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Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women

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Title: Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women
Authors: Hoyles, L
Fernández-Real, JM
Federici, M
Serino, M
Abbott, J
Charpentier, J
Heymes, C
Latorre Luque, J
Anthony, E
Barton, RH
Chilloux, J
Myridakis, A
Martinez-Gili, L
Moreno-Navarrete, JM
Rayah, F
Azalbert, V
Blasco-Baque, V
Puig, J
Xifra, G
Ricart, W
Tomlinson, C
Woodbridge, M
Cardellini, M
Davato, F
Cardolini, I
Porzio, O
Gentilieschi, P
Lopez, F
Foufelle, F
Butcher, SA
Holmes, E
Nicholson, JK
Postic, C
Burcelin, R
Dumas, ME
Item Type: Journal Article
Abstract: Hepatic steatosis is a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencing of fecal metagenomes with molecular phenomics (hepatic transcriptome and plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking the gut microbiome and the host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for the processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid metabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acid metabolism, successfully trigger steatosis and branched-chain amino acid metabolism. Molecular phenomic signatures were predictive (area under the curve = 87%) and consistent with the gut microbiome having an effect on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies.
Issue Date: 1-Jul-2018
Date of Acceptance: 12-Apr-2018
URI: http://hdl.handle.net/10044/1/57852
DOI: 10.1038/s41591-018-0061-3
ISSN: 1078-8956
Publisher: Nature Publishing Group
Start Page: 1
End Page: 17
Journal / Book Title: Nature Medicine
Volume: 24
Copyright Statement: © 2018 Springer Nature Limited. All rights reserved.
Sponsor/Funder: Commission of the European Communities
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
Funder's Grant Number: 305312
MR/M501797/1
MR/L01632X/1
MR/L01632X/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Medicine, Research & Experimental
Research & Experimental Medicine
FATTY LIVER-DISEASE
HUMAN GUT MICROBIOME
INSULIN-RESISTANCE
CARDIOVASCULAR-DISEASE
METABOLISM
GLUCOSE
DIET
IMPACT
ASSOCIATION
PHENOTYPE
Animals
Cells, Cultured
Cohort Studies
Confounding Factors, Epidemiologic
Diabetes Mellitus
Fecal Microbiota Transplantation
Female
Hepatocytes
Humans
Metabolome
Metabolomics
Metagenomics
Mice
Microbiota
Non-alcoholic Fatty Liver Disease
Obesity
Phenotype
Transcriptome
Cells, Cultured
Hepatocytes
Animals
Humans
Mice
Diabetes Mellitus
Obesity
Cohort Studies
Confounding Factors (Epidemiology)
Phenotype
Female
Metabolomics
Metabolome
Metagenomics
Transcriptome
Microbiota
Non-alcoholic Fatty Liver Disease
Fecal Microbiota Transplantation
Immunology
11 Medical and Health Sciences
Publication Status: Published
Online Publication Date: 2018-06-25
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Department of Surgery and Cancer
Faculty of Medicine
School of Public Health
Faculty of Natural Sciences