Prevention of Virus-Induced Type 1 Diabetes with Antibiotic Therapy

Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO 80045
The Journal of Immunology (Impact Factor: 4.92). 09/2012; 189(8):3805-14. DOI: 10.4049/jimmunol.1201257
Source: PubMed


Microbes were hypothesized to play a key role in the progression of type 1 diabetes (T1D). We used the LEW1.WR1 rat model of Kilham rat virus (KRV)-induced T1D to test the hypothesis that the intestinal microbiota is involved in the mechanism leading to islet destruction. Treating LEW1.WR1 rats with KRV and a combination of trimethoprim and sulfamethoxazole (Sulfatrim) beginning on the day of infection protected the rats from insulitis and T1D. Pyrosequencing of bacterial 16S rRNA and quantitative RT-PCR indicated that KRV infection resulted in a transient increase in the abundance of Bifidobacterium spp. and Clostridium spp. in fecal samples from day 5- but not day 12-infected versus uninfected animals. Similar alterations in the gut microbiome were observed in the jejunum of infected animals on day 5. Treatment with Sulfatrim restored the level of intestinal Bifidobacterium spp. and Clostridium spp. We also observed that virus infection induced the expression of KRV transcripts and the rapid upregulation of innate immune responses in Peyer's patches and pancreatic lymph nodes. However, antibiotic therapy reduced the virus-induced inflammation as reflected by the presence of lower amounts of proinflammatory molecules in both the Peyer's patches and pancreatic lymph nodes. Finally, Sulfatrim treatment reduced the number of B cells in Peyer's patches and downmodulated adaptive immune responses to KRV, but did not interfere with antiviral Ab responses or viral clearance from the spleen, pancreatic lymph nodes, and serum. The data suggest that gut microbiota may be involved in promoting virus-induced T1D in the LEW1.WR1 rat model.

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    • "l populations in the small intestine ( Kriegel et al . , 2011 ) . Despite these intriguing findings , our under - standing of the potentially causal relationship between gut microbes and T1D is limited . At least two studies show that antibiotics protect against diabetes in disease prone animals : sulfatrim attenuates virus - induced T1D in rats ( Hara et al . , 2012 ) and vancomycin treatment attenuates diabetes in NOD mice ( Hansen et al . , 2012 ) . Although neither of these studies examined the role of the gut barrier in facilitating T1D progression , studies have implicated a leaky gut in the pathogenesis of T1D in both patients and animal models ( Sapone et al . , 2006 ; Lee et al . , 2010 ) ."
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    ABSTRACT: Accumulating evidence supports that the intestinal microbiome is involved in Type 1 diabetes (T1D) pathogenesis through the gut-pancreas nexus. Our aim was to determine whether the intestinal microbiota in the non-obese diabetic (NOD) mouse model played a role in T1D through the gut. To examine the effect of the intestinal microbiota on T1D onset, we manipulated gut microbes by: (1) the fecal transplantation between non-obese diabetic (NOD) and resistant (NOR) mice and (2) the oral antibiotic and probiotic treatment of NOD mice. We monitored diabetes onset, quantified CD4+T cells in the Peyer's patches, profiled the microbiome and measured fecal short-chain fatty acids (SCFA). The gut microbiota from NOD mice harbored more pathobionts and fewer beneficial microbes in comparison with NOR mice. Fecal transplantation of NOD microbes induced insulitis in NOR hosts suggesting that the NOD microbiome is diabetogenic. Moreover, antibiotic exposure accelerated diabetes onset in NOD mice accompanied by increased T-helper type 1 (Th1) and reduced Th17 cells in the intestinal lymphoid tissues. The diabetogenic microbiome was characterized by a metagenome altered in several metabolic gene clusters. Furthermore, diabetes susceptibility correlated with reduced fecal SCFAs. In an attempt to correct the diabetogenic microbiome, we administered VLS#3 probiotics to NOD mice but found that VSL#3 colonized the intestine poorly and did not delay diabetes. We conclude that NOD mice harbor gut microbes that induce diabetes and that their diabetogenic microbiome can be amplified early in life through antibiotic exposure. Protective microbes like VSL#3 are insufficient to overcome the effects of a diabetogenic microbiome.The ISME Journal advance online publication, 14 August 2015; doi:10.1038/ismej.2015.114.
    The ISME Journal 08/2015; DOI:10.1038/ismej.2015.114 · 9.30 Impact Factor
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    • "The same study found that MyD88 deletion was associated with lower ratios of Firmicutes over Bacteroidetes, and increased counts of Lactobacilli, Rikenellaceae and Porphyromonadaceae. Another experimental study showed that antibiotic administration prevented insulitis and pancreatic β cell destruction in mice with virus-induced T1D through mechanisms involving reduction of the innate immune response in pancreatic lymph nodes and Peyer's patches [79]. These results support the hypothesis that the innate immune system is related to the development of T1D. "
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    Nutrition Journal 06/2014; 13(1):60. DOI:10.1186/1475-2891-13-60 · 2.60 Impact Factor
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    ABSTRACT: The gut immune system has a key role in the development of autoimmune diabetes, and factors that control the gut immune system are also regulators of beta-cell autoimmunity. Gut microbiota modulate the function of the gut immune system by their effect on the innate immune system, such as the intestinal epithelial cells and dendritic cells, and on the adaptive immune system, in particular intestinal T cells. Due to the immunological link between gut and pancreas, e.g. the shared lymphocyte homing receptors, the immunological changes in the gut are reflected in the pancreas. According to animal studies, changes in gut microbiota alter the development of autoimmune diabetes. This has been demonstrated by antibiotics that induce changes in the gut microbiota. Furthermore, gut-colonizing microbes may modify the incidence of autoimmune diabetes in animal models. Deficient toll-like receptor (TLR) signaling, mediating microbial stimulus in immune cells, prevents autoimmune diabetes, which appears to be dependent on alterations in the intestinal microbiota. Although few studies have been conducted in humans, recent studies suggest that the abundance of Bacteroides and lack of butyrate-producing bacteria in fecal microbiota are associated with beta-cell autoimmunity and type 1 diabetes. It is possible that altered gut microbiota are associated with immunological aberrancies in type 1 diabetes. The changes in gut microbiota could lead to alterations in the gut immune system, such as increased gut permeability, small intestinal inflammation, and impaired tolerance to food antigens, all of which are observed in type 1 diabetes. Poor fitness of gut microbiota could explain why children who develop type 1 diabetes are prone to enterovirus infections, and do not develop tolerance to cow milk antigens. These candidate risk factors of type 1 diabetes may imply an increased risk of type 1 diabetes due to the presence of gut microbiota that do not support health. Despite the complex interaction of microbiota, host, environment, and disease mechanisms, gut microbiota are promising novel targets in the prevention of type 1 diabetes.
    The Review of Diabetic Studies 01/2012; 9(4):251-259. DOI:10.1900/RDS.2012.9.251
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