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

Lesley Hoyles, José-Manuel Fernández-Real, Massimo Federici, Matteo Serino, James Abbott, Julie Charpentier, Christophe Heymes, Jèssica Latorre Luque, Elodie Anthony, Richard H Barton, Julien Chilloux, Antonis Myridakis, Laura Martinez-Gili, José Maria Moreno-Navarrete, Fadila Benhamed, Vincent Azalbert, Vincent Blasco-Baque, Josep Puig, Gemma Xifra, Wifredo RicartChristopher Tomlinson, Mark Woodbridge, Marina Cardellini, Francesca Davato, Iris Cardolini, Ottavia Porzio, Paolo Gentileschi, Frédéric Lopez, Fabienne Foufelle, Sarah A Butcher, Elaine Holmes, Jeremy K Nicholson, Catherine Postic, Rémy Burcelin, Marc-Emmanuel Dumas

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1070-1080
Number of pages11
JournalNature Medicine
Volume24
Issue number7
DOIs
Publication statusPublished - Jul 2018

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    Hoyles, L., Fernández-Real, J-M., Federici, M., Serino, M., Abbott, J., Charpentier, J., Heymes, C., Luque, J. L., Anthony, E., Barton, R. H., Chilloux, J., Myridakis, A., Martinez-Gili, L., Moreno-Navarrete, J. M., Benhamed, F., Azalbert, V., Blasco-Baque, V., Puig, J., Xifra, G., ... Dumas, M-E. (2018). Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nature Medicine, 24(7), 1070-1080. https://doi.org/10.1038/s41591-018-0061-3