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

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.

SUBMITTER: Hoyles L

PROVIDER: S-EPMC6140997 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Hoyles Lesley L Fernández-Real José-Manuel JM Federici Massimo M Serino Matteo M Abbott James J Charpentier Julie J Heymes Christophe C Luque Jèssica Latorre JL Anthony Elodie E Barton Richard H RH Chilloux Julien J Myridakis Antonis A Martinez-Gili Laura L Moreno-Navarrete José Maria JM Benhamed Fadila F Azalbert Vincent V Blasco-Baque Vincent V Puig Josep J Xifra Gemma G Ricart Wifredo W Tomlinson Christopher C Woodbridge Mark M Cardellini Marina M Davato Francesca F Cardolini Iris I Porzio Ottavia O Gentileschi Paolo P Lopez Frédéric F Foufelle Fabienne F Butcher Sarah A SA Holmes Elaine E Nicholson Jeremy K JK Postic Catherine C Burcelin Rémy R Dumas Marc-Emmanuel ME

Nature medicine 20180625 7

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 ha ...[more]

PMID: 29942096

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Project description:BackgroundPatients with metabolic syndrome, who are characterized by co-existence of insulin resistance, hypertension, hyperlipidemia, and obesity, are also prone to develop non-alcoholic fatty liver disease (NAFLD). Although the prevalence and severity of NAFLD is significantly greater in men than women, the mechanisms by which gender modulates the pathogenesis of hepatic steatosis are poorly defined. The obese spontaneously hypertensive (SHROB) rats represent an attractive model of metabolic syndrome without overt type 2 diabetes. Although pathological manifestation caused by the absence of a functional leptin receptor has been extensively studied in SHROB rats, it is unknown whether these animals elicited sex-specific differences in the development of hepatic steatosis.MethodsWe compared hepatic pathology in male and female SHROB rats. Additionally, we examined key biochemical and molecular parameters of signaling pathways linked with hyperinsulinemia and hyperlipidemia. Finally, using methods of quantitative polymerase chain reaction (qPCR) and western blot analysis, we quantified expression of 45 genes related to lipid biosynthesis and metabolism in the livers of male and female SHROB rats.ResultsWe show that all SHROB rats developed hepatic steatosis that was accompanied by enhanced expression of SREBP1, SREBP2, ACC1, and FASN proteins. The livers of male rats also elicited higher induction of Pparg, Ppara, Slc2a4, Atox1, Skp1, Angptl3, and Pnpla3 mRNAs. In contrast, the livers of female SHROB rats elicited constitutively higher levels of phosphorylated JNK and AMPK and enhanced expression of Cd36.ConclusionBased on these data, we conclude that the severity of hepatic steatosis in male and female SHROB rats was mainly driven by increased de novo lipogenesis. Moreover, male and female SHROB rats also elicited differential severity of hepatic steatosis that was coupled with sex-specific differences in fatty acid transport and esterification.

Dataset Information

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

Publications

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

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