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Integrated systems biology to study the contribution of the gut microbiome to steatosis in obese women

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Title: Integrated systems biology to study the contribution of the gut microbiome to steatosis in obese women
Authors: Hoyles, L
Fernández-Real, JM
Federici, M
Serino, M
Azalbert, V
Blasco, V
Abbott, J
Barton, RH
Puig, J
Xifra, G
Ricart, W
Woodbridge, M
Tomlinson, C
Cardellini, M
Davato, F
Cardolini, I
Porzio, O
Gentilieschi, P
Lopez, F
Foufelle, F
Postic, C
Butcher, SA
Holmes, E
Nicholson, JK
Burcelin, R
Dumas, ME
Item Type: Poster
Abstract: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease, increasing in worldwide prevalence as a result of the obesity epidemic. It manifests in hepatic cells as steatosis with or without lobular inflammation and/or ballooning. Animal and human studies have suggested the gut microbiome contributes to steatosis/NAFLD. The aim of this study was to use an integrated approach with various -omics and clinical data to evaluate the contribution of the gut microbiome to the molecular phenome (hepatic transcriptome, metabonome) of steatosis. Metagenomic (faecal microbiome), transcriptomic (liver biopsy), metabonomic (plasma and urine, 1H-NMR) and clinical data were collected for 56 morbidly obese (BMI >35) women from Italy (n = 31) and Spain (n = 25) who elected for bariatric surgery. Confounder analyses of clinical data were done using linear modelling. Histological examination of liver biopsies was used to grade steatosis. Faecal metagenomes were generated and analysed using the SCalable Automated Metagenomics Pipeline (SCAMP). Differentially expressed genes were identified in hepatic transcriptomes, and analysed using a range of different bioinformatics tools. 1H-NMR data were generated for plasma and urinary metabonomes. Clinical, metagenomic, transcriptomic and metabonomic data were integrated in the context of steatosis using partial Spearman's correlation, taking confounders (age, body mass index and cohort) into account. Steatosis was anti-correlated with microbial gene richness, and correlated with abundance of Proteobacteria. KEGG analyses of metagenomic data suggested increased microbial processing of dietary lipids and amino acids, as well as endotoxin-related processes related to Proteobacteria. Steatosis-associated hepatic transcriptomes were associated with branched-chain amino acid (BCAA) metabolism, endoplasmic reticulum/phagosome, and immune responses associated with non-specific microbial infections. Metabonomic profiles highlighted imbalances in choline metabolism, BCAA metabolism and gut-derived microbial metabolites resulting from metabolism of amino acids. Molecular phenomic signatures were stable and predictive regardless of sample size, and consistent with the microbiome making a significant contribution to the steatosis phenome. Validation studies (in vitro and in vivo) supported findings from the study. There is disruption of the gut-liver axis in steatosis, which can be seen in the gut microbiome, hepatic transcriptome and urinary and plasma metabonomes. Consistency of phenome signatures strongly supports a relationship between microbial amino acid metabolism and microbial gene richness, hepatic gene expression and biofluid metabonomes, and ultimately steatosis.
Issue Date: 13-Sep-2017
URI: http://hdl.handle.net/10044/1/52673
Copyright Statement: © 2017 The Authors
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: MR/L01632X/1
Conference Name: Exploring Human Host-Microbiome Interactions in Health and Disease
Notes: Invited to present poster and give talk (given on 15 September) on the work.
Appears in Collections:Department of Surgery and Cancer