Regulation of type 1 diabetes development and B-cell activation in nonobese diabetic mice by early life exposure to a diabetogenic environment

Abstract

Microbes, including viruses, influence type 1 diabetes (T1D) development, but many such influences remain undefined. Previous work on underlying immune mechanisms has focussed on cytokines and T cells. Here, we compared two nonobese diabetic (NOD) mouse colonies, NODlow and NODhigh, differing markedly in their cumulative T1D incidence (22% vs. 90% by 30 weeks in females). NODhigh mice harbored more complex intestinal microbiota, including several pathobionts; both colonies harbored segmented filamentous bacteria (SFB), thought to suppress T1D. Young NODhigh females had increased B-cell activation in their mesenteric lymph nodes. These phenotypes were transmissible. Co-housing of NODlow with NODhigh mice after weaning did not change T1D development, but T1D incidence was increased in female offspring of co-housed NODlow mice, which were exposed to the NODhigh environment both before and after weaning. These offspring also acquired microbiota and B-cell activation approaching those of NODhigh mice. In NODlow females, the low rate of T1D was unaffected by cyclophosphamide but increased by PD-L1 blockade. Thus, environmental exposures that are innocuous later in life may promote T1D progression if acquired early during immune development, possibly by altering B-cell activation and/or PD-L1 function. Moreover, T1D suppression in NOD mice by SFB may depend on the presence of other microbial influences. The complexity of microbial immune regulation revealed in this murine model may also be relevant to the environmental regulation of human T1D.

Gut Microbiome in BALB/c and C57BL/6J Mice Undergoing Experimental Thyroid Autoimmunity Associate with Differences in Immunological Responses and Thyroid Function

“…Recent studies in Hashimoto's disease and other autoimmune conditions such as multiple sclerosis and type 1 diabetes are beginning to provide compelling links with gut microbiota in disease pathogenesis [41][42][43][44][45][46]. However, studies on Hashimoto's disease in the human and experimental mouse model provide contrasting results on the role of gut microbiota in disease development [41,47].…”

Influence of maternal microbiota during pregnancy on infant immunity

“…Studies in rodent models of spontaneous type 1 diabetes (T1D) have linked the gut microbiota to disease susceptibility [62,63]. Studies in rodent models of spontaneous type 1 diabetes (T1D) have linked the gut microbiota to disease susceptibility [62,63].…”

“…Apart from allergy and asthma, the prenatal microbiome has also been implicated in other immune disorders, including type 1 diabetes and inflammatory bowel disease. Studies in rodent models of spontaneous type 1 diabetes (T1D) have linked the gut microbiota to disease susceptibility [62,63]. Livanos et al [64] demonstrated that administering a subtherapeutic lowdose penicillin (STAT) to mice during the late pregnancy period and postpartum accelerates the incidence of T1D in male offspring compared to untreated controls; however, whether these effects were mediated in the antepartum period is unclear.…”

Fresh Ideas, Foundational Experiments (FIFE): Immunology and Diabetes 2016 FIFE Symposium

“…Innate sensing can be altered by genetic variation, virus infections, and microbiome dysbiosis; all of which have been implicated in T1D ( 30 , 31 ). Certain differences in both the gut microbial communities and virome have recently been identified to be correlated with T1D development ( 32 , 33 ). For instance, butyrate- and acetate-producing bacteria have been associated with protection from spontaneous T1D in non-obese diabetic (NOD) mouse model of T1D ( 30 ).…”

“…Rather than simply removing cell subsets involved in T1D pathogenesis, the work of Dr. Piganelli exhibits how immune cell factors may be targeted and can potentially be programmed to adopt a more tolerogenic state. Recent literature has shown that environment early on in life is important for incidence of T1D in NOD mice and exposure to a “diabetogenic environment” is sufficient to promote incidence ( 32 ). It was also determined that composition of certain bacterial pathobionts can induce immunophenotypic changes in mice weaned in this “diabetogenic environment” and harbor B cells in gut-related lymphoid organs which are intrinsically more easily activated by local stimulation ( 32 ).…”