Luc Biedermann

Smoking cessation induces profound changes in the composition of the intestinal microbiota in humans.

Background The human intestinal microbiota is a crucial factor in the pathogenesis of various diseases, such as metabolic syndrome or inflammatory bowel disease (IBD). Yet, knowledge about the role of environmental factors such as smoking (which is known to influence theses aforementioned disease states) on the complex microbial composition is sparse. We aimed to investigate the role of smoking cessation on intestinal microbial composition in 10 healthy smoking subjects undergoing controlled smoking cessation. Methods During the observational period of 9 weeks repetitive stool samples were collected. Based on abundance of 16S rRNA genes bacterial composition was analysed and compared to 10 control subjects (5 continuing smokers and 5 non-smokers) by means of Terminal Restriction Fragment Length Polymorphism analysis and high-throughput sequencing. Results Profound shifts in the microbial composition after smoking cessation were observed with an increase of Firmicutes and Actinobacteria and a lower proportion of Bacteroidetes and Proteobacteria on the phylum level. In addition, after smoking cessation there was an increase in microbial diversity. Conclusions These results indicate that smoking is an environmental factor modulating the composition of human gut microbiota. The observed changes after smoking cessation revealed to be similar to the previously reported differences in obese compared to lean humans and mice respectively, suggesting a potential pathogenetic link between weight gain and smoking cessation. In addition they give rise to a potential association of smoking status and the course of IBD.

Smoking cessation alters intestinal microbiota: insights from quantitative investigations on human fecal samples using FISH.

Background:There has been a dramatic increase in investigations on the potential mechanistic role of the intestinal microbiota in various diseases and factors modulating intestinal microbial composition. We recently reported on intestinal microbial shifts after smoking cessation in humans. In this study, we aimed to conduct further microbial analyses and verify our previous results obtained by pyrosequencing using a direct quantitative microbial approach. Methods:Stool samples of healthy smoking human subjects undergoing controlled smoking cessation during a 9-week observational period were analyzed and compared with 2 control groups, ongoing smoking and nonsmoking subjects. Fluorescence in situ hybridization was applied to quantify specific bacterial groups. Results:Intestinal microbiota composition was substantially altered after smoking cessation as characterized by an increase in key representatives from the phyla of Firmicutes (Clostridium coccoides, Eubacterium rectale, and Clostridium leptum subgroup) and Actinobacteria (HGC bacteria and Bifidobacteria) as well as a decrease in Bacteroidetes (Prevotella spp. and Bacteroides spp.) and Proteobacteria (&bgr;- and &ggr;-subgroup of Proteobacteria). Conclusions:As determined by fluorescence in situ hybridization, an independent direct quantitative microbial approach, we could confirm that intestinal microbiota composition in humans is influenced by smoking. The characteristics of observed microbial shifts suggest a potential mechanistic association to alterations in body weight subsequent to smoking cessation. More importantly, regarding previously described microbial hallmarks of dysbiosis in inflammatory bowel diseases, a variety of observed microbial alterations after smoking cessation deserve further consideration in view of the divergent effect of smoking on the clinical course of Crohns disease and ulcerative colitis.

The intestinal microbiota: its role in health and disease.

AbstractThe intestinal microbiota (previously referred to as “intestinal flora”) has entered the focus of research interest not only in microbiology but also in medicine. Huge progress has been made with respect to the analysis of composition and functions of the human microbiota. An “imbalance” of the microbiota, frequently also called a “dysbiosis,” has been associated with different diseases in recent years. Crohn’s disease and ulcerative colitis as two major forms of inflammatory bowel disease, irritable bowel syndrome (IBS) and some infectious intestinal diseases such as Clostridium difficile colitis feature a dysbiosis of the intestinal flora. Whereas this is somehow expected or less surprising, an imbalance of the microbiota or an enrichment of specific bacterial strains in the flora has been associated with an increasing number of other diseases such as diabetes, metabolic syndrome, non-alcoholic fatty liver disease or steatohepatitis and even psychiatric disorders such as depression or multiple sclerosis. It is important to understand the different aspects of potential contributions of the microbiota to pathophysiology of the mentioned diseases. Conclusion: With the present manuscript, we aim to summarize the current knowledge and provide an overview of the different concepts on how bacteria contribute to health and disease in animal models and—more importantly—humans. In addition, it has to be borne in mind that we are only at the very beginning to understand the complex mechanisms of host-microbial interactions.

