Elsevier

Journal of Autoimmunity

Volume 53, September 2014, Pages 85-94
Journal of Autoimmunity

Long term effect of gut microbiota transfer on diabetes development

https://doi.org/10.1016/j.jaut.2014.03.005Get rights and content

Highlights

  • Gut microbiota transfer has a long-term effect on diabetes development.

  • Gut microbiota transfer alters the communities within the host gut microbiome.

  • Diabetes resistant B6 mice harbor diabetes promoting gut microbiota.

  • Diabetes protective gut microbiota increase IgA and TGF-β mucosal immune responses in the hosts.

  • This work supports the concept of a probiotic approach for prevention of type 1 diabetes.

Abstract

The composition of the gut microbiome represents a very important environmental factor that influences the development of type 1 diabetes (T1D). We have previously shown that MyD88-deficient non-obese diabetic (MyD88−/−NOD) mice, that were protected from T1D development, had a different composition of gut microbiota compared to wild type NOD mice. The aim of our study was to investigate whether this protection could be transferred. We demonstrate that transfer of gut microbiota from diabetes-protected MyD88-deficient NOD mice, reduced insulitis and significantly delayed the onset of diabetes. Gut bacteria from MyD88-deficient mice, administered over a 3-week period, starting at 4 weeks of age, stably altered the family composition of the gut microbiome, with principally Lachnospiraceae and Clostridiaceae increased and Lactobacillaceae decreased. The transferred mice had a higher concentration of IgA and TGFβ in the lumen that was accompanied by an increase in CD8+CD103+ and CD8αβ T cells in the lamina propria of the large intestine. These data indicate not only that gut bacterial composition can be altered after the neonatal/weaning period, but that the composition of the microbiome affects the mucosal immune system and can delay the development of autoimmune diabetes. This result has important implications for the development of probiotic treatment for T1D.

Introduction

Development of type 1 diabetes (T1D) requires a genetic predisposition that interacts with environmental factors [1]. The exact nature of these environmental factors has not been clearly understood, although infection has long been thought to play a role [2]. Recent evidence suggests that gut bacteria play a role in Non-Obese Diabetic (NOD) mouse and the BioBreeding (BB) rat models of T1D and this role is also true for humans [3].

The incidence of T1D has increased over the last 40 years, in common with allergic diseases [4], [5], [6]. To account for these changes in incidence and prevalence, the “Hygiene hypothesis” or a refinement of this, the “Old Friends hypothesis” has been suggested [5], [7]. This postulates that a reduction in exposure to microorganisms in the environment can lead to a failure of immunoregulation [8], [9], [10]. These “Old Friends” could either be non-pathogenic organisms, as in saprophytic mycobacteria [11] or lactobacilli [12], [13], or parasitic infections, such as with helminths [14], [15], [16] that are more common in developing countries. The idea is that these organisms influence the maturation of dendritic cells, stimulating regulatory T cells and reducing pathogenic effector cells [10]. In addition to the possible effect of increasing tolerance and/or bystander suppression, there may also be other mechanisms of importance.

It is interesting that the BB rat, the main rat model of T1D, was originally derived in germ-free (GF) conditions [17]. It was later reported that the BB rat has an abnormal intestinal barrier [18]. There are numerous studies, in both humans and animal models of human diseases, which strongly support the role of gut microbiota as an important factor in balancing health and disease. Development of inflammatory bowel disease (IBD) is influenced by gut microbiota as most, if not all, of the experimental IBD animal models are disease free if they are housed in GF conditions. There is an increasing public interest in probiotic compounds as an alternative medicine. Probiotics are cultures of beneficial bacteria from the healthy gut microbiota that improve the balance of the intestinal milieu by modifying the gut microbiota and suppressing inflammatory responses caused by the host immune cells in response to harmful microbes in the intestine. Recent studies have shown that oral probiotic administration prevents diabetes development in NOD mice [19]. This suggests that normal commensal microbes and their balance in the gut are extremely important for maintenance of health. In this study, we investigated the effect of gut microbiota transfer on diabetes development in NOD mice and our results suggested that transient gut microbiota transfer at a young age could have long-lasting effects on diabetes development in adulthood in the NOD mouse model of human T1D.

Section snippets

Mice

NOD/LtJ mice purchased from the Jackson Laboratory were used for studying diabetes development. NOD/Caj mice were originally obtained from the Jackson Laboratory (NOD/LtJ) and have been maintained at Yale University for over 25 years. MyD88−/−NOD mice were generated as described previously [20] and have been maintained at Yale University for over 7 years. MyD88−/−B6 mice were kindly provided by Dr. Akira [21] and have been maintained at Yale University for over 10 years. B6g7 breeders were

Transient gut microbiota transfer induces a delay in onset of diabetes and reduced insulitis in NOD mice

Our previous study suggested that gut microbiota play an important role in diabetes development [20] and the dysbiosis of gut microbiota in MyD88−/−NOD mice resulted in complete protection from diabetes development [20]. We hypothesized that gut bacteria from diabetes resistant mice could transfer diabetes protection to otherwise highly susceptible (to diabetes) hosts. To test our hypothesis, we transferred fecal bacteria from diabetes-resistant female MyD88−/−NOD to female NOD/LtJ mice

Discussion

Our studies have shown that the composition of gut bacteria can have a significant effect on development of diabetes in the genetically diabetes-predisposed NOD mouse. The innate immune response, together with mouse genetic background also has an influence on the composition of the gut microbiota. We have shown that mice of different genetic backgrounds, housed in similar environments, and fed with the same food and water have differences in their gut microbiota. This interaction between gut

Author contribution

JP performed the experiments and analyzed the data. SN helped with 16S rRNA gene sequencing and edited the manuscript. JRM and AB analyzed the data and edited the manuscripts. FSW analyzed the data and wrote the manuscript. WL designed the experiments, analyzed the data and wrote the manuscript.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgment

This study was supported by JDRF (5-2010-664), NIH (RC1DK087699 and RO1 DK088181).

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