Abstract

Humans with metabolic and inflammatory diseases frequently harbour lower levels of butyrate-producing bacteria in their gut. However, it is not known whether variation in the levels of these organisms is causally linked with disease development and whether diet modifies the impact of these bacteria on health. Here we show that a prominent gut-associated butyrate-producing bacterial genus (Roseburia) is inversely correlated with atherosclerotic lesion development in a genetically diverse mouse population. We use germ-free apolipoprotein E-deficient mice colonized with synthetic microbial communities that differ in their capacity to generate butyrate to demonstrate that Roseburia intestinalis interacts with dietary plant polysaccharides to: impact gene expression in the intestine, directing metabolism away from glycolysis and toward fatty acid utilization; lower systemic inflammation; and ameliorate atherosclerosis. Furthermore, intestinal administration of butyrate reduces endotoxaemia and atherosclerosis development. Together, our results illustrate how modifiable diet-by-microbiota interactions impact cardiovascular disease, and suggest that interventions aimed at increasing the representation of butyrate-producing bacteria may provide protection against atherosclerosis.

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Data availability:

The SRA accession ID for COPRO-Seq is SRP158926. The accession number for RNA sequencing data is GEO: GSE119141. The SRA accession ID for the Ath-HMDP microbiome data is SRP142550. Additional data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to thank C. Pan (UCLA) for help in 16S sequencing, G. A. Barrett-Wilt (University of Wisconsin Mass Spectrometry Facility) for technical support with GC/MS analysis, D. A. Roenneburg (Department of Surgery, University of Wisconsin School of Medicine and Public Health) for assistance with histology and B.D. Mickelson (Envigo) for assistance with diets. We also thank the University of Wisconsin Biotechnology Center DNA Sequencing Facility for providing sequencing and support services. This work was supported in part by grants NIH DK108259 (to F.E.R.) and HL30568 (to A.J.L.), by the National Institute of Food and Agriculture, US Department of Agriculture, under award number 2016-67017-24416 (to F.E.R.) and the Swedish Heart Lung Foundation (to F.B.). This work was also supported in part by a grant from a Transatlantic Networks of Excellence Award from the Leducq Foundation. K.K. is supported by the Astellas Foundation for Research on Metabolic Disorders, the International Atherosclerosis Society, the Yamada Science Foundation and the Sumitomo Life Welfare and Culture Foundation. K.A.K. is supported by NIH F30 DK108494-02.

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Affiliations

  1. Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA

    • Kazuyuki Kasahara
    • , Kymberleigh A. Romano
    • , Robert L. Kerby
    • , Eugenio I. Vivas
    •  & Federico E. Rey
  2. Wisconsin Institute for Discovery, Madison, WI, USA

    • Kimberly A. Krautkramer
    •  & John M. Denu
  3. Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI, USA

    • Kimberly A. Krautkramer
    •  & John M. Denu
  4. Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA

    • Elin Org
    • , Margarete Mehrabian
    •  & Aldons J. Lusis
  5. Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden

    • Fredrik Bäckhed

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Contributions

F.E.R. conceived, designed and supervised the project. K.K. designed the project, performed most of the experiments, analysed the results and generated figures and tables. K.A.K. performed the PTM analysis, analysed results and generated the figures. K.A.R. and K.K. performed COPRO-Seq analysis. R.L.K. cultured bacterial strains. F.B. provided GF ApoE/ mice and E.I.V. maintained the GF mouse facility. A.J.L. and M.M. conceived and performed the Ath-HMDP experiment, and E.O. generated and analysed 16S rRNA gene data. K.K., K.A.K., R.L.K. and F.E.R. wrote the manuscript. A.J.L., M.M., F.B. and J.M.D. provided critical feedback. All authors read and agreed on the final version of the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Federico E. Rey.

Supplementary information

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DOI

https://doi.org/10.1038/s41564-018-0272-x

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