Inhibition of Type 1 Diabetes Correlated to a Lactobacillus johnsonii N6.2-Mediated Th17 Bias

Abstract

Although it is known that resident gut flora contribute to immune system function and homeostasis, their role in the progression of the autoimmune disease type 1 diabetes (T1D) is poorly understood. Comparison of stool samples isolated from Bio-Breeding rats, a classic model of T1D, shows that distinct bacterial populations reside in spontaneous Bio-Breeding diabetes-prone (BBDP) and Bio-Breeding diabetes-resistant animals. We have previously shown that the oral transfer of Lactobacillus johnsonii strain N6.2 (LjN6.2) from Bio-Breeding diabetes-resistant to BBDP rodents conferred T1D resistance to BBDP rodents, whereas Lactobacillus reuteri strain TD1 did not. In this study, we show that diabetes resistance in LjN6.2-fed BBDP rodents was correlated to a Th17 cell bias within the mesenteric lymph nodes. The Th17 bias was not observed in the non-gut–draining axillary lymph nodes, suggesting that the Th17 bias was because of immune system interactions with LjN6.2 within the mesenteric lymph node. LjN6.2 interactions with the immune system were observed in the spleens of diabetes-resistant, LjN6.2-fed BBDP rats, as they also possessed a Th17 bias in comparison with control or Lactobacillus reuteri strain TD1–fed rats. Using C57BL/6 mouse in vitro assays, we show that LjN6.2 directly mediated enhanced Th17 differentiation of lymphocytes in the presence of TCR stimulation, which required APCs. Finally, we show that footpad vaccination of NOD mice with LjN6.2-pulsed dendritic cells was sufficient to mediate a Th17 bias in vivo. Together, these data suggest an interesting paradigm whereby T1D induction can be circumvented by gut flora-mediated Th17 differentiation.

Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice

“…Some investigators have argued for a critical role, in particular in later, effector processes (36)(37)(38), although others have cautioned about possible misinterpretations of findings from Th17 transfer experiments because of the conversion to or expansion of Th1 cells (39,40). In clear contradiction, IL-17-producing cells were found either to inhibit diabetes in NOD mice, as well as in BioBreeding rats, in several experimental contexts (41)(42)(43) or to have no effect (44). These divergent conclusions likely reflect multiple complexities: that different Th subsets may play variable roles according to the particular disease stage; that multiple cell types can produce IL-17; and that Th17 cells produce cytokines other than IL-17.…”

Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice

“…Here we found that NOD mice harbor different microbiota than resistant NOR mice, as characterized by specific microbes in the colon and ileum. The ileum microbiota of NOD mice was characterized by fewer SFB and Lactobacillus spp., both previously found to protect against T1D (Valladares et al, 2010;Kriegel et al, 2011;Lau et al, 2011). In the colon, there were no B. acidifaciens detected in NOD mice and fewer R. gnavus.…”

Up-regulation of small intestinal interleukin-17 immunity in untreated coeliac disease but not in potential coeliac disease or in type 1 diabetes

“…In a murine model of autoimmune diabetes, the induction of IL-17 immunity contributed to the progression of autoimmune diabetes during the effector phase of the disease [29] and IL-17 also induced apoptotic mechanisms in human islet cells [21]. Conversely, a recent study showed that a commensal bacteria strain which mediated protection from autoimmune diabetes in a rodent model caused induction of mucosal IL-17 immunity [30]. Our results suggest that the up-regulation of intestinal IL-17 immunity is related to the mechanisms of protection from tissue damage in the inflamed mucosa, as also suggested by others [31], and could thus explain the beneficial effects of mucosal IL-17 up-regulation in autoimmune diabetes.…”