excretion of 14C-mannitol and 99mTc-DTPA after 2, 4 or 6 h, respectively. Likewise, no significant differences in the 99mTc-DTPA/14C-mannitol ratios between patients and controls were detected after 2 h: 0.030 (0.008–0.130) versus 0.020 (0.007–0.030), p=0.19, after 4 h: 0.040 (0.009–0.180) versus 0.020 (0.008–0.040), p=0.14 or after 6 h: 0.040 (0.012–0.180) versus 0.020 (0.010–0.040), p=0.17. Conclusions. No alterations in intestinal permeability in patients with CC could be demonstrated. Impairment of the integrity of the mucosa of the small bowel and the presence of a general dysfunction of the small intestine in patients with CC seem unlikely.

Seroreactivity to E. coli outer membrane protein C antibodies in active inflammatory bowel disease; diagnostic value and correlation with phylogroup B2 E. coli infection

Abstract Background. Several serologic tests, including anti-outer membrane porin C antibody (Omp C), are used for screening and as marker of disease course in inflammatory bowel diseases (IBD). Our aim was to investigate possible differences in Omp C level in patients with active and inactive IBD compared to controls. Methods. All blood samples were tested for Omp C. Disease activity was evaluated by Harvey Bradshaw Index, Simple Clinical Activity Index and Modified Pouchitis Disease Activity Index. Results. Blood samples were collected from 113 patients and 60 controls. Patients with active IBD did not have a higher level of Omp C than patients in remission. Surprisingly, in patients with active Crohns disease a significantly lower level of Omp C was found compared with patients with inactive Crohns disease (p < 0.05). All other groups among patients with IBD did have a significantly higher level of Omp C, compared with controls, including patients with acute gastroenteritis (p < 0.05). Although IBD patients with phylogroup B2 E. coli cultured from their fecal samples, were more likely to have a positive Omp C test (p < 0.05), this could not explain the low Omp C level in the subgroup of patients with active Crohns disease. Conclusions. Omp C titer was not raised in patients with active IBD compared with patients in remission. In addition, there was no difference in Omp C level in patients with active Crohns disease compared with controls. These observations do not support the use of Omp C serology testing, either in disease activity assessment, or in screening for active Crohns disease.

Cyclooxygenase-2 immunoreactivity in collagenous colitis.

Collagenous colitis (CC) is an inflammatory bowel disease of unknown aetiology and pathogenesis. In ulcerative colitis and Crohns disease, prostaglandins may be involved in the pathogenesis of inflammation, and increased expression of cyclo‐oxygenase‐2 (COX‐2) has been detected. The purpose of this study was to examine the presence and cellular localization of COX‐2 in colonic mucosa of patients with CC. Using immunohistochemistry, immunoflouresence and Western blot analysis, COX‐2 expression was evaluated in colonic mucosal biopsies from 10 patients with active untreated CC, and compared with samples from eight normal controls, and samples from eight patients with ulcerative colitis or Crohns disease. Specimens from patients with CC expressed COX‐2 protein in increased amounts compared with controls, but similar to patients with ulcerative colitis and Crohns disease. COX‐2 expression was localized to the mononuclear cells of the lamina propria. COX‐2 expression was most evident in macrophages. Co‐localization of COX‐2 and macrophages was increased in number in comparison with controls. In conclusion COX‐2 is expressed in increased amounts primarily in the macrophage subpopulation of the inflammatory infiltrate of lamina propria in CC. Increased recruitment of macrophages, increased expression of COX‐2 and increased prostaglandin synthesis may be involved in the pathogenesis of CC.

Fecal Calprotectin Is Not Affected by Pregnancy: Clinical Implications for the Management of Pregnant Patients with Inflammatory Bowel Disease

