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

Abstract

Hepatic steatosis is a multifactorial condition often observed in obese patients and a prelude to non-alcoholic fatty liver disease. Here we combine shotgun sequencing of faecal metagenomes with molecular phenomics (hepatic transcriptome, plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking gut microbiome and host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid (AAA and BCAA) metabolism. We demonstrated that faecal microbiota transplants and chronic treatment with phenylacetic acid (PAA), a microbial product of AAA metabolism, successfully trigger steatosis and BCAA metabolism. Molecular phenomic signatures were predictive (AUC = 87%) and consistent with the gut microbiome making an impact on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies.