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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  • 09 August 2018

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Acknowledgements

We thank N. J. Gooderham for critical reading of the manuscript. This work was supported by EU-FP7 FLORINASH (Health-F2-2009-241913) to R.B., M.F., J.-M.F.-R., F.F., C.P., E.H. and J.K.N. This work used the computing resources of the UK MEDical BIOinformatics partnership—aggregation, integration, visualization and analysis of large, complex data (UK MED-BIO), which is supported by the Medical Research Council (grant number MR/L01632X/1). L.H. is in receipt of an MRC Intermediate Research Fellowship in Data Science (MR/L01632X/1, UK MED-BIO). This work was also supported by funding to R.B. ((Région Midi-Pyrénées 2009-2014 RPV09003BBA), Agence Nationale de la Recherche ANR 09-GEN TRANSFLORAP and GAD 08-2_378258), to M.F. (Ministry of University (MIUR) Progetti di Ricerca di Interesse Nazionale (PRIN) protocol number 2015MPESJS_004, Ministry of Health Ricerca Finalizzata RF-2011-02349921, Fondazione Roma call for Non-Communicable Diseases NCD 2014), to J.-M.F.-R. (Ministry of Health FIS project 15/01934, CIBERobn Pathophysiology of Obesity and Nutrition and FEDER funds) and to M.-E.D. (EU METACARDIS under agreement HEALTH-F4-2012-305312, Neuron II under agreement 291840 and the MRC MR/M501797/1). We acknowledge the support of the Imperial College National Institute of Biomedical Research andthe Clinical Phenotyping Centre for support.

Author information

Author notes

  1. These authors contributed equally: Lesley Hoyles, José-Manuel Fernández-Real, Massimo Federici.

Affiliations

  1. Division of Integrative Systems Medicine and Digestive Diseases, Department of Surgery and Cancer, Imperial College London, London, UK

    • Lesley Hoyles
    • , James Abbott
    • , Richard H. Barton
    • , Julien Chilloux
    • , Antonis Myridakis
    • , Laura Martinez-Gili
    • , Christopher Tomlinson
    • , Mark Woodbridge
    • , Sarah A. Butcher
    • , Elaine Holmes
    • , Jeremy K. Nicholson
    •  & Marc-Emmanuel Dumas
  2. Department of Endocrinology, Diabetes and Nutrition and Department of Medicine, Hospital of Girona “Dr Josep Trueta”, Universitat of Girona and CIBERobn Pathophysiology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain

    • José-Manuel Fernández-Real
    • , Jèssica Latorre Luque
    • , José Maria Moreno-Navarrete
    • , Josep Puig
    • , Gemma Xifra
    •  & Wifredo Ricart
  3. Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier, Rome, Italy

    • Massimo Federici
    • , Marina Cardellini
    • , Francesca Davato
    •  & Iris Cardolini
  4. Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France

    • Matteo Serino
    • , Julie Charpentier
    • , Christophe Heymes
    • , Vincent Azalbert
    • , Vincent Blasco-Baque
    • , Frédéric Lopez
    •  & Rémy Burcelin
  5. Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: ‘Intestinal Risk Factors, Diabetes, Dyslipidemia, and Heart Failure’, Toulouse, France

    • Matteo Serino
    • , Julie Charpentier
    • , Christophe Heymes
    • , Vincent Azalbert
    • , Vincent Blasco-Baque
    • , Frédéric Lopez
    •  & Rémy Burcelin
  6. Institut Cochin Inserm U1016 CNRS UMR 8104, Université Paris Descartes, Paris, France

    • Elodie Anthony
    • , Fadila Benhamed
    •  & Catherine Postic
  7. Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy

    • Ottavia Porzio
    •  & Paolo Gentileschi
  8. Department of Laboratory Medicine, Bambino Gesù Children’s Hospital, Rome, Italy

    • Ottavia Porzio
  9. Sorbonne Universités, UPMC Univ Paris 06, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France

    • Fabienne Foufelle

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Contributions

R.B., J.-M.F.-R., M.F., F.L., F.F., C.P., E.H. and J.K.N. designed the study and supervised all parts of the project. R.B. is the project leader and chaired the consortium. M.-E.D. led data integration and elaborated the primary interpretation of analytical outcomes with L.H., in close collaboration with M.F., J.-M.F.-R. and R.B. L.H. implemented the microarray data analysis workflow. C.T. and M.W. developed the data repository. J.A. developed the metagenomic data analysis pipeline in collaboration with L.H. S.A.B. supervised the development of the data repository and the pipeline. L.H., J.A., R.H.B. and M.-E.D. performed the data analyses. J.-M.F.-R. and M.F. designed the clinical protocol and oversaw the clinical activities. M.C., F.D., I.C., O.P., P.G., J.P., G.X. and W.R. recruited and phenotyped patients and collected biological samples and physiological data. M.S., V.A. and V.B.-B. performed the RNA and DNA extractions. R.B. and M.S. supervised the DNA sequencing and gene profiling. J.L.L. and J.M.M.-N. performed the cell culture experiments. F.B., E.A., J.Charpentier and C.H. performed the animal work. R.H.B., J.Chilloux and L.M.-G. performed the metabolic profiling of plasma and urine by 1H-NMR. E.H. and J.K.N. supervised the metabolic profiling. A.M. performed the methylamine quantifications. L.H. and M.-E.D. drafted the first versions of the paper with critical and substantial contributions from M.F., J.-M.F.-R. and R.B. All authors provided support and constructive criticism throughout the project and approved the final version of the paper.

Competing interests

L.H., J.-M.F.-R., M.F., R.H.B., J.L.L., E.H., J.K.N., C.P., R.B. and M.-E.D. are named as co-inventors on pending patents held by INSERM Transfert, INSERM, University of Rome Tor Vergata, University of Girona and Imperial College on NAFLD diagnostics and have the right to receive royalty payments for inventions or discoveries related to NAFLD diagnostics.

Corresponding authors

Correspondence to José-Manuel Fernández-Real or Massimo Federici or Rémy Burcelin or Marc-Emmanuel Dumas.

Supplementary information

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

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