Ulcerative Colitis: Lochs H

Lochs H, Dejong C, Hammarqvist F, Hebuterne X, Leon-Sanz M, Schütz T, van Gemert W, van Gossum A, Valentini L, Anonymous00249, Lübke H, Bischoff S, Engelmann N, Thul P, Anonymous00250. · Department of Gastroenterology, Charité-Universitätsmedizin, CCM, Berlin, Germany. · Clin Nutr. · Pubmed #16698129 No free full text.

Abstract: Undernutrition as well as specific nutrient deficiencies have been described in patients with Crohn's disease (CD), ulcerative colitis (UC) and short bowel syndrome (SBS). The present guideline gives evidence-based recommendations for the indication, application and type of formula of enteral nutrition (EN) (oral nutritional supplements (ONS) or tube feeding (TF)) in these patients. It was developed in an interdisciplinary consensus-based process in accordance with officially accepted standards and is based on all relevant publications since 1985. ONS and/or TF in addition to normal food is indicated in undernourished patients with CD or CU to improve nutritional status. In active CD EN is the first line therapy in children and should be used as sole therapy in adults mainly when treatment with corticosteroids is not feasible. No significant differences have been shown in the effects of free amino acid, peptide-based and whole protein formulae for TF. In remission ONS is recommended only in steroid dependent patients in CD. In patients with SBS TF should be introduced in the adaptation phase and should be changed with progressing adaptation to ONS in addition to normal food.

Lochs H, Anonymous00185. · No affiliation provided · Z Gastroenterol. · Pubmed #11215361 No free full text.

This publication has no abstract.

Meier R, Lochs H. · Medizinische Universitätsklinik, Abteilung für Gastroenterologie, Hepatologie und Ernährung, Kantonsspital, Liestal, Switzerland. · Ther Umsch. · Pubmed #17323288 No free full text.

Abstract: Nowadays, the regular consumption of pre- and probiotics is recommended to provide various positive health benefits. The in vitro and in vivo demonstrated actions on the intestinal microflora, the mucosal barrier and the immunological system are very interesting to propose beneficial health effects, but the scientific proof in humans is not demonstrated yet. Pre- and probiotics are very active in the intestinal tract (mainly in the colon) by maintaining a healthy gut microflora and influencing metabolic, trophic and protective mechanism. Prebiotics stimulates the growth of apathogen bacteria and increase the short chain fatty acid concentration by fermentation. Short chain fatty acids are necessary substrates for a healthy gut. Probiotics inhibit the growth of pathogen bacteria, reduce the translocation of bacteria and toxins and modulate the intestinal immune system. For some specific clinical diseases (ulcerative colitis, pouchitis, diarrhoea) a therapeutic and prophylactic effect with pre- and probiotics was shown. In the near future more indications for pre- and probiotics (used as a single strain or as in a combination) will be added. Promising results are already shown in irritable bowel syndrome, prevention of antibiotic induced diarrhoea, in surgical and in intensive care patients. Future studies should focus to determine the characteristics of a healthy gut and the evaluation of specific health benefits by well-designed, controlled human studies of adequate duration.

Stange EF, Riemann J, von Herbay A, Lochs H, Fleig WE, Schölmerich J, Kruis W, Porschen R, Bruch HP, Zeitz M, Schreiber S, Moser G, Matthes H, Selbmann HK, Goebell H, Caspary WF. · Abteilung Innere Medizin 1 Robert-Bosch-Krankenhaus Auerbachstrasse 110 70376 Stuttgart. · Z Gastroenterol. · Pubmed #11215358 No free full text.

This publication has no abstract.

Duchmann R, Lochs H, Kruis W. · Innere Medizin II, Universität des Saarlandes, Homburg/Saar. · MMW Fortschr Med. · Pubmed #10949626 No free full text.

Abstract: Crohn's disease (CD) and ulcerative colitis (UC) are clinical entities characterized by spontaneous relapses and are thought to be caused in large part by a dysregulated immune response to inflammatory stimuli. Specific infectious agents or antigens inducing or perpetuating inflammation, however, are not known. Recent results in contrast support the hypothesis, that the normal intestinal flora plays a central role in the pathogenesis of both diseases. Studies performed with E. coli Nissle 1917 demonstrated that this bacterium can positively affect the course of disease in UC and CD patients. The clinical efficacy of probiotics can yield valuable information about disease pathogenesis and, as a modification of current standard therapy, opens new and interesting therapeutic alternatives.

Tilg H, Vogelsang H, Ludwiczek O, Lochs H, Kaser A, Colombel JF, Ulmer H, Rutgeerts P, Krüger S, Cortot A, D'Haens G, Harrer M, Gasche C, Wrba F, Kuhn I, Reinisch W. · Department of Gastroenterology and Hepatology and Biostatistics, University Hospital Innsbruck, Austria. · Gut. · Pubmed #14633951 links to  free full text

