Prevention of Virus-Induced Type 1 Diabetes with Antibiotic Therapy

Microbes have been hypothesized to play a key role in the progression of type 1 diabetes (T1D) in humans and animals. We have 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 virus-induced 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. We also demonstrated that infection with KRV induced a transient alteration in gut bacterial communities, as evidenced by an increase in the abundance of Bifidobacterium spp. and Clostridium spp. in fecal samples from rats infected for 5 days, but not 12 days, when compared with uninfected rats. Similar alterations were seen in the jejunum of animals infected for 5 days. Treatment with sulfatrim restored the bacterial levels observed in fecal samples from 5 day-infected rats. Furthermore, viral infection induced the expression of KRV transcripts and the rapid upregulation of innate immune responses in Peyer’s patches. However, antibiotic therapy suppressed the virus-induced inflammation in the pancreatic lymph nodes and Peyer’s patches. Finally, sulfatrim therapy reduced the number of B cells in Peyer’s patches and down-modulated adaptive immune responses to KRV, but did not interfere with anti-viral antibody responses or viral clearance from the spleen and pancreatic lymph nodes. The data suggest that gut microbiota play a key role in promoting virus-induced T1D in the LEW1.WR1 rat model.