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      Differences in Visceral Fat and Fat Bacterial Colonization between Ulcerative Colitis and Crohn’s Disease. An In Vivo and In Vitro Study

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          Abstract

          Crohn’s disease (CD) is notably characterized by the expansion of visceral fat with small adipocytes expressing a high proportion of anti-inflammatory genes. Conversely, visceral fat depots in ulcerative colitis (UC) patients have never been characterized. Our study aims were a) to compare adipocyte morphology and gene expression profile and bacterial translocation in omental (OM) and mesenteric (MES) adipose tissue of patients with UC and CD, and b) to investigate the effect of bacterial infection on adipocyte proliferation in vitro. Specimens of OM and MES were collected from 11 UC and 11 CD patients, processed and examined by light microscopy. Gene expression profiles were evaluated in adipocytes isolated from visceral adipose tissue using microarray and RTqPCR validations. Bacteria within adipose tissue were immuno-detected by confocal scanning laser microscopy. Adipocytes were incubated with Enterococcus faecalis and cells counted after 24h. Morphology and molecular profile of OM and MES revealed that UC adipose tissue is less inflamed than CD adipose tissue. Genes linked to inflammation, bacterial response, chemotaxis and angiogenesis were down-regulated in adipocytes from UC compared to CD, whereas genes related to metallothioneins, apoptosis pathways and growth factor binding were up-regulated. A dense perinuclear positivity for Enterococcus faecalis was detected in visceral adipocytes from CD, whereas positivity was weak in UC. In vitro bacterial infection was associated with a five-fold increase in the proliferation rate of OM preadipocytes. Compared to UC, visceral adipose tissue from CD is more inflamed and more colonized by intestinal bacteria, which increase adipocyte proliferation. The influence of bacteria stored within adipocytes on the clinical course of IBD warrants further investigations.

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          Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis.

          The etiology of inflammatory bowel disease (IBD) is unknown but may relate to an unidentified bacterial pathogen or an immunological reaction to gut microbiota. Antibiotics have therefore been proposed as a therapy for Crohn's disease (CD) and ulcerative colitis (UC) to induce remission in active disease to prevent relapse. Current data are conflicting and we therefore conducted a systematic review of randomized controlled trials (RCTs) evaluating antibiotics in IBD. Only parallel group RCTs were considered eligible. Studies with adult patients receiving any dose of therapy for at least 7 days and up to 16 weeks for active disease, or at least 6 months of follow-up for preventing relapse in quiescent disease were analyzed. We included any antibiotics alone or in combination using predefined definitions of remission and relapse. Two reviewers independently assessed eligibility and extracted data. The primary outcome was remission or relapse using an intention-to-treat methodology. The data were summarized using relative risk (RR) and pooled using a random effects model. For active CD, there were 10 RCTs involving 1,160 patients. There was a statistically significant effect of antibiotics being superior to placebo (RR of active CD not in remission=0.85; 95% confidence interval (CI)=0.73-0.99, P=0.03). There was moderate heterogeneity between results (I(2)=48%) and a diverse number of antibiotics were tested (anti-tuberculosis therapy, macrolides, fluroquinolones, 5-nitroimidazoles, and rifaximin) either alone or in combination. Rifamycin derivatives either alone or in combination with other antibiotics appeared to have a significant effect at inducing remission in active CD. In perianal CD fistula there were three trials evaluating 123 patients using either ciprofloxacin or metronidazole. There was a statistically significant effect in reducing fistula drainage (RR=0.8; 95% CI=0.66-0.98) with no heterogeneity (I(2)=0%) and an number needed to treat 5 (95% CI=3-20). For quiescent CD, there were 3 RCTs involving 186 patients treated with different antibiotics combinations (all including antimycobacterials) vs. placebo. There was a statistically significant effect in favor of antibiotics vs. placebo (RR of relapse=0.62; 95% CI=0.46-0.84), with no heterogeneity (I(2)=0%). In active UC, there were 9 RCTs with 662 patients and there was a statistically significant benefit for antibiotics inducing remission (RR of UC not in remission=0.64; 95% CI=0.43-0.96). There was moderate heterogeneity (I(2)=69%) and antibiotics used were all different single or combination drugs. Antibiotic therapy may induce remission in active CD and UC, although the diverse number of antibiotics tested means the data are difficult to interpret. This systematic review is a mandate for further trials of antibiotic therapy in IBD.
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            Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept.