Abstract: BACKGROUND: Pilot studies of interferon alpha (IFN-alpha) suggest a high remission rate in the treatment of active ulcerative colitis. We evaluated the safety of pegylated interferon alpha (PegIFN) and its role in induction of remission in patients with active ulcerative colitis, in a multicentre placebo controlled trial. METHODS: Sixty patients with a clinical activity score (CAI) of >6 were randomised to receive placebo (n=20), PegIFN 0.5 microg/kg (n=19), or PegIFN 1.0 microg/kg body weight (n=21) once weekly (PegIntron; Schering-Plough, USA) over 12 weeks. Patients receiving 5-aminosalicylates, steroids, and/or azathioprine in stable dosages were included. RESULTS: Serious adverse events were seen in none of the placebo patients, in 3/19 patients in the PegIFN 0.5 microg/kg group (hospitalisation due to disease flare up n=3), and in 3/21 in the PegIFN 1.0 microg/kg group (hospitalisation due to disease flare up n=1; thrombosis n=1; grand mal seizure n=1). Otherwise, we observed only minor IFN-alpha side effects. Clinical remission rates at week 12 (CAI < or =4) were 7/20 (35%) in the placebo, 9/19 (47%) in the PegIFN 0.5 microg/kg group, and 7/21 (33%) in the PegIFN 1.0 microg/kg group (NS). Early withdrawal from the study was observed in 11/20 placebo patients, in 6/19 in the PegIFN 0.5 microg/kg group, and in 10/21 in the PegIFN 1.0 microg/kg group, mainly due to lack of efficacy. The higher PegIFN dose was associated with a significant decrease in levels of C reactive protein (p=0.003, day 0 v 85). CONCLUSIONS: PegIFN is safe but not effective, at the dosages used, in patients with ulcerative colitis.

Teml A, Kratzer V, Schneider B, Lochs H, Norman GL, Gangl A, Vogelsang H, Reinisch W. · Universitätsklinik für Innere Medizin IV, Abteilung für Gastroenterologie und Hepatologie, and Institut für Medizinische Statistik, Universtität Wien, Vienna, Austria. · Am J Gastroenterol. · Pubmed #14572572 No free full text.

Abstract: OBJECTIVES: An increased prevalence of elevated serum anti-Saccharomyces cerevisiae antibody (ASCA) levels in patients with Crohn's disease (CD) has been described. The aim of the present work was to investigate serum ASCA levels during the courses of prednisolone and mesalamine therapy in CD patients. METHODS: Serum samples of 25 patients with active CD were studied for ASCA levels before as well as 2 and 9 wk after initiation of a prednisolone tapering regimen. The influence of mesalamine (4 g o.d.) on serum ASCA levels compared to that of placebo was tested over 1 yr in 38 patients (20 mesalamine and 18 placebo) participating in a postoperative prophylaxis study. Serum IgG and IgA ASCA levels were measured by ELISA. Sera of 91 CD and 40 ulcerative colitis (UC) patients as well as 334 healthy donors were tested for ASCA to recalculate new cut-off values. RESULTS: For IgG ASCA cut-off values were determined to be 17.0 U and 25.0 U, and for IgA ASCA 9.3 U and 14.0 U. At baseline visit, 73.0% (46/63) of patients displayed serum ASCA positivity. During prednisolone therapy, a decrease in serum IgG and IgA ASCA levels from baseline to wk 2 (p < 0.0001 and p < 0.001, respectively) as well as to wk 9 (p < 0.001 and p = 0.01, respectively) was observed. A trend toward an association of ASCA positivity and steroid responsiveness was calculated (p = 0.07). During mesalamine treatment, no differences in changes of ASCA levels were observed compared to placebo at any time point. CONCLUSIONS: ASCA are stable markers during steroid and mesalamine treatment, highlighting their reliability for use in diagnosis of CD.

Bauditz J, Wedel S, Lochs H. · Charité University Hospital, 4th Department of Medicine, Berlin, Germany. · Gut. · Pubmed #11788559 links to  free full text

Abstract: BACKGROUND: Thalidomide improves clinical symptoms in patients with therapy refractory Crohn's disease, as shown in two recent studies. The mechanism of this effect however is still unknown. Suppression of tumour necrosis factor alpha (TNF-alpha) by thalidomide has been suggested as a possible mechanism. However, effects on other cytokines have not been adequately investigated. AIM: The aim of our study was to investigate the effects of thalidomide on cytokine production in patients with inflammatory bowel disease (IBD). METHODS: Ten patients with therapy refractory IBD (nine Crohn's disease, one ulcerative colitis) received thalidomide 300 mg daily in a 12 week open label study. Production of TNF-alpha, interleukin (IL)-1 beta, IL-6, and IL-12 was investigated in short term cultures of stimulated colonic lamina propria mononuclear cells (LPMC) and peripheral blood monocytes (PBMC) before and after 12 weeks of treatment. LPMC were also cultured with graded doses of thalidomide. RESULTS: Three patients discontinued treatment because of sedative side effects. In the other patients, disease activity decreased significantly, with four patients achieving remission. Production of TNF-alpha and IL-12 decreased during treatment with thalidomide: LPMC (TNF-alpha: 42.3 (8.3) pg/ml v 16.4 (6.3); IL-12: 9.7 (3.3) v 5.0 (2.5); p<0.04) and PBMC (TNF-alpha: 62.8 (14.6) v 22.5 (9.2); p<0.02). Production of IL-1 beta and IL-6 did not change significantly. Culturing of LPMC with thalidomide showed a dose dependent decrease in TNF-alpha and IL-12 production. CONCLUSION: The clinical effects of thalidomide in Crohn's disease may be mediated by reduction of both TNF-alpha and IL-12.

Gasche C, Dejaco C, Reinisch W, Tillinger W, Waldhoer T, Fueger GF, Lochs H, Gangl A. · University of California, San Diego, La Jolla, Calif., USA. · Digestion. · Pubmed #10343140 No free full text.

