Ceftiofur induced intestinal flora disorder exacerbates liver toxicity via microbiota-gut-liver axis

As a common antibiotic, ceftiofur was widely used in animal husbandry. It is estimated that the consumption of ceftiofur (CEF) in animal production will continue to increase due to the role of promoting growth. Accumulating evidences showed that excessive supplementation of ceftiofur in feed disrupted the intestinal flora. However, the mechanism of liver injury caused by excessive supplementation of ceftiofur induced intestinal flora disturbance remains unclear. In this study, our finding indicated that excessive ceftiofur uptake significantly disrupted intestinal flora, which lead to serious liver injury through the gut-liver axis. Our results showed that CEF exposure causes significantly decreased the expression of jejunum tight junction proteins (ZO-1, Claudin, and Occludin); and reduced the number of intestinal goblet cells. In addition, excessive CEF uptake significantly promoted the expression of inflammatory-related proteins in jejunum. Meanwhile, 16s rDNA analysis found that CEF exposure disrupted the abundance of Lactobacillus, HT002, Escherichia-Shigella, Klebaiella, Enterococcus, and Citrobacter, thereby affecting metal iron binding, molecular function, and mitochondrial function in the liver. Furthermore, CEF exposure caused ferroptosis in hepatocytes, as shown by increased the expression of TFR1, FACL4, FLC, COX2, HMGB1, and TXNIP protein, and reduced the expression of GPX4, XCT, and Ferritin protein. These results suggest that the significant adverse impacts of excessive CEF supplementation on gut-liver axis in mice may increase the long-term risks related to liver diseases. [Display omitted] •Excessive ceftiofur aggravated the intestinal barrier impairment and jejunum inflammation.•Ceftiofur exposure induced the disorder of intestinal flora.•Imbalance of intestinal flora can cause hepatocytes ferroptosis via gut-liver axis.