The early-life intestinal microbiota plays a key role in shaping host immune system development. We found that a single early-life antibiotic course (1PAT) accelerated type 1 diabetes (T1D) development in male NOD mice. The single course had deep and persistent effects on the intestinal microbiome, leading to altered cecal, hepatic, and serum metabolites. The exposure elicited sex-specific effects on chromatin states in the ileum and liver and perturbed ileal gene expression, altering normal maturational patterns. The global signature changes included specific genes controlling both innate and adaptive immunity. Microbiome analysis revealed four taxa each that potentially protect against or accelerate T1D onset, that were linked in a network model to specific differences in ileal gene expression. This simplified animal model reveals multiple potential pathways to understand pathogenesis by which early-life gut microbiome perturbations alter a global suite of intestinal responses, contributing to the accelerated and enhanced T1D development.
Bibliographical noteFunding Information:
For assistance with these studies, we thank Savannah Costa, Yunzhu Li, Menghan Liu, Xuhui Zheng, James Zhou, Chad Trent, Matthew Farkouh, and Zhan Gao of New York University Medical Center, Shijia Zhu and Gang Fang of Mount Sinai Medical Center, NYU Langone Health Genome Technology Center, and NYU Metabolomics Core Resource Laboratory. These studies were supported by Jans-sen Labs London (15-A0-00-00-0039-29-01), NIH Grants [5T35DK007421, R37GM059785, F30 DK108494, T32GM008692, R01DK110014], −33.17CVD01 (TransAtlantic Networks of Excellence Program) from the Fondation Leducq, and the C and D fund.
© Zhang et al.