            Evidence suggests that bacterial components in blood could play an early role in events leading to diabetes. To test this hypothesis, we studied the capacity of a broadly specific bacterial marker (16S rDNA) to predict the onset of diabetes and obesity in a general population. Data from an Epidemiological Study on the Insulin Resistance Syndrome (D.E.S.I.R.) is a longitudinal study with the primary aim of describing the history of the metabolic syndrome. The 16S rDNA concentration was measured in blood at baseline and its relationship with incident diabetes and obesity over 9 years of follow-up was assessed. In addition, in a nested case-control study in which participants later developed diabetes, bacterial phylotypes present in blood were identified by pyrosequencing of the overall 16S rDNA gene content. We analysed 3,280 participants without diabetes or obesity at baseline. The 16S rDNA concentration was higher in those destined to have diabetes. No difference was observed regarding obesity. However, the 16S rDNA concentration was higher in those who had abdominal adiposity at the end of follow-up. The adjusted OR (95% CIs) for incident diabetes and for abdominal adiposity were 1.35 (1.11, 1.60), p = 0.002 and 1.18 (1.03, 1.34), p = 0.01, respectively. Moreover, pyrosequencing analyses showed that participants destined to have diabetes and the controls shared a core blood microbiota, mostly composed of the Proteobacteria phylum (85-90%). 16S rDNA was shown to be an independent marker of the risk of diabetes. These findings are evidence for the concept that tissue bacteria are involved in the onset of diabetes in humans.
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              Mesenteric fat as a source of C reactive protein and as a target for bacterial translocation in Crohn's disease

              Objective Mesenteric fat hyperplasia is a hallmark of Crohn's disease (CD), and C reactive protein (CRP) is correlated with disease activity. The authors investigated whether mesenteric adipocytes may be a source of CRP in CD and whether inflammatory and bacterial triggers may stimulate its production by adipocytes. Design CRP expression in the mesenteric and subcutaneous fats of patients with CD and the correlation between CRP plasma concentrations and mesenteric messenger RNA (mRNA) levels were assessed. The impact of inflammatory and bacterial challenges on CRP synthesis was tested using an adipocyte cell line. Bacterial translocation to mesenteric fat was studied in experimental models of colitis and ileitis and in patients with CD. Results CRP expression was increased in the mesenteric fat of patients with CD, with mRNA levels being 80±40 (p<0.05) and 140±65 (p=0.04) times higher than in the mesenteric fat of patients with ulcerative colitis and in the subcutaneous fat of the same CD subjects, respectively, and correlated with plasma levels. Escherichia coli (1230±175-fold, p<0.01), lipopolysaccharide (26±0.5-fold, p<0.01), tumour necrosis factor α (15±0.3-fold, p<0.01) and interleukin-6 (10±0.7-fold, p<0.05) increased CRP mRNA levels in adipocyte 3T3-L1 cells. Bacterial translocation to mesenteric fat occurred in 13% and 27% of healthy and CD subjects, respectively, and was increased in experimental colitis and ileitis. Human mesenteric adipocytes constitutively expressed mRNA for TLR2, TLR4, NOD1 and NOD2. Conclusion Mesenteric fat is an important source of CRP in CD. CRP production by mesenteric adipocytes may be triggered by local inflammation and bacterial translocation to mesenteric fat, providing a mechanism whereby mesenteric fat hyperplasia may contribute to inflammatory response in CD.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                24 October 2013
                : 8
                : 10
                : e78495
                Affiliations
                [1 ]Diabetes Research Laboratory, Istituto Auxologico Italiano, Milan, Italy
                [2 ]Laboratory of Molecular Biology, Istituto Auxologico Italiano, Milan, Italy
                [3 ]Department of Clinical Sciences, Luigi Sacco Hospital, University of Milan, Milan, Italy
                [4 ]Department of Medical and Surgical Pathophysiology and Transplants, University of Milan, Milan, Italy
                [5 ]Microbiology Laboratory, Istituto Auxologico Italiano, Milan, Italy
                [6 ]Department of Medical Sciences and Rehabilitation, Istituto Auxologico Italiano, Milan, Italy
                Charité, Campus Benjamin Franklin, Germany
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: AZ RC PD CI. Performed the experiments: AZ RC CR DG. Analyzed the data: AZ RC CI. Contributed reagents/materials/analysis tools: AMDB GM EC. Wrote the manuscript: AZ RC CI.

                Article
                PONE-D-13-29026
                10.1371/journal.pone.0078495
                3813471
                24205244
                772dd65c-44bd-4f72-85c2-24b49c64939f
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 15 July 2013
                : 13 September 2013
                Funding
                This study was supported by Istituto Auxologico Italiano. Istituto Auxologico Italiano, funder of this study, had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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