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

Lesley Hoyles 1 José-Manuel Fernández-Real 2 Massimo Federici 3 Matteo Serino 4 James Abbott 1 Julie Charpentier 5 Christophe Heymes 5 Jèssica Luque 2 Elodie Anthony 6 Richard Barton 7 Julien Chilloux 1 Antonis Myridakis 1 Laura Martinez-Gili 1 José Moreno-Navarrete 2 Fadila Benhamed 6 Vincent Azalbert 5 Vincent Blasco-Baque 5 Josep Puig 2 Gemma Xifra 2 Wifredo Ricart 2 Christopher Tomlinson 1 Mark Woodbridge 1 Marina Cardellini 8 Francesca Davato 8 Iris Cardolini 8 Ottavia Porzio 8, 9 Paolo Gentileschi 8 Frédéric Lopez 5 Fabienne Foufelle 10 Sarah Butcher 1 Elaine Holmes 1 Jeremy Nicholson 1 Catherine Postic 6 Rémy Burcelin 6 Marc-Emmanuel Dumas 1
1 Imperial College London
2 ISC - Instituto de Salud Carlos III [Madrid]
3 University of Rome "Tor Vergeta"
4 I2MR - Institut de médecine moléculaire de Rangueil
5 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
6 IC UM3 (UMR 8104 / U1016) - Institut Cochin
7 Cardiff Business School
8 University of Rome TorVergata
9 Bambino Gesù Children’s Hospital [Rome, Italy]
10 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
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.
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https://hal-cnrs.archives-ouvertes.fr/hal-03090150
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Submitted on : Friday, November 26, 2021 - 12:41:18 PM
Last modification on : Tuesday, January 18, 2022 - 2:26:08 PM

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Lesley Hoyles, José-Manuel Fernández-Real, Massimo Federici, Matteo Serino, James Abbott, et al.. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nature Medicine, Nature Publishing Group, 2018, 24, pp.1070 - 1080. ⟨10.1038/s41591-018-0061-3⟩. ⟨hal-03090150⟩

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