Abstract: BACKGROUND: Intravenous iron and erythropoietin have been shown to be effective in Crohn's disease-associated anemia. The aim of this study was to test the sequential treatment of anemia in ulcerative colitis with intravenous iron in the first phase and erythropoietin in the second. PATIENTS AND METHODS: Twenty patients with ulcerative colitis-associated anemia (hemoglobin < or = 10.5 g/dl) entered this open-label trial. In the first phase all patients received intravenous iron saccharate for 8 weeks. A response was defined as an increase in hemoglobin > or = 2.0 g/dl; a final hemoglobin >10.5 g/dl was regarded as full response, < or = 10.5 g/dl as partial response. A hemoglobin increase < 2.0 g/dl was regarded as nonresponse. In the second phase (n = 4) erythropoietin was initiated in patients without response. Patients with partial response were continued on iron saccharate for another 8 weeks. RESULTS: During the first phase the hemoglobin increased from 8.3 to 11.9 g/dl (mean hemoglobin difference 3.6+/-2.3 g/dl, p < 0.001). Fifteen patients (75%) showed a full response (mean hemoglobin difference 4.5+/-1.5 g/dl), 1 (5%) a partial response (hemoglobin difference 2.1 g/dl) and 4 no response (mean hemoglobin difference 0.4+/-1.8 g/dl) with a need for blood transfusions in a single patient. In the second study phase erythropoietin was highly effective in previous nonresponders (mean hemoglobin difference 3.3+/-1.9 g/dl). The single patient with partial response had a minor hemoglobin increase (hemoglobin difference 1.0 g/dl). CONCLUSION: Most patients with ulcerative colitis-associated anemia improve on intravenous iron alone. Erythropoietin is effective in those who do not respond.

Valentini L, Wirth EK, Schweizer U, Hengstermann S, Schaper L, Koernicke T, Dietz E, Norman K, Buning C, Winklhofer-Roob BM, Lochs H, Ockenga J. · Department of Gastroenterology, Hepatology and Endocrinology, Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany. · Nutrition. · Pubmed #18849144 No free full text.

Abstract: OBJECTIVE: Adipokines are fat-derived hormones and cytokines with immune-modulating and metabolic properties. Most of them are associated with insulin resistance. The aim of the present investigation was to evaluate circulating levels of adipokines and glucose homeostasis in patients with inflammatory bowel disease (IBD) and to evaluate possible associations with the course and characteristics of the disease. METHODS: Serum leptin, resistin, visfatin, retinol-binding protein-4, adiponectin, glucose, insulin, and inflammatory parameters were analyzed in 93 patients with inactive IBD (49 with Crohn's disease [CD], 44 with ulcerative colitis [UC]), 35 patients with active IBD (18 with CD, 17 with UC), and 37 age- and body mass index-matched healthy controls. Ninety-two patients were followed for 6 mo. RESULTS: Leptin was similar in patients with IBD and controls, whereas resistin and visfatin were increased in patients with active disease but not in those in remission. In active and inactive disease, adiponectin was decreased (P < 0.001) and retinol-binding protein-4 was increased (P < 0.001) compared with controls. About 60% of patients with IBD showed increased levels of insulin, whereas serum glucose remained normal, resulting in increased homeostasis model assessment values in most patients. Hyperinsulinemia was associated with the decrease in adiponectin (r = -0.572, P < 0.001) and proved to be an independent protective factor for 6-mo maintenance of remission (P = 0.016). CONCLUSION: IBD led to largely similar alterations in circulating adipokines and hyperinsulinemia in patients with CD and those with UC. The unexpected protective effect of hyperinsulinemia on relapse rate denotes the role of the metabolic-inflammatory response as a modulator in IBD.

Valentini L, Schaper L, Buning C, Hengstermann S, Koernicke T, Tillinger W, Guglielmi FW, Norman K, Buhner S, Ockenga J, Pirlich M, Lochs H. · Department of Gastroenterology, Hepatology and Endocrinology, CCM, Charité-Universitätsmedizin Berlin, Berlin, Germany. · Nutrition. · Pubmed #18499398 No free full text.

Abstract: OBJECTIVE: This prospective, controlled, and multicentric study evaluated nutritional status, body composition, muscle strength, and quality of life in patients with inflammatory bowel disease in clinical remission. In addition, possible effects of gender, malnutrition, inflammation, and previous prednisolone therapy were investigated. METHODS: Nutritional status (subjective global assessment [SGA], body mass index, albumin, trace elements), body composition (bioelectrical impedance analysis, anthropometry), handgrip strength, and quality of life were assessed in 94 patients with Crohn's disease (CD; 61 female and 33 male, Crohn's Disease Activity Index 71 +/- 47), 50 patients with ulcerative colitis (UC; 33 female and 17 male, Ulcerative Colitis Activity Index 3.1 +/- 1.5), and 61 healthy control subjects (41 female and 20 male) from centers in Berlin, Vienna, and Bari. For further analysis of body composition, 47 well-nourished patients with inflammatory bowel disease were pair-matched by body mass index, sex, and age to healthy controls. Data are presented as median (25th-75th percentile). RESULTS: Most patients with inflammatory bowel disease (74%) were well nourished according to the SGA, body mass index, and serum albumin. However, body composition analysis demonstrated a decrease in body cell mass (BCM) in patients with CD (23.1 kg, 20.8-28.7, P = 0.021) and UC (22.6 kg, 21.0-28.0, P = 0.041) compared with controls (25.0 kg, 22.0-32.5). Handgrip strength correlated with BCM (r = 0.703, P = 0.001) and was decreased in patients with CD (32.8 kg, 26.0-41.1, P = 0.005) and UC (31.0 kg, 27.3-37.8, P = 0.001) compared with controls (36.0 kg, 31.0-52.0). The alterations were seen even in patients classified as well nourished. BCM was lower in patients with moderately increased serum C-reactive protein levels compared with patients with normal levels. CONCLUSION: In CD and UC, selected micronutrient deficits and loss of BCM and muscle strength are frequent in remission and cannot be detected by standard malnutrition screening.