Bilberry ingestion improves disease activity in mild to moderate ulcerative colitis — An open pilot study

BACKGROUND AND AIMS A significant fraction of patients with ulcerative colitis (UC) is not sufficiently controlled with conventional therapy or suffers from therapy related side effects. Anthocyanins, highly abundant in bilberries (Vaccinium myrtillus), were shown to have antioxidative and anti-inflammatory effects. We aimed to explore the therapeutic potential of bilberries in active UC. METHODS In an open pilot trial with a total follow-up of 9 weeks the effect of a daily standardized anthocyanin-rich bilberry preparation was tested in 13 patients with mild to moderate UC. Clinical, biochemical, endoscopic and histologic parameters were assessed. RESULTS At the end of the 6 week treatment interval 63.4% of patients achieved remission, the primary endpoint, while 90.9% of patients showed a response. In all patients a decrease in total Mayo score was detected (mean: 6.5 and 3.6 at screening and week 7, respectively; p<0.001). Fecal calprotectin levels significantly decreased during the treatment phase (baseline: mean 778 μg/g, range 192-1790 μg/g; end of treatment: mean 305 μg/g, range <30-1586 μg/g; p=0.049), including 4 patients achieving undetectable levels at end of treatment. A decrease in endoscopic Mayo score and histologic Riley index confirmed the beneficial effect. However, an increase of calprotectin levels and disease activity was observed after cessation of bilberry intake. No serious adverse events were observed. CONCLUSIONS This is the first report on the promising therapeutic potential of a standardized anthocyanin-rich bilberry preparation in UC in humans. These results clearly indicate a therapeutic potential of bilberries in UC. Further studies on mechanisms and randomized clinical trials are warranted.

Fc Gamma Receptor CD64 Modulates the Inhibitory Activity of Infliximab

Background Tumor necrosis factor (TNF) is an important cytokine in the pathogenesis of inflammatory bowel disease (IBD). Anti-TNF antibodies have been successfully implemented in IBD therapy, however their efficacies differ among IBD patients. Here we investigate the influence of CD64 Fc receptor on the inhibitory activity of anti-TNFs in cells of intestinal wall. Methods Intestinal cell lines, monocytes/macrophages and peripheral blood mononuclear cells (PBMCs) were used as models. The efficacies of adalimumab, infliximab and certolizumab-pegol were assessed by RT-PCR for target genes. Protein levels and localizations were examined by Western blotting and immunofluorescence. Antibody fragments were obtained by proteolytic digestion, immunoprecipitation and protein chip analysis. Knock-down of specific gene expression was performed using siRNAs. Results Infliximab had limited efficacy towards soluble TNF in cell types expressing Fc gamma receptor CD64. Both adalimumab and infliximab had lower efficacies in PBMCs of IBD patients, which express elevated levels of CD64. Infliximab-TNF complexes were more potent in activating CD64 in THP-1 cells than adalimumab, which was accompanied by distinct phospho-tyrosine signals. Blocking Fc parts and isolation of Fab fragments of infliximab improved its efficacy. IFN-γ-induced expression of CD64 correlated with a loss of efficacy of infliximab, whereas reduction of CD64 expression by either siRNA or PMA treatment improved inhibitory activity of this drug. Colonic mRNA expression levels of CD64 and other Fc gamma receptors were significantly increased in the inflamed tissues of infliximab non-responders. Conclusions CD64 modulates the efficacy of infliximab both in vitro and ex vivo, whereas the presence of this receptor has no impact on the inhibitory activity of certolizumab-pegol, which lacks Fc fragment. These data could be helpful in both predicting and evaluating the outcome of anti-TNF therapy in IBD patients with elevated systemic and local levels of Fc receptors.

Periodontitis and gingivitis in inflammatory bowel disease: a case-control study.

Background:The oral cavity is frequently affected in patients with inflammatory bowel disease (IBD), especially in patients with Crohns disease (CD). Periodontitis is thought to influence systemic autoimmune or inflammatory diseases. We aimed to analyze the relationship of periodontitis and gingivitis markers with specific disease characteristics in patients with IBD and to compare these data with healthy controls. Methods:In a prospective 8-month study, systematic oral examinations were performed in 113 patients with IBD, including 69 patients with CD and 44 patients with ulcerative colitis. For all patients, a structured personal history was taken. One hundred thirteen healthy volunteers served as a control group. Oral examination focussed on established oral health markers for periodontitis (bleeding on probing, loss of attachment, and periodontal pocket depth) and gingivitis (papilla bleeding index). Additionally, visible oral lesions were documented. Results:Both gingivitis and periodontitis markers were higher in patients with IBD than in healthy control. In univariate analysis and logistic regression analysis, perianal disease was a risk factor for periodontitis. Nonsmoking decreased the risk of having periodontitis. No clear association was found between clinical activity and periodontitis in IBD. In only the CD subgroup, high clinical activity (Harvey–Bradshaw index > 10) was associated with 1 periodontitis marker, the loss of attachment at sites of maximal periodontal pocket depth. Oral lesions besides periodontitis and gingivitis were not common, but nevertheless observed in about 10% of patients with IBD. Conclusions:IBD, and especially perianal disease in CD, is associated with periodontitis. Optimal therapeutic strategies should probably focus on treating both local oral and systemic inflammation.

