Liver injury is a clinical disorder caused by toxins, drugs, and alcohol stimulation without effective therapeutic approaches thus far. Scutellarin (SCU), isolated from the edible herb Erigeron breviscapus (Vant.) Hand. -Mazz. showed potential hepatoprotective effects, but the mechanisms remain unknown. In this study, transcriptomics combined with nontargeted metabolomics and 16S rRNA amplicon sequencing were performed to elucidate the functional mechanisms of SCU in carbon tetrachloride (CCl₄)–induced liver injury in mice. The results showed that SCU exerted potential hepatoprotective effects against CCl₄-induced liver injury by repressing CYP2E1 and IκBα/NF-κB signaling pathways, modulating the gut microbiota (especially enriching Lactobacillus), and regulating the endogenous metabolites involved in lipid metabolism and bile acid homeostasis. SCU originates from a functional food that appears to be a promising agent to guard against liver injury.

Scutellarein (SCU) is an herbal flavonoid, showing hepatoprotective potentials. The study was aimed to investigate whether the hepatoprotective effect of SCU is dependent on the integrity of gut microbiota. Mice received repeated intraperitoneal injections of CCl₄, followed with or without SCU treatment (15, 30, and 60 mg/kg). Gut microbial community of mice was disrupted by administrating a cocktail of antibiotics (ampicillin, neomycin sulfate, metronidazole, and vancomycin) in drinking water. The results showed SCU plus antibiotics aggravated CCl₄‐induced chronic liver injury, as demonstrated by liver function analysis, histological analysis, and TUNEL assay. SCU activated CYP2E1 expression and worsened CYP2E1‐mediated lipid peroxidation and oxidative stress as coadministered with antibiotics. Moreover, when gut microbiota was disrupted by antibiotics, SCU activated IκBα/NF‐κB pathway and promoted the release of subsequent proinflammatory cytokines including interleukin‐6 (IL‐6), interleukin‐1β (IL‐1β), and tumor necrosis factor‐α (TNF‐α). Remarkably, the 16 S rRNA sequencing demonstrated that SCU greatly decreased the relative abundance of Bifidobacterium and Lactobacillus and increased the relative abundance of Enterococcus in gut microbiota‐dysbiosis mice. Spearman correlation analysis showed that Lactobacillus was positively correlated with SOD and negatively correlated with AST. Collectively, the hepatoprotective effect of SCU is reversed under antibiotics intervention, which may partly involve the activation of CYP2E1 and IκBα/NF‐κB pathway and diminishment of Lactobacillus.

1. Breviscapine was an active ingredient of flavonoid glycosides. Our present study was conducted to evaluate the impact of breviscapine on the pharmacokinetics of losartan and its active metabolite E-3174, and that relationship with the gene polymorphism of CYP2C9 in healthy Chinese volunteers, to provide a basis for clinical rational drug use. 2. The genotypes of 217 healthy Chinese subjects were determined using PCR-RFLP. Twelve healthy subjects were selected and were known CYP2C9 genotypes (six CYP2C9*1/*3 and six CYP2C9*1/*1) in a two-phase randomised crossover design study. These subjects were given daily doses of 120 mg (40 mg, three times a day) of breviscapine or a placebo for 14 days, followed by 50 mg losartan on day 15. 3. Compared with individuals carrying the CYP2C9*1/*1 genotype, the CYP2C9*1/*3 genotype showed an increase in the AUC_(0–36) (833.6 ± 379.8 ng h ml⁻¹ vs. 526.1 ± 140.1 ng h ml⁻¹, p < 0.05) and a decrease in the MR (the metabolic ratio of losartan, AUC_E-3174/AUC_losartan) (2.67 ± 1.40 vs. 4.56 ± 0.83, p < 0.05) of losartan during the placebo treatment phase. Individuals with genotype CYP2C9*1/*3 showed a significant increase in AUC_(0–36) (2335 ± 851.8 ng h ml⁻¹ vs. 1927 ± 949.5 ng h ml⁻¹, p < 0.05) and AUC_(0–∞) (2363 ± 875.6 ng h ml⁻¹ vs. 1966 ± 966.1 ng h ml⁻¹, p < 0.05) of E-3174 after breviscapine treatment compared to the placebo group. 4. In healthy subjects, breviscapine had no significant effect on the pharmacokinetics of losartan. The activity of CYP2C9 enzyme to losartan metabolism was more significant in subjects with CYP2C9*1/*3 than those with CYP2C9*1/*1 genotype.