Background Liver fibrosis (LF) is a progressive injury that frequently advances to cirrhosis and hepatocellular carcinoma, yet effective intervention strategies remain limited. Alhagi honey polysaccharide (AHPN), a bioactive macromolecule with a molecular weight of 9.35 × 10ł Da primarily composed of mannose (29.384%), glucose (41.804%), and galactose (28.810%), represents a promising candidate for antifibrotic therapy. Methods This study established a carbon tetrachloride (CCl 4 )-induced liver fibrosis mouse model to evaluate AHPN’s intervention effect. Liver injury, collagen deposition, and fibrosis progression were assessed histologically and biochemically. The underlying mechanisms were explored through analysis of the TGF-β1/Smad3 signaling pathway, hepatic stellate cell activation, Nrf2/HO-1 antioxidant pathway, inflammatory cytokine profiles, and fibrosis marker expression. Additionally, 16S rDNA sequencing and metabolomics were employed to investigate AHPN’s regulatory effects on gut microbiota composition and hepatic metabolism. Results AHPN administration significantly attenuated hepatic injury, reduced collagen deposition, and suppressed fibrosis progression by inhibiting TGF-β1/Smad3 signaling and hepatic stellate cell activation, accompanied by restored liver function. Mechanistically, AHPN activated the Nrf2/HO-1 pathway to alleviate oxidative stress, decreased serum levels of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), and downregulated fibrosis-related markers (α-SMA, collagen I, LN, PCIII, IV-C). Notably, 16S rDNA sequencing revealed that AHPN enriched beneficial gut bacteria including Bacteroidaceae , Lactobacillaceae , and Marinifilaceae while restoring intestinal tight junction proteins (Occludin, ZO-1). Metabolomics analysis further demonstrated that AHPN improved hepatic metabolic disorders. Conclusion These findings indicate that AHPN ameliorates CCl 4 -induced liver fibrosis through a multi-targeted mechanism involving suppression of TGF-β1/Smad3 signaling, activation of the Nrf2/HO-1 antioxidant pathway, reduction of inflammatory responses, and crucially, modulation of the gut microbiota-liver metabolism axis. These findings underscore the potential of dietary polysaccharides in modulating the gut microbiota-liver metabolism axis and provide a basis for developing nutritional strategies against liver fibrosis.
Song et al. (Thu,) studied this question.