We investigated the influence of spontaneous gut leakage upon polymicrobial sepsis
in a lupus model with Fc gamma receptor IIb-deficient (FcGRIIb-/-) mice aged 8 and
40 weeks, as representing asymptomatic and symptomatic lupus, respectively. Spontaneous
gut leakage, determined by (i) the presence of FITC-dextran, (ii) elevated serum endotoxin,
and (iii) elevated serum (1→3)-β-D-glucan (BG), was demonstrated in symptomatic lupus
but not in the asymptomatic group. In parallel, spontaneous gut leakage, detected
by elevated serum BG without fungal infection, was demonstrated in patients with active
lupus nephritis. Gut leakage induced by dextran sulfate solution (DSS) or endotoxin
administration together with BG or endotoxin alone, but not BG alone, enhanced the
severity of cecal ligation and puncture (CLP) sepsis more prominently in 8-week-old
FcGRIIb-/- mice. Additionally, the bone marrow-derived macrophages of FcGRIIb-/- mice
produced higher cytokine levels when coexposed to endotoxin and BG, when compared
to wild-type mice. In summary, spontaneous gut leakage was demonstrated in symptomatic
FcGRIIb-/- mice and the induction of gut permeability worsened sepsis severity. Gut
translocation of endotoxin and BG had a minor effect on wild-type mice, but the synergistic
effect of BG and endotoxin was prominent in FcGRIIb-/- mice. The data suggest that
therapeutic strategies addressing gut leakage may be of interest in sepsis conditions
in patients with lupus.