Complex immune disorders such as Type 1 diabetes (T1D) and inflammatory bowel diseases (IBD) have increased dramatically over the past century. These “new age” disorders have risen particularly in populations that have undergone rapid changes in industrialization (Thia et al., 2008; Bager et al., 2012; Molodecky et al., 2012; Ungaro et al., 2014). While a genetic basis for these diseases exist, environmental risk factors play a role in triggering disease in genetically susceptible individuals (Anderson et al., 2011; Noble and Erlich, 2012; J. Z. Liu et al., 2015; Mejía-León and Barca, 2015; Liu and Stappenbeck, 2016). Increasing evidence supports the role of the gut microbiome, including disturbances in microbial communities (dysbiosis) and host-microbe interactions, in the pathogenesis of these diseases. This may be particularly relevant during infancy when critical developmental events in microbial assemblage and immunity are occurring. We utilized the interleukin-10 deficient (IL-10 KO) murine model of IBD under several environmental conditions to understand the role of gut microbiota as modifiers of disease development. We examined this model under three main scenarios: 1) raised germ-free (GF) in the absence of bacteria; 2) conventionally-raised specific-pathogen-free (SPF) in the presence of bacteria; and 3) conventionally-raised in the absence of Helicobacter hepaticus but exposed to antibiotic-induced maternal dysbiosis at birth. Under the 1st and 2nd scenarios, we made the surprising observation that the absence of gut microbiota leads to the manifestation of immune infiltration in the pancreas of GF IL-10 KO mice, which resembles the pathology of T1D. This was absent in SPF IL-10 KO, which instead manifest with spontaneous colitis resembling IBD. Under the 3rd scenario, we discovered that disruptions to microbial communities early in life, via acquisition of an antibiotic-induced maternal dysbiosis at birth, perturbs the immune system and increases the risk for IBD development. Thus, the IL-10 KO model represents two different facets of complex immune disorders, T1D and IBD, in which gut microbiota modify disease pathogenesis.




Downloads Statistics

Download Full History