Article

Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice

  • Nature Microbiology 1, Article number: 16140 (2016)
  • doi:10.1038/nmicrobiol.2016.140
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Abstract

The early life microbiome plays important roles in host immunological and metabolic development. Because the incidence of type 1 diabetes (T1D) has been increasing substantially in recent decades, we hypothesized that early-life antibiotic use alters gut microbiota, which predisposes to disease. Using non-obese diabetic mice that are genetically susceptible to T1D, we examined the effects of exposure to either continuous low-dose antibiotics or pulsed therapeutic antibiotics (PAT) early in life, mimicking childhood exposures. We found that in mice receiving PAT, T1D incidence was significantly higher, and microbial community composition and structure differed compared with controls. In pre-diabetic male PAT mice, the intestinal lamina propria had lower Th17 and Treg proportions and intestinal SAA expression than in controls, suggesting key roles in transducing the altered microbiota signals. PAT affected microbial lipid metabolism and host cholesterol biosynthetic gene expression. These findings show that early-life antibiotic treatments alter the gut microbiota and its metabolic capacities, intestinal gene expression and T-cell populations, accelerating T1D onset in non-obese diabetic mice.

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Acknowledgements

Research support funding was provided by the Juvenile Diabetes Research Foundation, the Diane Belfer Program for Human Microbial Ecology, the Knapp Family, the Ziff Family and C&D Funds (to M.J.B.), the Howard Hughes Medical Institute and the Defendi Fellowship (to A.E.L.). Sequencing was performed at the NYUMC Genome Technology Center, partially supported by a Cancer Center Support Grant (P30CA016087) at the Laura and Isaac Perlmutter Cancer Center. The authors thank T. Battaglia and P. Meyn for informatic and technical assistance.

Author information

Affiliations

  1. Departments of Medicine and Microbiology, Human Microbiome Program, New York University Langone Medical Center, Medical Service, New York, New York 10016, USA

    • Alexandra E. Livanos
    • , Jennifer Chung
    • , Jiho Sohn
    • , Sara Kim
    • , Zhan Gao
    • , Cecily Barber
    • , Joanne Kim
    • , Sandy Ng
    • , Xue-Song Zhang
    • , Alexander Alekseyenko
    •  & Martin J. Blaser
  2. Department of Molecular and Clinical Medicine, University of Gothenburg, 40530 Gothenburg, Sweden

    • Thomas U. Greiner
    •  & Fredrik Bäckhed
  3. Biomedical Informatics and Computational Biology Program, University of Minnesota, Minneapolis, Minneapolis 55455, USA

    • Pajau Vangay
  4. Systems and Translational Sciences, RTI International, Research Triangle Park, North Carolina 27709, USA

    • Wimal Pathmasiri
    • , Delisha Stewart
    • , Susan McRitchie
    •  & Susan Sumner
  5. Departments of Population Health, New York University Langone Medical Center, New York, New York 10016, USA

    • Huilin Li
  6. Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts 01536, USA

    • Arlin B. Rogers
  7. Department of Microbiology, New York University Langone Medical Center, New York, New York 10016, USA

    • Ken Cadwell
  8. Skirball Institute, New York University Langone Medical Center, New York, New York 10016, USA

    • Ken Cadwell
  9. Computer Science and Engineering, University of Minnesota, Minneapolis, Minneapolis 55455, USA

    • Dan Knights
  10. Biotechnology Institute, University of Minnesota, Saint Paul, Minneapolis 55108, USA

    • Dan Knights
  11. CHIBI, New York University Langone Medical Center, New York, New York 10016, USA

    • Alexander Alekseyenko
  12. Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark

    • Fredrik Bäckhed
  13. New York Harbor Veterans Affairs Medical Center, New York, New York 10010, USA

    • Martin J. Blaser

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Contributions

A.E.L. and M.J.B. conceived and designed the study. A.E.L., T.U.G., P.V., W.P., D.S., J.C., J.S., S.K., Z.G., C.B., J.K., S.N., A.R. and X.-S.Z. acquired the data. A.E.L., S.M., H.L., A.B.R., S.S., X.-S.Z., K.C., D.K., A.A., F.B. and M.J.B. analysed and interpreted the data. A.E.L., T.U.G., S.M., H.L., A.B.R., S.S., X.-S.Z., K.C., D.K., A.A., F.B. and M.J.B. drafted or revised the article. A.E.L., T.U.G., P.V., W.P., D.S., S.M., H.L., J.C., J.S., S.K., Z.G., C.B., J.K., S.N., A.B.R., S.S., X.-S.Z., K.C., D.K., A.A., F.B. and M.J.B. approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Martin J. Blaser.

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    Supplementary information

    Supplementary References, Supplementary Figures 1–9, Supplementary Tables 1–7.