Long-Term Treatment of Eosinophilic Esophagitis With Swallowed Topical Corticosteroids: Development and Evaluation of a Therapeutic Concept

Objectives:Swallowed topical corticosteroids (STCs) are efficacious in inducing and presumably maintaining remission in patients with active eosinophilic esophagitis (EoE). Hitherto, it has not been evaluated whether long-lasting remission can be achieved, and whether treatment can be stopped once patients have achieved this remission.Methods:Since 2007, EoE patients included into a large database at the Swiss EoE Clinics were put on STCs as induction/maintenance therapy. Disease activity was assessed on an annual basis. In patients who achieved long-lasting (≥6 months) clinical, endoscopic, and histological (=deep) remission, treatment was stopped. Data on all patients treated using this therapeutic strategy were analyzed retrospectively.Results:Of the 351 patients, 33 (9.4%) who were treated with STCs achieved deep remission. Median age of remitters at disease onset was 32.6 years (interquartile range (IQR) 19.1–49.3), and diagnostic delay was 5.4 years (IQR 1.2–11.4). Deep remission was achieved after 89.0 weeks (IQR 64.6–173.8). Female gender was the only independent prognostic factor for achieving deep remission (odds ratio (OR) 2.518, 95% confidence interval (CI) 1.203–5.269). Overall, STCs were stopped after 104.7 weeks (IQR 65.5–176.6). No mucosal damage was observed upon histological examination. In 27 of the 33 remitters (81.8%), a clinical relapse occurred after a median of 22.4 weeks (95% CI 5.1–39.7). Six remitters (18.2%) did not experience a clinical relapse during a follow-up of 35.1 weeks (IQR 18.3–44.9). Hence, a total of 1.7% (6/351) patients were able to discontinue STCs in the long term.Conclusions:Long-term EoE treatment with STCs was well tolerated, but only a minority achieved deep remission. Female gender is the only prognostic factor for attainment of such remission. After treatment cessation, the majority experienced a clinical relapse.

Use of thiopurines in inflammatory bowel disease

The use of thiopurines as immunosuppression for the treatment of refractory or chronic active inflammatory bowel disease is established for both Crohns disease and ulcerative colitis. Nevertheless, many questions remain concerning the optimal treatment regimens of azathioprine, 6-mercaptopurine and thioguanine. We will briefly summarize dose recommendations, indications for thiopurine therapy and side effects which are relevant in clinical practice. We discuss some currently debated topics, including the combination of azathioprine and allopurinol, switching of thiopurine therapy in case of side effects, the use of azathioprine in pregnancy, the infection risk using thiopurines and the evidence when to stop thiopurines. Excellent reviews have been published on the thiopurine metabolic pathway which will not be discussed here in detail.

Periodontitis and Gingivitis in Inflammatory Bowel Disease

Background:The oral cavity is frequently affected in patients with inflammatory bowel disease (IBD), especially in patients with Crohns disease (CD). Periodontitis is thought to influence systemic autoimmune or inflammatory diseases. We aimed to analyze the relationship of periodontitis and gingivitis markers with specific disease characteristics in patients with IBD and to compare these data with healthy controls. Methods:In a prospective 8-month study, systematic oral examinations were performed in 113 patients with IBD, including 69 patients with CD and 44 patients with ulcerative colitis. For all patients, a structured personal history was taken. One hundred thirteen healthy volunteers served as a control group. Oral examination focussed on established oral health markers for periodontitis (bleeding on probing, loss of attachment, and periodontal pocket depth) and gingivitis (papilla bleeding index). Additionally, visible oral lesions were documented. Results:Both gingivitis and periodontitis markers were higher in patients with IBD than in healthy control. In univariate analysis and logistic regression analysis, perianal disease was a risk factor for periodontitis. Nonsmoking decreased the risk of having periodontitis. No clear association was found between clinical activity and periodontitis in IBD. In only the CD subgroup, high clinical activity (Harvey–Bradshaw index > 10) was associated with 1 periodontitis marker, the loss of attachment at sites of maximal periodontal pocket depth. Oral lesions besides periodontitis and gingivitis were not common, but nevertheless observed in about 10% of patients with IBD. Conclusions:IBD, and especially perianal disease in CD, is associated with periodontitis. Optimal therapeutic strategies should probably focus on treating both local oral and systemic inflammation.

First-Line Therapies in Inflammatory Bowel Disease

Background and Aims: Medical therapy of inflammatory bowel disease (IBD) is becoming more complex, given the increasing choice of drugs to treat Crohn’s disease (CD) and ulcerative colitis (UC). We aimed to summarize the current guidelines for first-line treatments in IBD. Methods: An extensive literature search with focus on the guidelines of the European Crohn’s and Colitis Organisation for the diagnosis and treatment of CD and UC was performed. First-line treatments were defined as the following drug categories: 5-aminosalicylates, budesonide, systemic steroids, azathioprine, 6-mercaptopurine, methotrexate, infliximab, adalimumab and certolizumab pegol. The following drug categories were not included: cyclosporine and tacrolimus (not yet approved by Swissmedic for IBD treatment). Results: Treatment recommendations for the following clinically frequent situations are presented according to disease severity: ileocecal CD, colonic CD, proximal small bowel CD and perianal CD. For UC the following situations are presented: ulcerative proctitis, left-sided colitis and pancolitis. Conclusions: We provide a summary on the use of first-line therapies for clinically frequent situations in patients with CD and UC.