Abstract
The antifungal agent voriconazole (VRC) exhibits extreme inter-individual and intra-individual variation in terms of its clinical efficacy and toxicity. Inflammation, as reflected by C-reactive protein (CRP) concentrations, significantly affects the metabolic ratio and trough concentrations of voriconazole. Bacteroides fragilis (B. fragilis) is an important component of the human intestinal microbiota. Clinical data have shown that B. fragilis abundance is comparatively higher in patients not presenting with adverse drug reactions, and inflammatory cytokine (IL-1β) levels are negatively correlated with B. fragilis abundance. B. fragilis natural product capsular polysaccharide A (PSA) prevents various inflammatory disorders. We tested the hypothesis that PSA ameliorates abnormal voriconazole metabolism by inhibiting inflammation. Germ-free animals were administered PSA intragastrically for 5 days after lipopolysaccharide (LPS) stimulation. Their blood and liver tissues were collected to measure VRC concentrations. PSA administration dramatically improved the resolution phase of LPS-induced hepatic VRC metabolism and inflammatory factor secretion. It reversed inflammatory lesions and alleviated hepatic pro-inflammatory factor secretion. Both in vitro and in vivo data demonstrate that PSA reversed LPS-induced IL-1β secretion, downregulated the TLR4/NF-κB signaling pathway and upregulated CYP2C19 and P-gp. To the best of our knowledge, this study is the first to show that PSA from the probiotic B. fragilis ameliorates abnormal voriconazole metabolism by inhibiting TLR4-mediated NF-κB transcription and regulating drug metabolizing enzyme and transporter expression. Thus, PSA could serve as a clinical adjunct therapy.