Antibiotic-induced acceleration of type 1 diabetes alters maturation of innate intestinal immunity
- New York University Langone Medical Center, United States
- University of Wisconsin School of Medicine and Public Health, United States
- University of North Carolina at Chapel Hill School of Public Health, United States
- University of Minnesota, United States
- Janssen Pharmaceutical Companies of Johnson and Johnson, United Kingdom
- Tufts University, United States
- New York University, United States
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.
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.
Metrics
-
- 5,372
- views
-
- 811
- downloads
-
- 80
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Antibiotic-induced acceleration of type 1 diabetes alters maturation of innate intestinal immunity
eLife 7:e37816.
https://doi.org/10.7554/eLife.37816
Further reading
-
A dose of antibiotics early in life may increase the risk of type 1 diabetes.
-
- Immunology and Inflammation
Antibodies are powerful tools for the therapy and diagnosis of various diseases. In addition to conventional hybridoma-based screening, recombinant antibody-based screening has become a common choice; however, its application is hampered by two factors: (1) screening starts after Ig gene cloning and recombinant antibody production only, and (2) the antibody is composed of paired chains, heavy and light, commonly expressed by two independent expression vectors. Here, we introduce a method for the rapid screening of recombinant monoclonal antibodies by establishing a Golden Gate-based dual-expression vector and in-vivo expression of membrane-bound antibodies. Using this system, we demonstrate the rapid isolation of influenza cross-reactive antibodies with high affinity from immunized mice within 7 days. This system is particularly useful for isolating therapeutic or diagnostic antibodies, for example during foreseen pandemics.
