Abstract

In tackling the obesity pandemic, considerable efforts are devoted to the development of effective weight reduction strategies, yet many dieting individuals fail to maintain a long-term weight reduction, and instead undergo excessive weight regain cycles. The mechanisms driving recurrent post-dieting obesity remain largely elusive. Here we identify an intestinal microbiome signature that persists after successful dieting of obese mice and contributes to faster weight regain and metabolic aberrations upon re-exposure to obesity-promoting conditions. Faecal transfer experiments show that the accelerated weight regain phenotype can be transmitted to germ-free mice. We develop a machine-learning algorithm that enables personalized microbiome-based prediction of the extent of post-dieting weight regain. Additionally, we find that the microbiome contributes to diminished post-dieting flavonoid levels and reduced energy expenditure, and demonstrate that flavonoid-based ‘post-biotic’ intervention ameliorates excessive secondary weight gain. Together, our data highlight a possible microbiome contribution to accelerated post-dieting weight regain, and suggest that microbiome-targeting approaches may help to diagnose and treat this common disorder.

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Acknowledgements

We thank the members of the Elinav and Segal laboratories for discussions and C. Bar-Nathan for germ-free mouse work. C.A.T. received a Boehringer Ingelheim Fonds PhD Fellowship. D.R. received a Levi Eshkol PhD Scholarship for Personalized Medicine by the Israeli Ministry of Science. Y.K. is the incumbent of the Sarah and Rolando Uziel Research Associate Chair. E.S. is supported by the Crown Human Genome Center; the Else Kroener Fresenius Foundation; D. L. Schwarz; J. N. Halpern; L. Steinberg; and grants funded by the European Research Council, the National Institute of Health, and the Israel Science Foundation. E.E. is supported by Y. and R. Ungar; the Abisch Frenkel Foundation for the Promotion of Life Sciences; the Gurwin Family Fund for Scientific Research; the Leona M. and Harry B. Helmsley Charitable Trust; the Crown Endowment Fund for Immunological Research; the estate of J. Gitlitz; the estate of L. Hershkovich; the Benoziyo Endowment Fund for the Advancement of Science; the Adelis Foundation; J. L. and V. Schwartz; A. and G. Markovitz; A. and C. Adelson; the French National Center for Scientific Research (CNRS); D. L. Schwarz; the V. R. Schwartz Research Fellow Chair; L. Steinberg; J. N. Halpern; A. Edelheit; and by grants funded by the European Research Council; a Marie Curie Integration grant; the German-Israeli Foundation for Scientific Research and Development; the Israel Science Foundation; the Minerva Foundation; the Rising Tide Foundation; the Helmholtz Foundation; and the European Foundation for the Study of Diabetes. E.E. is the incumbent of the Rina Gudinski Career Development Chair and a senior fellow of the Canadian Institute for Advanced Research (CIFAR).

Author information

Author notes

    • Christoph A. Thaiss
    • , Shlomik Itav
    •  & Daphna Rothschild

    These authors contributed equally to this work.

    • Eran Segal
    •  & Eran Elinav

    These authors jointly supervised this work.

Affiliations

  1. Immunology Department, Weizmann Institute of Science, 76100 Rehovot, Israel

    • Christoph A. Thaiss
    • , Shlomik Itav
    • , Mariska T. Meijer
    • , Maayan Levy
    • , Claudia Moresi
    • , Lenka Dohnalová
    • , Sofia Braverman
    • , Shachar Rozin
    • , Mally Dori-Bachash
    • , Hagit Shapiro
    •  & Eran Elinav
  2. Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, 76100 Rehovot, Israel

    • Daphna Rothschild
    •  & Eran Segal
  3. Department of Molecular Cell Biology, Weizmann Institute of Science, 76100 Rehovot, Israel

    • Daphna Rothschild
    •  & Eran Segal
  4. Department of Plant and Environmental Sciences, Weizmann Institute of Science, 76100 Rehovot, Israel

    • Sergey Malitsky
    •  & Asaph Aharoni
  5. Department of Veterinary Resources, Weizmann Institute of Science, 76100 Rehovot, Israel

    • Yael Kuperman
    • , Inbal Biton
    •  & Alon Harmelin
  6. The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot 76100, Israel

    • Arieh Gertler
  7. Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel

    • Zamir Halpern
  8. Digestive Center, Tel Aviv Sourasky Medical Center, 64239 Tel Aviv, Israel

    • Zamir Halpern

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Contributions

C.A.T. conceived and led the project, designed and performed experiments, and wrote the manuscript. S.I. designed and performed experiments, and wrote the manuscript. D.R. developed and performed bioinformatics methods and analysis, and wrote the manuscript. M.M., M.L., C.M., L.D., S.B. and S.R. performed experiments. S.M., M.D.-B., Y.K. and I.B. performed flavonoid measurements, next-generation sequencing, metabolic measurements, and MRI, respectively. A.G. provided essential tools. A.H., H.S., Z.H. and A.A. provided insights and supervised parts of the experimental work. E.S. and E.E. conceived and directed the project, designed experiments, supervised the participants, and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Eran Segal or Eran Elinav.

Reviewer Information

Nature thanks C. Nagler and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature20796

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