tauromuricholate and Chemical-and-Drug-Induced-Liver-Injury

The link between antibiotic treatment and IF-associated liver disease (IFALD) is unclear. Here, we study the effect of antibiotic treatment on bile acid (BA) metabolism and investigate the involved mechanisms. The results showed that pediatric IF patients with cholestasis had a significantly lower abundance of BA-biotransforming bacteria than patients without cholestasis. In addition, the BA composition was altered in the serum, feces, and liver of pediatric IF patients with cholestasis, as reflected by the increased proportion of primary BAs. In the ileum, farnesoid X receptor (FXR) expression was reduced in patients with cholestasis. Correspondingly, the serum FGF19 levels decreased significantly in patients with cholestasis. In the liver, the expression of the rate-limiting enzyme in bile salt synthesis, cytochrome P450 7a1 (CYP7A1), increased noticeably in IF patients with cholestasis. In mice, we showed that oral antibiotics (gentamicin, GM or vancomycin, VCM) reduced colonic microbial diversity, with a decrease in both Gram-negative bacteria (GM affected Eubacterium and Bacteroides) and Gram-positive bacteria (VCM affected Clostridium, Bifidobacterium and Lactobacillus). Concomitantly, treatment with GM or VCM decreased secondary BAs in the colonic contents, with a simultaneous increase in primary BAs in plasma. Moreover, the changes in the colonic BA profile especially that of tauro-beta-muricholic acid (TβMCA), were predominantly associated with the inhibition of the FXR and further altered BA synthesis and transport. In conclusion, the administration of antibiotics significantly decreased the intestinal microbiota diversity and subsequently altered the BA composition. The alterations in BA composition contributed to cholestasis in IF patients by regulating FXR signaling.

Topics: Animals; Bacterial Proteins; Bacteroides; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cholestasis; Cytochrome P-450 Enzyme System; Eubacterium; Female; Fibroblast Growth Factors; Gastrointestinal Microbiome; Gentamicins; Gram-Positive Bacteria; Humans; Infant; Intestines; Liver; Male; Mice; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Taurocholic Acid; Vancomycin

Polygoni Multiflori Radix (PMR) has been widely used as a tonic for centuries. However, hepatotoxicity cases linked to PMR have been frequently reported and appropriate biomarkers for clinical diagnosis are currently lacking. Here, an approach using UPLC-QqQ/MS-based targeted metabolomics of bile acids (BAs) complemented with biochemistry and histopathology was applied to characterize the development and recovery processes of PMR-induced hepatotoxicity in rats and to identify biomarkers. The expression of bile salt export pump (Bsep) and sodium taurocholate cotransporting polypeptide (Ntcp) were evaluated to investigate the underlying mechanism. Steatosis and inflammatory cell infiltration were observed in PMR-treated rats, which were accompanied by the elevation of serum biochemistry. The metabolic profiles of BAs were analyzed by Principal Component Analysis, hyodeoxycholic acid (HDCA) in serum and tauro-β-muricholic acid (TβMCA) in urine were identified as potential biomarkers for PMR-induced hepatotoxicity. The elevated expression of Bsep and decreased expression of Ntcp in the liver of PMRtreated rats indicated that hepatotoxicity was related to the disorders of BAs metabolism. Our study demonstrated that BAs may be used for clinical diagnosis of PMR-induced hepatotoxicity. Urine TβMCA was identified as a promising biomarker to facilitate the clinical monitoring of PMR-induced hepatotoxicity and may serve as potential therapeutic target.

Topics: Animals; Bile Acids and Salts; Biomarkers; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Fallopia multiflora; Male; Metabolomics; Rats; Rats, Sprague-Dawley; Taurocholic Acid