AUTHOR=Wang Xiaokang , Ye Chunxiao , Xun Tianrong , Mo Liqian , Tong Yong , Ni Wensi , Huang Suping , Liu Bin , Zhan Xia , Yang Xixiao 

TITLE=Bacteroides Fragilis Polysaccharide A Ameliorates Abnormal Voriconazole Metabolism Accompanied With the Inhibition of TLR4/NF-κB Pathway

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.663325

DOI=10.3389/fphar.2021.663325

ISSN=1663-9812

ABSTRACT=<p>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. <italic>Bacteroides fragilis</italic> (<italic>B. fragilis</italic>) is an important component of the human intestinal microbiota. Clinical data have shown that <italic>B. fragilis</italic> abundance is comparatively higher in patients not presenting with adverse drug reactions, and inflammatory cytokine (IL-1β) levels are negatively correlated with <italic>B. fragilis</italic> abundance. <italic>B. fragilis</italic> 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 <italic>in vitro</italic> and <italic>in vivo</italic> 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 <italic>B. fragilis</italic> 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.</p>