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

Nature Microbiology volume 1, Article number: 16140 (2016) Cite this article

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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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Figure 1: Effect of PAT/STAT on the development of T1D and insulitis severity in NOD mice.
Figure 2: PAT alters ileal gene expression.
Figure 3: PAT alters metabolic gene expression pathways as well as metabolite composition in caecum, liver and serum.
Figure 4: Microbiota characteristics of control, STAT and PAT NOD mice.
Figure 5: Microbiota perturbation and composition in relation to the development of T1D.
Figure 6: Inoculation of germ-free NOD mice with control or PAT microbiota.

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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.

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Authors and Affiliations

  1. Departments of Medicine and Microbiology, Human Microbiome Program, New York University Langone Medical Center, Medical Service, New York, 10016, New York, 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, 55455, Minneapolis, 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, 10016, New York, USA

    Huilin Li

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

    Arlin B. Rogers

  7. Department of Microbiology, New York University Langone Medical Center, New York, 10016, New York, 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, 55455, Minneapolis, USA

    Dan Knights

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

    Dan Knights

  11. CHIBI, New York University Langone Medical Center, New York, 10016, New York, 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, 10010, New York, USA

    Martin J. Blaser

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  1. Alexandra E. Livanos
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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.

Corresponding author

Correspondence to Martin J. Blaser.

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The authors declare no competing financial interests.

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Livanos, A., Greiner, T., Vangay, P. et al. Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice. Nat Microbiol 1, 16140 (2016). https://doi.org/10.1038/nmicrobiol.2016.140

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