The Incidence of Type-1 Diabetes in NOD Mice Is Modulated by Restricted Flora Not Germ-Free Conditions

Cecile King,Nora Sarvetnick,Matthias Von Herrath

doi:10.1371/journal.pone.0017049

Abstract

In the NOD mouse, the incidence of type-1 diabetes is thought to be influenced by the degree of cleanliness of the mouse colony. Studies collectively demonstrate that exposure to bacterial antigen or infection in the neonatal period prevents diabetes [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], supporting the notion that immunostimulation can benefit the maturation of the postnatal immune system [11]. A widely accepted extrapolation from this data has been the notion that NOD mice maintained under germ-free conditions have an increased incidence of diabetes. However, evidence supporting this influential concept is surprisingly limited [12]. In this study, we demonstrate that the incidence of diabetes in female NOD mice remained unchanged under germ-free conditions. By contrast, a spontaneous monoculture with a gram-positive aerobic spore-forming rod delayed the onset and reduced the incidence of diabetes. These findings challenge the view that germ-free NOD mice have increased diabetes incidence and demonstrate that modulation of intestinal microbiota can prevent the development of type-1 diabetes.

Highlights

The development of the postnatal immune system is guided by the interactions of lymphocytes with self-MHC/peptide ligands derived from our body’s own tissues and those from the environment, such as the commensal microbial flora of the gastrointestinal tract and the diet
The incidence of type-1 diabetes in non-obese diabetic (NOD) mice is thought to reflect the degree of cleanliness of the colony
Control female NOD mice were housed under specific pathogen-free (SPF) conditions at Taconic and the Scripps rodent colony, which were handled in accordance with the TSRI Animal Care and Use Committee, which approved this study (A3194-01)

Summary

Introduction

The development of the postnatal immune system is guided by the interactions of lymphocytes with self-MHC/peptide ligands derived from our body’s own tissues and those from the environment, such as the commensal microbial flora of the gastrointestinal tract and the diet. The important role of the gastrointestinal microbiota has been emphasized by the evidence of reduced intestinal lymphatic tissue and underdeveloped lymphoid organs in germ-free mice [13,14,15,16]. Studies on local immune function demonstrate that IgA secreting plasmablasts are reduced in germ free mice [17] and the induction of commensal specific IgA [18] has been shown to occur in response to current bacterial exposure [19].

Results

Conclusion