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 Ricart; Christopher 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

doi:10.1038/s41591-018-0061-3

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

Lesley Hoyles, José-Manuel Fernández-Real (Lead / Corresponding author), Massimo Federici (Lead / Corresponding author), 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 (Lead / Corresponding author), Marc-Emmanuel Dumas (Lead / Corresponding author)

Computational Biology

Research output: Contribution to journal › Article › peer-review

569 Citations (Scopus)

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 language	English
Pages (from-to)	1070–1080
Number of pages	11
Journal	Nature Medicine
Volume	24
DOIs	https://doi.org/10.1038/s41591-018-0061-3
Publication status	Published - 25 Jul 2018

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41591-018-0061-3

Cite this

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, 1070–1080. https://doi.org/10.1038/s41591-018-0061-3

@article{5703c68ebcbf4dbf8f358825426d7078,

title = "Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women",

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.",

author = "Lesley Hoyles and Jos{\'e}-Manuel Fern{\'a}ndez-Real and Massimo Federici and Matteo Serino and James Abbott and Julie Charpentier and Christophe Heymes and Luque, \{J{\`e}ssica Latorre\} and Elodie Anthony and Barton, \{Richard H.\} and Julien Chilloux and Antonis Myridakis and Laura Martinez-Gili and Moreno-Navarrete, \{Jos{\'e} Maria\} and Fadila Benhamed and Vincent Azalbert and Vincent Blasco-Baque and Josep Puig and Gemma Xifra and Wifredo Ricart and Christopher Tomlinson and Mark Woodbridge and Marina Cardellini and Francesca Davato and Iris Cardolini and Ottavia Porzio and Paolo Gentileschi and Fr{\'e}d{\'e}ric Lopez and Fabienne Foufelle and Butcher, \{Sarah A.\} and Elaine Holmes and Nicholson, \{Jeremy K.\} and Catherine Postic and R{\'e}my Burcelin and Marc-Emmanuel Dumas",

year = "2018",

month = jul,

day = "25",

doi = "10.1038/s41591-018-0061-3",

language = "English",

volume = "24",

pages = "1070–1080",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Research",

}

Hoyles, L, Fernández-Real, J-M, Federici, M, Serino, M, Abbott, J, Charpentier, J, Heymes, C, Luque, JL, Anthony, E, Barton, RH, Chilloux, J, Myridakis, A, Martinez-Gili, L, Moreno-Navarrete, JM, Benhamed, F, Azalbert, V, Blasco-Baque, V, Puig, J, Xifra, G, Ricart, W, Tomlinson, C, Woodbridge, M, Cardellini, M, Davato, F, Cardolini, I, Porzio, O, Gentileschi, P, Lopez, F, Foufelle, F, Butcher, SA, Holmes, E, Nicholson, JK, Postic, C, Burcelin, R & Dumas, M-E 2018, 'Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women', Nature Medicine, vol. 24, pp. 1070–1080. https://doi.org/10.1038/s41591-018-0061-3

TY - JOUR

T1 - Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women

AU - Hoyles, Lesley

AU - Fernández-Real, José-Manuel

AU - Federici, Massimo

AU - Serino, Matteo

AU - Abbott, James

AU - Charpentier, Julie

AU - Heymes, Christophe

AU - Luque, Jèssica Latorre

AU - Anthony, Elodie

AU - Barton, Richard H.

AU - Chilloux, Julien

AU - Myridakis, Antonis

AU - Martinez-Gili, Laura

AU - Moreno-Navarrete, José Maria

AU - Benhamed, Fadila

AU - Azalbert, Vincent

AU - Blasco-Baque, Vincent

AU - Puig, Josep

AU - Xifra, Gemma

AU - Ricart, Wifredo

AU - Tomlinson, Christopher

AU - Woodbridge, Mark

AU - Cardellini, Marina

AU - Davato, Francesca

AU - Cardolini, Iris

AU - Porzio, Ottavia

AU - Gentileschi, Paolo

AU - Lopez, Frédéric

AU - Foufelle, Fabienne

AU - Butcher, Sarah A.

AU - Holmes, Elaine

AU - Nicholson, Jeremy K.

AU - Postic, Catherine

AU - Burcelin, Rémy

AU - Dumas, Marc-Emmanuel

PY - 2018/7/25

Y1 - 2018/7/25

N2 - 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.

AB - 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.

UR - https://doi.org/10.1038/s41591-018-0061-3

U2 - 10.1038/s41591-018-0061-3

DO - 10.1038/s41591-018-0061-3

M3 - Article

SN - 1078-8956

VL - 24

SP - 1070

EP - 1080

JO - Nature Medicine

JF - Nature Medicine

ER -

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

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this