Abstract
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.
Data availability
RNA-Seq data that support the findings of this study have been deposited in ArrayExpress database (www.ebi.ac.uk/arrayexpress) with the accession code E-MTAB-6826 (https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-6826). 16S rRNA data has been deposited in QIITA (https://qiita.ucsd.edu/) with the identifier 11242 (https://qiita.ucsd.edu/study/description/11242). Ileal NanoString data have been deposited in NCBI's Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) and are accessible through GEO Series accession number, GSE101721 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE10172). Shotgun metagenomics data have been deposited in the European Nucleotide Archive (ENA) (https://www.ebi.ac.uk/metagenomics/) under the accession number, PRJEB26585 (http://www.ebi.ac.uk/ena/data/view/PRJEB26585).Metabolomics data have been deposited at the NIH Common Fund Metabolomics Workbench (www.metabolomicsworkbench.org; doi: 10.21228/M8C39R)
Article and author information
Author details
Funding
Janssen Labs London (15-A0-00-00-0039-29-01)
- Martin J Blaser
Fondation Leducq (-33.17CVD01)
- Martin J Blaser
National Institutes of Health (R01DK110014)
- Huilin Li
National Institutes of Health (R37GM059785)
- John M Denu
National Institutes of Health (5T35DK007421)
- Sandy Ng
- Rachel A Sibley
National Institutes of Health (F30DK108494)
- Kimberly A Krautkramer
C & D fund
- Martin J Blaser
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (160623) of the New York University Langone Medical Center.
Reviewing Editor
- Lora V Hooper, University of Texas Southwestern Medical Center, United States
Publication history
- Received: April 24, 2018
- Accepted: July 12, 2018
- Accepted Manuscript published: July 24, 2018 (version 1)
- Accepted Manuscript updated: July 25, 2018 (version 2)
- Version of Record published: August 9, 2018 (version 3)
- Version of Record updated: August 13, 2018 (version 4)
Copyright
© 2018, Zhang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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