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

Hoyles L1, Fernández-Real JM2, Federici M3, Serino M4,5, Abbott J1, Charpentier J4,5, Heymes C4,5, Luque JL6, Anthony E7, Barton RH1, Chilloux J1, Myridakis A1, Martinez-Gili L1, Moreno-Navarrete JM6, Benhamed F7, Azalbert V4,5, Blasco-Baque V4,5, Puig J6, Xifra G6, Ricart W6, Tomlinson C1, Woodbridge M1, Cardellini M8, Davato F8, Cardolini I8, Porzio O9,10, Gentileschi P9, Lopez F4,5, Foufelle F11, Butcher SA1, Holmes E1, Nicholson JK1, Postic C7, Burcelin R12,13, Dumas ME14.

2018 Jul;24(7):1070-1080. doi: 10.1038/s41591-018-0061-3. Epub 2018 Jun 25.

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.