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Intergenerational transfer of antibiotic-perturbed microbiota enhances colitis in susceptible mice

Abstract

Antibiotic exposure in children has been associated with the risk of inflammatory bowel disease (IBD). Antibiotic use in children or in their pregnant mother can affect how the intestinal microbiome develops, so we asked whether the transfer of an antibiotic-perturbed microbiota from mothers to their children could affect their risk of developing IBD. Here we demonstrate that germ-free adult pregnant mice inoculated with a gut microbial community shaped by antibiotic exposure transmitted their perturbed microbiota to their offspring with high fidelity. Without any direct or continued exposure to antibiotics, this dysbiotic microbiota in the offspring remained distinct from controls for at least 21 weeks. By using both IL-10-deficient and wild-type mothers, we showed that both inoculum and genotype shape microbiota populations in the offspring. Because IL10−/− mice are genetically susceptible to colitis, we could assess the risk due to maternal transmission of an antibiotic-perturbed microbiota. We found that the IL10−/− offspring that had received the perturbed gut microbiota developed markedly increased colitis. Taken together, our findings indicate that antibiotic exposure shaping the maternal gut microbiota has effects that extend to the offspring, with both ecological and long-term disease consequences.

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Fig. 1: Microbiome transfer to pregnant germ-free mice colonized 23 dams and 112 pups.
Fig. 2: Intergenerational microbiota transfer efficiency and stability over time.
Fig. 3: STAT microbiota in IL10–/– mouse increases colonic inflammation.

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Acknowledgements

The authors thank M. Bower and the National Gnotobiotic Rodent Resource Center, University of North Carolina, Chapel Hill, for supplying mice, the NYUMC Genome Technology Center for help with sequencing (partially supported by a Cancer Center Support grant, P30CA016087, at the Laura and Isaac Perlmutter Cancer Center) and the NYUMC Histology Core for assistance preparing samples for histology. These studies were supported by NIH grants DK090989, OD010995 and DK034987 and the Crohn’s and Colitis Foundation of America, by the Ziff Family, Knapp Family and C&D funds, the Judith & Stewart Colton Center for Autoimmunity, and the Diane Belfer Program for Human Microbial Ecology.

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A.F.S., R.B.S. and M.J.B. designed experiments and interpreted data. A.F.S. performed experiments and participated in analysis of the data. Y.A. and V.E.R. contributed to interpretation of immunological data. Y.A. and M.H. performed protein expression assays. T.B. advised on microbiome analytical methods and performed data analyses. L.B. performed odds ratio calculations and other statistical tests. S.R., T.W. and D.K. contributed to microbiota stability analysis. A.B.R. performed histological analyses. L.M.C. and R.B.S. provided essential reagents and procedural advice. A.F.S. and M.J.B. were responsible for writing the manuscript, which was reviewed and edited by all authors.

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Correspondence to Martin J. Blaser.

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Schulfer, A.F., Battaglia, T., Alvarez, Y. et al. Intergenerational transfer of antibiotic-perturbed microbiota enhances colitis in susceptible mice. Nat Microbiol 3, 234–242 (2018). https://doi.org/10.1038/s41564-017-0075-5

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