Baumgart DC, Buning C, Geerdts L, Schmidt HH, Genschel J, Fiedler T, Gentz E, Molnar T, Nagy F, Lonovics J, Lochs H, Wiedenmann B, Nickel R, Witt H, Dignass A. · Division of Gastroenterology and Hepatology, Department of Medicine, Charité Medical School, Humboldt University of Berlin, Berlin, Germany. · Digestion. · Pubmed #18174680 No free full text.

Abstract: BACKGROUND: Inflammatory bowel disease (IBD) results from an aberrant immune response to the indigenous intestinal flora in genetically susceptible hosts. Therefore, the study of candidate genes involved in host pathogen interactions is of key interest. METHODS: In this two-center, retrospective German and Hungarian cohort study, patients with Crohn's disease (CD) (n = 379; German n = 235, Hungarian n = 144) and ulcerative colitis (UC) (n = 263; German n = 145, Hungarian n = 118) and healthy controls (n = 605; German n = 403, Hungarian n = 202) were genotyped for the presence of the CD14 c.1-260C>T promoter variant and the TLR4 c.896A>G (p.D299G) variant by melting curve analysis using fluorescence resonance energy transfer probes. Data were stratified according to the presence of NOD2 (CARD15) mutations and a detailed genotype-phenotype analysis was performed. RESULTS: In the German cohort the CD14 single-nucleotide polymorphism was associated with UC, but not CD (UC p = 0.016 vs. CD p = 0.190), while the opposite was found in the Hungarian cohort (UC p = 0.083 vs. CD p = 0.019). No association of IBD with the TLR4 single-nucleotide polymorphism was found in either cohort (UC p = 0.430, CD p = 0.783 vs. UC p = 0.745, CD p = 0.383). CONCLUSION: IBD appears to be associated with the CD14 c.1-260C>T promoter variant in Germans and Hungarians, but not with the TLR4 c.896A>G (p.D299G) variant.

Büning C, Schmidt HH, Molnár T, Drenth JP, Fiedler T, Gentz E, Todorov T, Baumgart DC, Sturm A, Nagy F, Lonovics J, de Jong DJ, Landt O, Kage A, Nickel R, Büttner J, Lochs H, Witt H. · Department of Gastroenterology, Hepatology & Endocrinology, Charité, Campus Mitte, Universitätsmedizin Berlin, Germany. · Inflamm Bowel Dis. · Pubmed #18092344 links to  free full text

Abstract: BACKGROUND: A recent study reported that the c.30T>A (p.Cys10Ter; rs2043211) variant, in the CARD8 (TUCAN) gene, is associated with Crohn's disease (CD). The aim of this study was to analyze the frequency of p.C10X in 3 independent European (IBD) cohorts from Germany, Hungary, and the Netherlands. METHODS: We included a European IBD cohort of 921 patients and compared the p.C10X genotype frequency to 832 healthy controls. The 3 study populations analyzed were: (1) Germany [CD, n = 317; ulcerative colitis (UC), n = 180], (2) Hungary (CD, n = 149; UC, n = 119), and (3) the Netherlands (CD, n = 156). Subtyping analysis was performed in respect to NOD2 variants (p.Arg702Trp, p.Gly908Arg, c.3020insC) and to clinical characteristics. Ethnically matched controls were included (German, n = 413; Hungarian, n = 202; Dutch, n = 217). RESULTS: We observed no significant difference in p.C10X genotype frequency in either patients with CD or patients with UC compared with controls in all 3 cohorts. Conversely to the initial association study, we found a trend toward lower frequencies of the suggestive risk wild type in CD from the Netherlands compared with controls (P = 0.14). We found neither evidence for genetic interactions between p.C10X and NOD2 nor the C10X variant to be associated with a CD or UC phenotype. CONCLUSIONS: Analyzing 3 independent European IBD cohorts, we found no evidence that the C10X variant in CARD8 confers susceptibility for CD.

Büning C, Schmidt HH, Molnar T, De Jong DJ, Fiedler T, Bühner S, Sturm A, Baumgart DC, Nagy F, Lonovics J, Drenth JP, Landt O, Nickel R, Büttner J, Lochs H, Witt H. · Department of Gastroenterology, Hepatology and Endocrinology, Charité, Campus Mitte, Universitätsmedizin Berlin, Berlin, Germany. · Aliment Pharmacol Ther. · Pubmed #17877509 No free full text.

