Polysaccharide A-dependent opposing effects of mucosal and systemic exposures to human gut commensalBacteroides fragilisin type 1 diabetes

Bacteroides fragilis (BF), a Gram-negative bacterium, is an integral component of the human colonic commensal microbiota. BF is also the most commonly isolated organism from clinical cases of intra-abdominal abscesses suggesting its potential to induce pro-inflammatory responses, upon accessing the systemic compartment. Hence, we examined the impact of intestinal and systemic exposure to BF on type 1 diabetes (T1D) incidence in non-obese diabetic (NOD) mice. The impact of intestinal exposure to BF under chemically-induced enhanced gut permeability condition, which permits microbial translocation to systemic compartment, in T1D was also examined. While oral administration of pre-diabetic mice with heat-killed (HK) BF caused enhanced immune regulation and significant suppression of autoimmunity resulting in delayed hyperglycemia, mice that received small amounts of HK BF by i.v. injection showed pro-inflammatory immune response and rapid disease progression. Importantly, polysaccharide-A deficient (ΔPSA) BF failed to produce these opposing effects upon oral and systemic deliveries. Further, BF induced modulation of disease progression was observed in WT, but not TLR2-deficient, NOD mice. Interestingly, oral administration of BF under chemically-induced enhanced gut permeability condition resulted in accelerated disease progression and rapid onset of hyperglycemia in NOD mice. Overall, these observations suggest that BF-like gut commensals can cause pro-inflammatory responses upon gaining access to systemic compartment and trigger/accelerate autoimmunity and contribute to T1D in at-risk subjects.