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

Hepatic steatosisis a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencingof fecal metagenomeswith 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 microbiomeand the host phenometo hepatic steatosis. Patients with steatosishave 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 acidmetabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acidmetabolism, successfully trigger steatosisand branched-chain amino acidmetabolism. Molecular phenomicsignatures were predictive ( area underthe curve = 87%) and consistent with the gut microbiomehaving an effect on the steatosis phenome(>75% shared variation) and, therefore, actionable via microbiome-based therapies.