Abstract: BACKGROUND: A recent study reported that a non-synonymous single nucleotide polymorphism (rs11209026, p.Arg381Gln) located in the IL23R gene is a protective marker for inflammatory bowel disease. AIM: To analyse the frequency of p.Arg381Gln in three independent European inflammatory bowel disease cohorts and to evaluate how this variant influences disease behaviour. METHODS: We assessed a European cohort of 919 inflammatory bowel disease patients and compared the IL23R p.Arg381Gln genotype frequency with 845 healthy controls. Inflammatory bowel disease patients originated from Germany [Crohn's disease (CD): n = 318; ulcerative colitis (UC): n = 178], Hungary (CD: n = 148; UC: n = 118) and the Netherlands (CD: n = 157). Ethnically matched controls were included. We performed subtyping analysis in respect to CARD15 alterations and clinical characteristics. RESULTS: The frequency of the glutamine allele of p.Arg381Gln was significantly lower in inflammatory bowel disease patients compared with controls in a pooled analysis of all three cohorts (P < 0.000001) as well as in the individual cohorts (Germany: P = 0.001, Hungary: P = 0.02 and the Netherlands: P = 0.0002). The p.Arg381Gln genotype distribution was similar between CD and UC. We did not observe either statistical interactions between p.Arg381Gln and CARD15 variants or any significant associations between p.Arg381Gln genotype and subphenotypes. CONCLUSIONS: The p.Arg381Gln IL23R variant confers a protective effect against both CD and UC, but does not determine disease phenotype.

Fiedler T, Büning C, Reuter W, Pitre G, Gentz E, Schmidt HH, Büttner J, Ockenga J, Gerloff T, Meisel C, Lochs H, Roots I, Köpke K, Johne A. · Department of Gastroenterology, Hepatology & Endocrinology, Charité - Universitätsmedizin Berlin, CCM, Charitéplatz 1, Berlin, 10117, Germany. · Eur J Clin Pharmacol. · Pubmed #17665184 No free full text.

Abstract: BACKGROUND: The role of the single nucleotide polymorphisms (SNPs) on positions 2677G>T/A and 3435C>T of the multi-drug-resistance gene 1 (MDR1) in inflammatory bowel disease (IBD) remains unclear. AIMS: To further elucidate the potential impact of MDR1 two-locus genotypes on susceptibility to IBD and disease behaviour. PATIENTS AND METHODS: Three hundred eighty-eight German IBD patients [244 with Crohn's disease (CD), 144 with ulcerative colitis (UC)] and 1,005 German healthy controls were genotyped for the two MDR1 SNPs on positions 2677G>T/A and 3435C>T. Genotype-phenotype analysis was performed with respect to disease susceptibility stratified by age at diagnosis as well as disease localisation and behaviour. RESULTS: Genotype distribution did not differ between all UC or CD patients and controls. Between UC and CD patients, however, we observed a trend of different distribution of the combined genotypes derived from SNPs 2677 and 3435 (chi(2) = 15.997, df = 8, p = 0.054). In subgroup analysis, genotype frequencies between UC patients with early onset of disease and controls showed significant difference for combined positions 2677 and 3435 (chi(2) = 16.054, df = 8, p = 0.034 for age at diagnosis >or=25, lower quartile). Herein the rare genotype 2677GG/3435TT was more frequently observed (odds ratio = 7.0, 95% confidence interval 2.5 - 19.7). In this group severe course of disease behaviour depended on the combined MDR1 SNPs (chi(2) = 16.101, df = 6, p = 0.017 for age at diagnosis >or=25). No association of MDR1 genotypes with disease subgroups in CD was observed. CONCLUSIONS: While overall genotype distribution did not differ, combined MDR1 genotypes derived from positions 2677 and 3435 are possibly associated with young age onset of UC and severe course of disease in this patient group.

Swidsinski A, Loening-Baucke V, Bengmark S, Lochs H, Dörffel Y. · Humboldt University, Charité Hospital, CCM, Laboratory for Molecular Genetics, Polymicrobial Infections and Bacterial Biofilms, 10098 Berlin, Germany. · Inflamm Bowel Dis. · Pubmed #17206639 links to  free full text

Abstract: BACKGROUND: The impact of azathioprine and 5-aminosalicylic acid (5-ASA) on the innate immunity and mucosal flora is unknown. The study investigated the influence of IBD treatment on the concentrations and spatial organization of mucosal bacteria using fluorescence in situ hybridization with 16s r-RNA targeting probes. METHODS: We prospectively investigated colonoscopic biopsies from five groups of 20 subjects each: patients with ulcerative or indeterminate colitis treated with azathioprine (group 1), azathioprine and 5-ASA (group 2), 5-ASA (group 3), untreated IBD (group 4), and healthy controls. RESULTS: The elevated numbers of leukocytes in mucus of IBD patients were reduced nearly to norm in patients treated with azathioprine alone. In contrast, 5-ASA therapy had no influence on mucus leukocyte migration and was associated with the lowest concentrations of mucosal bacteria of all IBD groups. The suppressed migration of leukocytes in azathioprine-treated patients was accompanied by a 28-fold higher concentration of mucosal bacteria when compared with the 5-ASA group or a 1000-fold increase when compared with healthy controls. The percent of the epithelial surface covered with adherent bacteria (P < 0.001) and the amenability of mucosal bacteria (P = 0.01) were also significantly increased in the azathioprine-treated group compared with all other IBD groups. The patients receiving both 5-ASA and azathioprine did not differ statistically from untreated IBD patients either in mucus leukocyte migration or in bacterial concentrations. CONCLUSIONS: Azathioprine and 5-ASA induce opposite effects on the mucus barrier. Concomitant therapy of 5-ASA and azathioprine mutually neutralizes the effects of both on the mucosal flora and the barrier function.

Swidsinski A, Loening-Baucke V, Theissig F, Engelhardt H, Bengmark S, Koch S, Lochs H, Dörffel Y. · Humboldt University, Charité, CCM, 10098 Berlin, Germany. · Gut. · Pubmed #16908512 No free full text.

Abstract: AIM: To study the role of mucus in the spatial separation of intestinal bacteria from mucosa. PATIENTS AND METHODS: Mucus barrier characteristics were evaluated using histological material obtained by biopsy from purged colon, colon prepared with enema and material from untreated appendices fixed with non-aqueous Carnoy solution. Bacteria were evaluated using fluorescence in situ hybridization, with bacterial 16S RNA probes and related to the periodic acid Schiff alcian blue stain. Biopsies from controls (n = 20), patients with self-limiting colitis (SLC; n = 20), ulcerative colitis (n = 20) and 60 randomly selected appendices were investigated. RESULTS: The mucosal surface beneath the mucus layer was free of bacteria in > or =80% of the normal appendices and biopsies from controls. The thickness of the mucus layer and its spread decreased with increasing severity of the inflammation; the epithelial surface showed bacterial adherence, epithelial tissue defects and deep mucosal infiltration with bacteria and leucocytes. Bacteria and leucocytes were found within mucus in all biopsy specimens from patients with ulcerative colitis, SLC, and acute appendicitis. The concentration of bacteria within mucus was inversely correlated to the numbers of leucocytes. CONCLUSIONS: The large bowel mucus layer effectively prevents contact between the highly concentrated luminal bacteria and the epithelial cells in all parts of the normal colon. Colonic inflammation is always accompanied by breaks in the mucus barrier. Although the inflammatory response gradually reduces the number of bacteria in mucus and faeces, the inflammation itself is not capable of preventing bacterial migration, adherence to and invasion of the mucosa.

Norman K, Kirchner H, Lochs H, Pirlich M. · Klinik mit Schwerpunkt Gastroenterologie, Hepatologie und Endokrinologie, Charité-Universitätsmedizin Berlin Campus Mitte, Germany. · World J Gastroenterol. · Pubmed #16733855 links to  free full text

Abstract: AIM: To investigate the association between malnutrition and quality of life in patients with benign gastrointestinal disease. METHODS: Two hundred patients (104 wellnourished and 96 malnourished) were assessed according to the Subjective Global Assessment, anthropometric measurements and bioelectrical impedance analysis. Quality of life was determined with the validated Medical Outcomes Study 36-item Short-Form General Health Survey (SF 36). Muscle function was assessed by hand grip strength and peak flow. RESULTS: Body mass index, body cell mass, arm muscle area and hand grip strength were significantly lower in the malnourished patients. Quality of life was generally lower when compared to norm values. Seven out of eight quality of life scales (excluding bodily pain) were significantly reduced in the malnourished patients. Comparing patients with liver cirrhosis and inflammatory bowel disease (IBD), patients with IBD experienced significantly lower values in the perception of bodily pain,social functioning and mental health. Malnourished liver cirrhotics suffered reductions in more scales (six out of eight) than malnourished IBD patients did (four out of eight). CONCLUSION: Quality of life is generally low in benign gastrointestinal disease and is further reduced in patients who are classified as malnourished. It appears that liver cirrhosis patients experience a higher quality of life than IBD patients do, but the impact of malnutrition seems to be greater in liver cirrhosis than in IBD.

Büning C, Geerdts L, Fiedler T, Gentz E, Pitre G, Reuter W, Luck W, Buhner S, Molnar T, Nagy F, Lonovics J, Dignass A, Landt O, Nickel R, Genschel J, Lochs H, Schmidt HH, Witt H. · Department of Gastroenterology, Hepatology & Endocrinology, Charité, Campus Mitte, Universitätsmedizin Berlin, Berlin, Germany. · Am J Gastroenterol. · Pubmed #16494592 No free full text.

Abstract: OBJECTIVES: Genetic variants within DLG5 were recently reported to be associated with inflammatory bowel disease (IBD). The aim of our study was to test for allelic and haplotype associations of six DLG5 variants in 668 IBD patients from two European populations. Furthermore, we evaluated whether DLG5 variants alter gastrointestinal permeability in Crohn's disease (CD). METHODS: Six DLG5 variants (p.R30Q, p.P1371Q, p.G1066G, rs2289308, DLG_e26, p.D1507D) were genotyped in two study populations: (1) German IBD patients (CD n = 250; ulcerative colitis (UC) n = 150) and German healthy controls (n = 422); (2) Hungarian IBD patients (CD n = 144; UC n = 124) and Hungarian healthy controls (n = 205). Subtyping analysis was performed in respect of CARD15 mutations and clinical characteristics. We also tested for differences within DLG5 genotypes in German CD patients with respect to gastroduodenal and intestinal permeability measured by triple-sugar-test. RESULTS: Allele as well as genotype frequencies of DLG5 variants did not differ between IBD patients and controls in either study population. Indeed, the p.R30Q polymorphism was found more frequently in controls than in patients. The distribution of DLG5 genotypes in German and Hungarian CD patients with CARD15 mutations was not different from patients without mutated CARD15. We did also not observe any association between DLG5 variants and clinical parameters. Importantly, DLG5 variants were not associated with gastroduodenal or intestinal permeability. CONCLUSIONS: We could not replicate that DLG5 is a relevant disease susceptibility gene for IBD in German or Hungarian subjects. In addition, we have no evidence that DLG5 variants are involved in altered gastrointestinal permeability in CD.

Ockenga J, Borchert K, Stüber E, Lochs H, Manns MP, Bischoff SC. · Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Germany. · Eur J Clin Nutr. · Pubmed #16077744 No free full text.

