Ginkgolide-A attenuates bacterial translocation through activating PXR and improving antimicrobial peptide Reg 3A in experimental cirrhosis

Abstract

Background and aims: Bacterial translocation (BT) is strongly associated with disease progression and poor outcome in cirrhotic patients. The role of Pregnane X receptor (PXR) in regulating bacterial translocation in cirrhosis is unknown. We previously showed that Ginkgolide-A (GA), a natural PXR ligand, attenuated BT in cirrhotic mice by abrogating inflammation along the gut-liver-axis, and by protecting small intestinal tight junctions (TJ). Here, we aimed to investigate the effect of GA in activating PXR and associated antimicrobial peptides (AMPs) in regulating BT in experimental cirrhosis.

Methods: Male Swiss albino mice were administered CCl₄ (0.5 mL/kg body-weight, i.p twice a week) for 12 consecutive weeks. After the 12th week, mice were randomized and administered with GA (100-mg/kg body-weight, oral) every-day for 2 weeks. At termination, blood, gut and liver tissues were collected for molecular studies.

Results: GA treatment to cirrhotic mice significantly increased the expression of small intestinal PXR and Regenerating family member 3 alpha (Reg3A), which were otherwise reduced in CCl4 cirrhotic mice. Moreover, compared to naive mice a significantly reduced Lactobacillus, and increased Bacteroides and Enterococcus 16s rRNA levels were observed in the small intestine and liver of cirrhotic mice. Treatment with GA to cirrhotic mice significantly reduced intestinal overgrowth and translocation of Enterococcus and Bacteroides to the liver. Furthermore, GA treatment significantly attenuated intestinal permeability and BT marker soluble-CD14 (sCD14), which were increased in CCl₄ cirrhotic mice.

Conclusion: The study showed for the first time that, GA treatment to cirrhotic rodents attenuates BT, by improving PXR and Reg3A expression.

Keywords: Antimicrobial peptides; Bacterial translocation; Cirrhosis; Ginkgolide-A; PXR.