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      Metabonomics of human fecal extracts characterize ulcerative colitis, Crohn's disease and healthy individuals.

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          Abstract

          This study employs spectroscopy-based metabolic profiling of fecal extracts from healthy subjects and patients with active or inactive ulcerative colitis (UC) and Crohn's disease (CD) to substantiate the potential use of spectroscopy as a non-invasive diagnostic tool and to characterize the fecal metabolome in inflammatory bowel disease (IBD). Stool samples from 113 individuals (UC 48, CD 44, controls 21) were analyzed by 1H nuclear magnetic resonance (NMR) spectroscopy (Bruker 600 MHz, Bruker BioSpin, Rheinstetten, Germany). Data were analyzed with principal component analysis and orthogonal-projection to latent structure-discriminant analysis using SIMCA-P + 12 and MATLAB. Significant differences were found in the metabolic profiles making it possible to differentiate between active IBD and controls and between UC and CD. The metabolites holding differential power primarily belonged to a range of amino acids, microbiota-related short chain fatty acids, and lactate suggestive of an inflammation-driven malabsorption and dysbiosis of the normal bacterial ecology. However, removal of patients with intestinal surgery and anti-TNF-α antibody treatment eliminated the discriminative power regarding UC versus CD. This study consequently demonstrates that 1H NMR spectroscopy of fecal extracts is a potential non-invasive diagnostic tool and able to characterize the inflammation-driven changes in the metabolic profiles related to malabsorption and dysbiosis. Intestinal surgery and medication are to be accounted for in future studies, as it seems to be factors of importance in the discriminative process.

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          Most cited references55

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          Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides.

          Resistant starch (RS) is starch and products of its small intestinal digestion that enter the large bowel. It occurs for various reasons including chemical structure, cooking of food, chemical modification, and food mastication. Human colonic bacteria ferment RS and nonstarch polysaccharides (NSP; major components of dietary fiber) to short-chain fatty acids (SCFA), mainly acetate, propionate, and butyrate. SCFA stimulate colonic blood flow and fluid and electrolyte uptake. Butyrate is a preferred substrate for colonocytes and appears to promote a normal phenotype in these cells. Fermentation of some RS types favors butyrate production. Measurement of colonic fermentation in humans is difficult, and indirect measures (e.g., fecal samples) or animal models have been used. Of the latter, rodents appear to be of limited value, and pigs or dogs are preferable. RS is less effective than NSP in stool bulking, but epidemiological data suggest that it is more protective against colorectal cancer, possibly via butyrate. RS is a prebiotic, but knowledge of its other interactions with the microflora is limited. The contribution of RS to fermentation and colonic physiology seems to be greater than that of NSP. However, the lack of a generally accepted analytical procedure that accommodates the major influences on RS means this is yet to be established.
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            Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn's disease.

            Proinflammatory cytokines are key factors in the pathogenesis of Crohn's disease (CD). Activation of nuclear factor kappa B (NFkappaB), which is involved in their gene transcription, is increased in the intestinal mucosa of CD patients. As butyrate enemas may be beneficial in treating colonic inflammation, we investigated if butyrate promotes this effect by acting on proinflammatory cytokine expression. Intestinal biopsy specimens, isolated lamina propria cells (LPMC), and peripheral blood mononuclear cells (PBMC) were cultured with or without butyrate for assessment of secretion of tumour necrosis factor (TNF) and mRNA levels. NFkappaB p65 activation was determined by immunofluorescence and gene reporter experiments. Levels of NFkappaB inhibitory protein (IkappaBalpha) were analysed by western blotting. The in vivo efficacy of butyrate was assessed in rats with trinitrobenzene sulphonic acid (TNBS) induced colitis. Butyrate decreased TNF production and proinflammatory cytokine mRNA expression by intestinal biopsies and LPMC from CD patients. Butyrate abolished lipopolysaccharide (LPS) induced expression of cytokines by PBMC and transmigration of NFkappaB from the cytoplasm to the nucleus. LPS induced NFkappaB transcriptional activity was decreased by butyrate while IkappaBalpha levels were stable. Butyrate treatment also improved TNBS induced colitis. Butyrate decreases proinflammatory cytokine expression via inhibition of NFkappaB activation and IkappaBalpha degradation. These anti-inflammatory properties provide a rationale for assessing butyrate in the treatment of CD.
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              Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases.

              Gut microbiota metabolises bile acids (BA). As dysbiosis has been reported in inflammatory bowel diseases (IBD), we aim to investigate the impact of IBD-associated dysbiosis on BA metabolism and its influence on the epithelial cell inflammation response. Faecal and serum BA rates, expressed as a proportion of total BA, were assessed by high-performance liquid chromatography tandem mass spectrometry in colonic IBD patients (42) and healthy subjects (29). The faecal microbiota composition was assessed by quantitative real-time PCR. Using BA profiles and microbiota composition, cluster formation between groups was generated by ranking models. The faecal BA profiles in germ-free and conventional mice were compared. Direct enzymatic activities of BA biotransformation were measured in faeces. The impact of BA on the inflammatory response was investigated in vitro using Caco-2 cells stimulated by IL-1β. IBD-associated dysbiosis was characterised by a decrease in the ratio between Faecalibacterium prausntizii and Escherichia coli. Faecal-conjugated BA rates were significantly higher in active IBD, whereas, secondary BA rates were significantly lower. Interestingly, active IBD patients exhibited higher levels of faecal 3-OH-sulphated BA. The deconjugation, transformation and desulphation activities of the microbiota were impaired in IBD patients. In vitro, secondary BA exerted anti-inflammatory effects, but sulphation of secondary BAs abolished their anti-inflammatory properties. Impaired microbiota enzymatic activity observed in IBD-associated dysbiosis leads to modifications in the luminal BA pool composition. Altered BA transformation in the gut lumen can erase the anti-inflammatory effects of some BA species on gut epithelial cells and could participate in the chronic inflammation loop of IBD.
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                Author and article information

                Journal
                Metabolomics
                Metabolomics : Official journal of the Metabolomic Society
                Springer Science and Business Media LLC
                1573-3882
                1573-3882
                January 20 2015
                : 11
                Affiliations
                [1 ] Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark ; Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
                [2 ] Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Centre for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, The Chinese Academy of Sciences, Wuhan, People's Republic of China ; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People's Republic of China.
                [3 ] Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Centre for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, The Chinese Academy of Sciences, Wuhan, People's Republic of China.
                [4 ] Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
                [5 ] HWB-NMR, School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham, UK.
                Article
                677
                10.1007/s11306-014-0677-3
                4289537
                25598765
                a8528c2f-49b5-44c3-856a-05e58d2f4a04
                History

                Diagnostic tool,Dysbiosis,Inflammatory bowel disease,Metabolomics,NMR spectroscopy

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