Polysaccharide A-dependent opposing effects of mucosal and systemic exposures to human gut commensal Bacteroides fragilis in type 1 diabetes

Bacteroides fragilis (BF) 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 mucosal and systemic exposures 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, in T1D was also examined. While oral administration of pre-diabetic mice with heat-killed (HK) BF caused enhanced immune regulation and suppression of autoimmunity resulting in delayed hyperglycemia, mice that received HK BF by i.v. injection showed 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 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 contribute to T1D in at-risk subjects. * TID : Type 1 Diabetes NOD : non-obese diabetic TLR : Toll-like receptor PSA : polysaccharide A BF : Bacteroides fragilis ΔPSA : PSA deficient HK : heat-killed MLN : mesenteric lymph node PnLN : pancreatic lymph node SiLP : small intestinal lamina propria LiLP : large intestinal lamina propria PP : Peyer’s patch DSS : Dextran sulfate sodium