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

TY - JOUR

T1 - Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women

AU - Hoyles, Lesley

AU - Fernández-Real, José-Manuel

AU - Federici, Massimo

AU - Serino, Matteo

AU - Abbott, James

AU - Charpentier, Julie

AU - Heymes, Christophe

AU - Luque, Jèssica Latorre

AU - Anthony, Elodie

AU - Barton, Richard H.

AU - Chilloux, Julien

AU - Myridakis, Antonis

AU - Martinez-Gili, Laura

AU - Moreno-Navarrete, José Maria

AU - Benhamed, Fadila

AU - Azalbert, Vincent

AU - Blasco-Baque, Vincent

AU - Puig, Josep

AU - Xifra, Gemma

AU - Ricart, Wifredo

AU - Tomlinson, Christopher

AU - Woodbridge, Mark

AU - Cardellini, Marina

AU - Davato, Francesca

AU - Cardolini, Iris

AU - Porzio, Ottavia

AU - Gentileschi, Paolo

AU - Lopez, Frédéric

AU - Foufelle, Fabienne

AU - Butcher, Sarah A.

AU - Holmes, Elaine

AU - Nicholson, Jeremy K.

AU - Postic, Catherine

AU - Burcelin, Rémy

AU - Dumas, Marc-Emmanuel

PY - 2018/7/25

Y1 - 2018/7/25

N2 - 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.

AB - 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.

UR - https://doi.org/10.1038/s41591-018-0061-3

U2 - 10.1038/s41591-018-0061-3

DO - 10.1038/s41591-018-0061-3

M3 - Article

SN - 1078-8956

VL - 24

SP - 1070

EP - 1080

JO - Nature Medicine

JF - Nature Medicine

ER -