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

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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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.

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Correspondence to Martin J. Blaser.

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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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