Abstract: BACKGROUND: Studies in animal models of inflammatory bowel disease (IBD) suggest that supplementation of total parenteral nutrition with glutamine (gln), a conditionally essential amino acid in catabolic conditions, increases gln plasma concentrations, reduces intestinal damage, improves nitrogen balance and may improve the course of the disease. However, human data supporting this assumption are missing. METHODS: A total of 24 consecutive patients with an acute exacerbation of IBD (19 Crohn's disease; five ulcerative colitis) and scheduled for total parenteral nutrition (TPN) (>7 days) were randomised. Parallel to a standardised anti-inflammatory therapy, the patients received either a TPN with 1.5 g/kg body weight of a standard amino acid or an isonitrogenic, isocaloric TPN with 1.2 g/kg body weight of a standard amino acid and 0.3 g/kg L-alanine-L-glutamine. Primary end points were gln plasma concentrations and intestinal permeability assessed by urinary lactulose and D-xylose ratio. RESULTS: Gln plasma levels did not differ significantly in either group throughout the study. Intestinal permeability did not change within 7 days either with or without gln supplementation (Delta-lactulose/xylose ratio: 0.01+/-0.05 (gln+) vs 0.02+/-0.1 (gln-)). The observed changes in inflammatory and nutritional parameters, and also disease activity, length of TPN and hospital stay, were independent of glutamine substitution. Five (41%) patients in the gln+ group and three (25%) patients in the gln- group needed surgical intervention. CONCLUSION: Although limited by the sample size, these results do not support the hypothesis that glutamine substitution has an obvious biochemical or clinical benefit in patients with active IBD scheduled for total parenteral nutrition.

Swidsinski A, Weber J, Loening-Baucke V, Hale LP, Lochs H. · Innere Klinik, Gastroenterologie, Charité Humboldt Universität, 10098 Berlin, Germany. · J Clin Microbiol. · Pubmed #16000463 links to  free full text

Abstract: The composition and spatial organization of the mucosal flora in biopsy specimens from patients with inflammatory bowel disease (IBD; either Crohn's disease or ulcerative colitis), self-limiting colitis, irritable-bowel syndrome (IBS), and healthy controls were investigated by using a broad range of fluorescent bacterial group-specific rRNA-targeted oligonucleotide probes. Each group included 20 subjects. Ten patients who had IBD and who were being treated with antibiotics were also studied. Use of nonaqueous Carnoy fixative to preserve the mucus layer was crucial for detection of bacteria adherent to the mucosal surface (mucosal bacteria). No biofilm was detectable in formalin-fixed biopsy specimens. Mucosal bacteria were found at concentrations greater than 10(9)/ml in 90 to 95% of IBD patients, 95% of patients with self-limiting colitis, 65% of IBS patients, and 35% of healthy controls. The mean density of the mucosal biofilm was 2 powers higher in IBD patients than in patients with IBS or controls, and bacteria were mostly adherent. Bacteroides fragilis was responsible for >60% of the biofilm mass in patients with IBD but for only 30% of the biofilm mass in patients with self-limiting colitis and <15% of the biofilm mass in patients with IBS. In contrast, bacteria which positively hybridized with the probe specific for Eubacterium rectale-Clostridium coccoides accounted for >40% of the biofilm in IBS patients but for <15% of the biofilm in IBD patients. In patients treated with (5-ASA) or antibiotics, the biofilm could be detected with 4,6-diamidino-2-phenylindole but did not hybridize with fluorescence in situ hybridization probes. A Bacteroides fragilis biofilm is the main feature of IBD. This was not previously recognized due to a lack of appropriate tissue fixation. Both 5-ASA and antibiotics suppress but do not eliminate the adherent biofilm.

Büning C, Molnar T, Nagy F, Lonovics J, Weltrich R, Bochow B, Genschel J, Schmidt H, Lochs H. · Department of Gastroenterology, Hepatology and Endocrinology, Charité Campus Mitte, Berlin, Germany. · World J Gastroenterol. · Pubmed #15637755 links to  free full text

Abstract: AIM: To analyse the impact of NOD2/CARD15 mutations on the clinical course of Crohn's disease patients from an eastern European country (Hungary). METHODS: We investigated the prevalence of the three common NOD2/CARD15 mutations (Arg702Trp, Gly908Arg, 1007finsC) in 148 patients with Crohn's disease, 128 patients with ulcerative colitis and 208 controls recruited from the University of Szeged, Hungary. In patients with Crohn's disease, the prevalence of NOD2/CARD15 mutations was correlated to the demographical and clinical parameters. RESULTS: In total, 32.4% of Crohn's disease patients carried at least one mutant allele within NOD2/CARD15 compared to 13.2% of patients with ulcerative colitis (P = 0.0002) and to 11.5% of controls (P<0.0001). In Crohn's disease patients, the allele frequencies for Arg702Trp, Gly908Arg and 1007finsC were 7.1%, 3.0% and 10.8% respectively. Interestingly, only the 1007finsC mutation was associated with a distinct clinical phenotype. The patients positive for the 1007finsC mutation suffered more frequently from stenotic disease behaviour (P = 0.008). Furthermore, 51.9% of patients positive for the 1007finsC mutation underwent a surgical resection within the ileum compared to only 17.4% of patients without the 1007finsC mutation (P = 0.001). With respect to the other two mutations (Arg702Trp and Gly908Arg), no associations were found with all investigated clinical parameters. CONCLUSION: NOD2/CARD15 mutations are frequently found in Crohn's disease patients from Hungary. The 1007finsC mutation is associated with stenotic disease behaviour and frequent ileal resections.

