Article

Artificial sweeteners induce glucose intolerance by altering the gut microbiota

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Abstract

Non-caloric artificial sweeteners (NAS) are among the most widely used food additives worldwide, regularly consumed by lean and obese individuals alike. NAS consumption is considered safe and beneficial owing to their low caloric content, yet supporting scientific data remain sparse and controversial. Here we demonstrate that consumption of commonly used NAS formulations drives the development of glucose intolerance through induction of compositional and functional alterations to the intestinal microbiota. These NAS-mediated deleterious metabolic effects are abrogated by antibiotic treatment, and are fully transferrable to germ-free mice upon faecal transplantation of microbiota configurations from NAS-consuming mice, or of microbiota anaerobically incubated in the presence of NAS. We identify NAS-altered microbial metabolic pathways that are linked to host susceptibility to metabolic disease, and demonstrate similar NAS-induced dysbiosis and glucose intolerance in healthy human subjects. Collectively, our results link NAS consumption, dysbiosis and metabolic abnormalities, thereby calling for a reassessment of massive NAS usage.

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Accessions

Primary accessions

European Nucleotide Archive

Data deposits

Sequencing data are deposited in the European Nucleotide Archive accession PRJEB6996.

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Acknowledgements

We thank the members of the Elinav and Segal laboratories for discussions. We acknowledge C. Bar-Nathan for germ-free mouse caretaking. We thank the Weizmann Institute management and the Nancy and Stephen Grand Israel National Center for Personalized Medicine (INCPM) for providing financial and infrastructure support. We thank G. Malka, N. Kosower and R. Bikovsky for coordinating the human clinical trials, and M. Pevsner-Fischer, T. Avnit-Sagi and M. Lotan-Pompan for assistance with microbiome sample processing. C.A.T. is the recipient of a Boehringer Ingelheim Fonds PhD Fellowship. G.Z.-S. is supported by the Morris Kahn Fellowships for Systems Biology. This work was supported by grants from the National Institute of Health (NIH) and the European Research Council (ERC) to E.S., and support and grants to E.E. provided by Y. and R. Ungar, the Abisch Frenkel Foundation for the Promotion of Life Sciences, the Gurwin Family Fund for Scientific Research, Leona M. and Harry B. Helmsley Charitable Trust, Crown Endowment Fund for Immunological Research, estate of J. Gitlitz, estate of L. Hershkovich, Rising Tide foundation, Minerva Stiftung foundation, and the European Research Council. E.E. is the incumbent of the Rina Gudinski Career Development Chair.

Author information

Author notes

    • Tal Korem
    • , David Zeevi
    •  & Gili Zilberman-Schapira

    These authors contributed equally to this work.

Affiliations

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

    • Jotham Suez
    • , Gili Zilberman-Schapira
    • , Christoph A. Thaiss
    • , Ori Maza
    • , Hagit Shapiro
    •  & Eran Elinav
  2. Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel

    • Tal Korem
    • , David Zeevi
    • , Adina Weinberger
    •  & Eran Segal
  3. Day Care Unit and the Laboratory of Imaging and Brain Stimulation, Kfar Shaul hospital, Jerusalem Center for Mental Health, Jerusalem 91060, Israel

    • David Israeli
  4. Internal Medicine Department, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel

    • Niv Zmora
  5. Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

    • Niv Zmora
    •  & Zamir Halpern
  6. Digestive Center, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel

    • Niv Zmora
    •  & Zamir Halpern
  7. The Nancy and Stephen Grand Israel National Center for Personalized Medicine (INCPM), Weizmann Institute of Science, Rehovot 76100, Israel

    • Shlomit Gilad
  8. Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel

    • Yael Kuperman
    •  & Alon Harmelin
  9. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel

    • Ilana Kolodkin-Gal

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Contributions

J.S. conceived the project, designed and performed experiments, interpreted the results, and wrote the manuscript. T.K., D.Z. and G.Z.-S. performed the computational and metagenomic microbiota analysis and the analysis of the retrospective and prospective human study, and are listed alphabetically. C.A.T., O.M., A.W. and H.S. helped with experiments. Y.K. helped with the metabolic cage experiments. S.G. designed the metagenomic library protocols and generated the libraries. I.K.-G. performed the SCFA quantification experiments. D.I., N.Z., and Z.H. performed and supervised human experimentation. A.H. supervised the germ-free mouse experiments. E.S. and E.E. conceived and directed the project, designed experiments, interpreted the results, and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Eran Segal or Eran Elinav.

Extended data

Supplementary information

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    Supplementary Information

    This file contains Supplementary Tables 1-7.