Molecular Phenomics and Metagenomics of Hepatic Steatosis in Non-Diabetic Obese Women

By L. Hoyles, José Fernández-Real, M. Federici, M. Serino, J. Abbott, J. Charpentier, C. Heymes, Jèssica Latorre Luque, Élodie Anthony, R. H. Barton and 25 more. Nature Medicine, 2018

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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. Metabolic activity of specific human gut microorganisms contributes to liver steatosis in obese women.

Subfields: Epidemiology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/95928b78c00de22480cf16a53a5c05b9c288d335

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Citations in the corpus

Dietary lipids, gut microbiota and lipid metabolism (2019, background): “Hoyles et al recently show that patients with steatosis have decreased microbial gene richness and altered genetic potential for several functions including the processing of dietary lipids [46].”
Gut microbiota-derived metabolites as central regulators in metabolic disorders (2020, background): “34 The dysregulation of SCFA 35 and bile acid (BA) 36 metabolism are also associated with metabolic diseases, including obesity, type 2 diabetes mellitus and non-alcoholic fatty liver diseases.”
Mechanisms and disease consequences of nonalcoholic fatty liver disease (2021, background): “A link betweenNAFLD/NASH and themicrobiome is supported by several studies (Caussy et al., 2019; Da Silva et al., 2018; Hoyles et al., 2018; Loomba et al., 2017; Oh et al., 2020; Raman et al., 2013; Schwimmer et al., 2019; Sharpton et al., 2019).”
NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications (2020, neutral): “83 Other gut-derived metabolites might be involved in NAFLD pathogenesis.”