Büning C, Halangk J, Dignass A, Ockenga J, Deindl P, Nickel R, Genschel J, Landt O, Lochs H, Schmidt H, Witt H. · Department of Gastroenterology, Hepatology and Endocrinology, Universitätsmedizin Berlin, Charité, Campus Mitte, Schumannstrasse 20/21, D-10117 Berlin, Germany. · Dig Liver Dis. · Pubmed #15248378 No free full text.

Abstract: BACKGROUND: Keratin 8 is a major component of intermediate filaments in single-layered epithelia of the gastrointestinal tract. Keratin 8 deficient mice display signs of colitis and diarrhoea characteristic for inflammatory bowel disease. Very recently, two keratin 8 mutations, Y54H and G62C, were identified. AIMS: We investigated if these keratin 8 missense mutations were associated with inflammatory bowel disease. PATIENTS: In total, 217 German patients with Crohn' s disease, 131 German patients with ulcerative colitis, and 560 German control subjects were enrolled in this study. METHODS: Samples were analysed by PCR amplification and subsequent melting curve analysis using fluorescence resonance energy transfer probes. RESULTS: The G62C mutation was detected in five (2.3%) patients presenting with Crohn's disease and in three (2.3%) with ulcerative colitis. In comparison, 9 (1.6%) out of 560 controls were heterozygous for this mutation. No patient or control was homozygous for this mutation. Patients carrying one mutant allele did not show any noticeable characteristics in their corresponding phenotype. In contrast, the Y54H mutation was observed in neither any of the 348 patients with inflammatory bowel disease nor in any control subject. CONCLUSIONS: Our data indicate that both keratin 8 mutations, G62C and Y54H, do not play a relevant pathogenic role in inflammatory bowel disease.

Büning C, Genschel J, Bühner S, Krüger S, Kling K, Dignass A, Baier P, Bochow B, Ockenga J, Schmidt HH, Lochs H. · Department of Gastroenterology, Hepatology & Endocrinology, Charité, Campus Mitte, Humboldt University, Schumannstrasse 20/21, 10117 Berlin, Germany. · Aliment Pharmacol Ther. · Pubmed #15142196 links to  free full text

Abstract: BACKGROUND: Mutations within the NOD2/CARD15 gene have recently been shown to be associated with Crohn's disease. AIMS: To investigate the clinical impact of the three common NOD2/CARD15 mutations in patients with Crohn's disease. METHODS: We investigated the prevalence of the three common NOD2/CARD15 mutations (Arg702Trp, Gly908Arg, 3020insC) in 180 patients with Crohn's disease, 70 patients with ulcerative colitis and 97 controls. In patients with Crohn's disease, prevalence of NOD2/CARD15 mutations were correlated to clinical and demographical parameters. RESULTS: In Crohn's disease patients, 35.6% carried at least one mutant allele of NOD2/CARD15 mutations compared with 14.3% of patients with ulcerative colitis (P = 0.006) and to 15.5% of controls (P = 0.0001). Genotype phenotype analyses revealed that NOD2/CARD15 mutations determined younger age at disease diagnosis (P = 0.03), ileal disease location (P = 0.01) and ileocecal resections (P = 0.0002). Interestingly, reoperation with resection of the anastomosis was significantly more frequent in patients with NOD2/CARD15 mutations (P = 0.01). CONCLUSIONS: Our investigations support the current hypothesis that NOD2/CARD15 mutations are associated with a phenotype of Crohn's disease with younger age at diagnosis, ileal involvement, ileocecal resections and a high risk of postoperative relapse and reoperation. NOD2/CARD15 mutations might therefore be used to identify high risk patients for relapse prevention strategies.

Büning C, Genschel J, Weltrich R, Lochs H, Schmidt H. · Humboldt University, Berlin, Germany. · Eur J Immunogenet. · Pubmed #14641539 No free full text.

Abstract: Genetic predisposition has been suggested to play an important role in the pathogenesis of inflammatory bowel diseases (IBDs). Linkage studies have identified a Crohn's disease susceptibility locus on chromosome 14 (14q11-12; IBD4). Interleukin-25 (IL-25) is a newly identified proinflammatory cytokine that has been shown to promote Th2 responses by inducing cytokines such as IL-4, IL-5 and IL-13. The IL-25 gene is located within this susceptibility region at 14q11.2. As IBDs are characterized by an imbalance of the Th1/Th2 cytokine response, we hypothesized that genetic alterations within the IL-25 gene might contribute to IBD. First, direct sequencing of the coding regions of the IL-25 gene in 40 patients with Crohn's disease or ulcerative colitis revealed only a newly reported polymorphism (c424C/A) in exon 2. Next, the frequency of this polymorphism was further investigated in 151 patients with Crohn's disease, 111 patients with ulcerative colitis, and 119 healthy controls to determine its clinical relevance. The genotypes of the c424C/A polymorphism did not reveal any significant differences between patients with Crohn's disease or ulcerative colitis and controls. Genoytype-phenotype relations in patients with Crohn's disease showed a comparable distribution of the c424C/A polymorphism in all subgroups of the Vienna classification. In summary, our data indicate that genetic alterations in the coding regions of the IL-25 gene are unlikely to play a role in IBDs, but the c424C/A polymorphism in the IL-25 gene should be investigated for a potential association with other chronic inflammatory and inherited disorders such as autoimmune diseases.