Dietary flavonoids target the gut-liver axis for the management of cholestatic liver injury.

Abstract

Cholestatic liver injury (CLI) is a progressive liver disorder characterized by impaired bile acid (BA) synthesis, transport, and excretion. This dysfunction leads to the intrahepatic accumulation of toxic BAs, which in turn triggers hepatic oxidative stress, inflammation, and subsequent fibrogenesis. Through enterohepatic circulation, the gut and liver form an integrated gut-liver axis that regulates BA metabolism. Gut microbiota and nuclear receptor farnesoid X receptor (FXR) are tightly involved in modulating this axis and play a critical role in maintaining BA homeostasis. Disruption of the gut-liver axis under cholestatic conditions contributes to gut dysbiosis, BA imbalance, impaired intestinal barrier integrity, hepatic inflammation, and fibrotic progression. Flavonoids, a major class of polyphenols present in various foods, possess microbial-dependent biotransformation and gut enrichment characteristics. Through coordinated modulation of gut microbiota, BA metabolism, and host signaling pathways, flavonoids display promising protective effects against multiple pathological outcomes associated with CLI. This review summarizes the pathological mechanisms of CLI and the molecular interactions through which dietary flavonoids modulate the gut microbiota-BA-FXR axis. It further discusses the dietary exposure, bioavailability, and translational relevance of flavonoids by comparing human dietary intake and systemic exposure with preclinical doses, while evaluating safety considerations and available clinical trial evidence. These insights provide a framework for evaluating the nutritional relevance of flavonoids and their potential as functional food ingredients for the prevention and management of CLI.