Figure 5

Model mechanism for how a contemporary microbiota influences the age-dependent decline in T1D susceptibility. An elevated innate inflammatory state, that includes hyper-responsiveness to TLR stimulation, is associated T1D susceptibility in human T1D families and diabetic rat models. In human T1D families, this state is independent of the HLA, presence of anti-islet antibodies, and progression of diabetes. In BioBreeding DR rats, this state is independent of insulitis, and disease progression, but is associated with the ability of Kilham’s rat virus to trigger disease progression³⁵. This inflammatory state may be the consequence of genetics, diet, and intestinal microbiome. We hypothesize that this heightened inflammatory state represents a ‘‘fertile field’’ where inflammatory excursions mediated through viral infection lead to the breaking of immunologic tolerance and the progression of autoimmunity in susceptible hosts⁸⁶. This underlying inflammatory state is subsequently supplanted by induction of an immunoregulatory state over time. As these endogenous regulatory processes become more robust, the immune balance makes environmental triggering of T1D progression less likely^33,35. We further hypothesize modern lifestyles foster the growth of a suboptimal gut microbiota, promoting intestinal barrier leakage, increased microbial antigen exposure and systemic inflammation, while impairing induction of robust counter-regulatory mechanisms.