Antibiotics in Early Life Alter the Gut Microbiome and Increase Disease Incidence in a Spontaneous Mouse Model of Autoimmune Insulin-Dependent Diabetes

PLoS One. 2015 May 13;10(5):e0125448. doi: 10.1371/journal.pone.0125448. eCollection 2015.

Abstract

Insulin-dependent or type 1 diabetes is a prototypic autoimmune disease whose incidence steadily increased over the past decades in industrialized countries. Recent evidence suggests the importance of the gut microbiota to explain this trend. Here, non-obese diabetic (NOD) mice that spontaneously develop autoimmune type 1 diabetes were treated with different antibiotics to explore the influence of a targeted intestinal dysbiosis in the progression of the disease. A mixture of wide spectrum antibiotics (i.e. streptomycin, colistin and ampicillin) or vancomycin alone were administered orally from the moment of conception, treating breeding pairs, and during the postnatal and adult life until the end of follow-up at 40 weeks. Diabetes incidence significantly and similarly increased in male mice following treatment with these two antibiotic regimens. In NOD females a slight yet not significant trend towards an increase in disease incidence was observed. Changes in gut microbiota composition were assessed by sequencing the V3 region of bacterial 16S rRNA genes. Administration of the antibiotic mixture resulted in near complete ablation of the gut microbiota. Vancomycin treatment led to increased Escherichia, Lactobacillus and Sutterella genera and decreased members of the Clostridiales order and Lachnospiraceae, Prevotellaceae and Rikenellaceae families, as compared to control mice. Massive elimination of IL-17-producing cells, both CD4+TCRαβ+ and TCRγδ+ T cells was observed in the lamina propria of the ileum and the colon of vancomycin-treated mice. These results show that a directed even partial ablation of the gut microbiota, as induced by vancomycin, significantly increases type 1 diabetes incidence in male NOD mice thus prompting for caution in the use of antibiotics in pregnant women and newborns.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / adverse effects*
  • Anti-Bacterial Agents / therapeutic use
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / microbiology*
  • Female
  • Gastrointestinal Microbiome / drug effects*
  • Incidence
  • Lymphocytes / immunology
  • Male
  • Mice, Inbred NOD
  • Mucous Membrane / immunology
  • Spleen / immunology
  • Vancomycin / adverse effects*
  • Vancomycin / therapeutic use

Substances

  • Anti-Bacterial Agents
  • Vancomycin

Grant support

This work was supported by a grant from the European Research Council (ERC, Hygiene N°: 250290). Institutional support was also provided by the Institut National de la Santé et de la Recherche Médicale (INSERM), the Centre National de la Recherche Scientifique (CNRS) and the Faculté Paris Descartes. Additional support was provided by Fondation Day Solvay and by the Juvenile Diabetes Research Foundation (JDRF). The laboratory (INSERM U1151) is also part of the RTRS (Réseau Thématique de Recherche et de Soins) « Centaure » and of the Leducq Network. LC is supported in part by the Institut Universitaire de France. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.