Long-term effects on liver metabolism induced by ceftriaxone sodium pretreatment.

Ceftriaxone is an emerging contaminant due to its potential harm, while its effects on liver are still need to be clarified. In this study, we first pretreated the 8-week-old C57BL/6J mice with high dose ceftriaxone sodium (Cef, 400 mg/mL, 0.2 mL per dose) for 8 days to prepare a gut dysbiosis model, then treated with normal feed for a two-month recovery period, and applied non-targeted metabolomics (including lipidomics) to investigate the variations of fecal and liver metabolome, and coupled with targeted determination of fecal short-chain fatty acids (SCFAs) and bile acids (BAs). Lastly, the correlations and mediation analysis between the liver metabolism and gut metabolism/microbes were carried, and the potential mechanisms of the mal-effects on gut-liver axis induced by Cef pretreatment were accordingly discussed. Compared to the control group, Cef pretreatment reduced the rate of weight gain and hepatosomatic index, induced bile duct epithelial cells proliferated around the central vein and appearance of binucleated hepatocytes, decreased the ratio of total branching chains amino acids (BCAAs) to total aromatic amino acids (AAAs) in liver metabolome. In fecal metabolome, the total fecal SCFAs and BAs did not change significantly while butyric acid decreased and the primary BAs increased after Cef pretreatment. Correlation and mediation analysis revealed one potential mechanism that Cef may first change the intestinal microbiota (such as destroying its normal structure, reducing its abundance and the stability of the microbial network or certain microbe abundance like Alistipes), and then change the intestinal metabolism (such as acetate, caproate, propionate), leading to liver metabolic disorder (such as spermidine, inosine, cinnamaldehyde). This study proved the possibility of Cef-induced liver damage, displayed the overall metabolic profile of the liver following Cef pretreatment and provided a theoretical framework for further research into the mechanism of Cef-induced liver damage.