Background: Noninvasive biomarkers of inflammation for monitoring inflammatory bowel disease (IBD) are important in pregnancy. Clinical and laboratory markers are often affected by the physiological adaption that occurs during pregnancy, although, few, if any, data exist on fecal calprotectin (FC). We investigated FC concentrations in pregnant controls and IBD women, and whether FC correlated with physician global assessment (PGA), C-reactive protein (CRP), and Harvey–Bradshaw Index (HBI)/Simple Clinical Colitis Activity Index (SCCAI) before and after pregnancy, as well as during each trimester. Methods: The study is a prospective multicenter study of 46 pregnant women with and 21 without IBD in Denmark, Australia, and New Zealand. Demographics, clinical parameters, and HBI/SCCAI were recorded. Stool and blood samples were obtained to determine FC and CRP concentrations. Results: From pregnant IBD women and pregnant controls, 174 and 21 fecal samples were collected, respectively. The median FC concentration in pregnant IBD women was 131 &mgr;g/g (range 0–3600) and in controls 0 &mgr;g/g (range 0–84) (P < 0.0001). FC strongly correlated with PGA at all 5 timepoints (r ≥ 0.80; P < 0.0001) and with HBI/SCCAI before (r = 0.66; P < 0.0001) and after pregnancy (r = 0.47; P < 0.003) but not during pregnancy (P > 0.05). An FC cutoff concentration of 250 &mgr;g/g significantly correlated with active disease according to PGA in all 5 periods (P ⩽ 0.0002). CRP only significantly correlated with FC (P = 0.0007) and PGA in the second trimester (P = 0.0003). No significant correlation was found between CRP and HBI/SCCAI at any timepoint (P > 0.05). Conclusions: The physiological changes that occur during pregnancy do not affect FC, in contrast to CRP and HBI/SCCAI. The combined use of FC and PGA seems optimal to assess disease activity in IBD during pregnancy.

Chenodeoxycholic acid stimulated fibroblast growth factor 19 response - a potential biochemical test for bile acid diarrhoea.

Bile acid diarrhoea is underdiagnosed and better diagnostic tests are needed. Fasting serum fibroblast growth factor‐19 (FGF19) has insufficient diagnostic value, but this may be improved by stimulation.

The Danish National Registry for Biological Therapy in Inflammatory Bowel Disease

Aim The aims of The Danish National Registry for Biological Therapy in Inflammatory Bowel Disease are to ensure that biological therapy and the clinical management of patients with inflammatory bowel disease (IBD) receiving biological treatment are in accordance with the national clinical guidelines and, second, the database allows register-based clinical epidemiological research. Study population The study population comprises all Danish patients with IBD (both children and adults) with ulcerative colitis, Crohn’s disease, and IBD unclassified who receive biological therapy. Patients will be enrolled consecutively when biological treatment is initiated. Main variables The variables in the database are: diagnosis, time of diagnosis, disease manifestation, indication for biological therapy, previous biological and nonbiological therapy, date of visit, clinical indices, physician’s global assessment, pregnancy and breastfeeding (women), height (children), weight, dosage (current biological agent), adverse events, surgery, endoscopic procedures, and radiology. Descriptive data Eleven clinical indicators have been selected to monitor the quality of biological treatment. For each indicator, a standard has been defined based on the available evidence. National results will be published in an annual report and local results on a quarterly basis. The indicators will be reported as department-specific proportions with 95% confidence intervals, and the national average will be provided for comparison. An estimated 1,200–1,300 new biological therapies are initiated each year in Danish patients with IBD. Conclusion The database will be available for research during 2016. Data will be made available by The Danish Clinical Registries (www.rkkp.dk).

Risk of osteoporosis in microscopic colitis

ABSTRACT Objectives: Patients with microscopic colitis (MC) have several risk factors for osteoporosis. The prevalence of osteopenia and osteoporosis in MC is unknown. The primary purpose of this study was to evaluate bone mineral status in MC. Methods: Patients with MC and disease activity within the last 2 years were included. Bone turnover markers were analyzed and bone mineral density (BMD) was measured with Dual Energy X-ray Absorptiometry (DXA) at inclusion and after one year. Medical history, demographics, risk factors for osteoporosis, disease activity and treatment with cumulative budesonide dosage at least 3 years before inclusion was registered. Adrenal function was tested by adrenocortico-tropic hormone (ACTH) and an ACTH stimulation test at inclusion. Results were compared with age and sex-matched controls. Results: Fifty MC patients (44 women) were included. Median age 67 (range 45–93); median disease duration 28 month (range 2–163); median cumulative budesonide dosage 702 mg (range 0–5400). No difference in number of patients with osteoporosis or osteopenia and BMD was detected between groups. The bone mineral formation marker specific alkaline phosphatase was lower in MC than controls 12 (5–69) µg/l versus 16 (10–35) µg/l (p < 0.005). Patients more often smoked (34% versus 10%, p = 0.001). Disease duration and cumulative budesonide dose was associated with lower BMD and T-score in hip (Spearman’s rho; p < 0.05) with a cut of point of 2500 mg budesonide predicting osteopenia. Budesonide treatment did not affect adrenal gland function. Conclusion: The risk of osteoporosis in patients with MC is not increased. However, DXA scan is recommended in MC patients with known risk factors or active disease requiring longstanding budesonide treatment. Supplementation of calcium and vitamin-D in patients treated with budesonide is recommended.