The gut-liver axis mediates the hepatoprotective effect of mulberry polysaccharide MBPS-02A

Mulberry leaf is a traditional Chinese herbal medicine with hepatoprotective properties, but the role of its polysaccharides in counteracting drug-induced liver injury (DILI) remains unexplored. Herein, a polysaccharide named MBPS-02A was isolated from mulberry leaves, which featured a backbone of 1,2-α-Rhap, 1,4-α-GalpA, 1,4-α-Galp and 1,6-β-Galp, with branches including 1,4-β-Galp, t-β-Galp, t-β-GlcpA, 1,5-α-Araf, t-α-Araf and t-α-GalpA. MBPS-02A attenuated acetaminophen (APAP)-induced DILI in mice, as evidenced by reduced hepatic inflammatory damage and oxidative stress. Additionally, it strengthened intestinal barrier integrity and reshaped the gut microbiota, promoting Akkermansia proliferation both in vivo and in vitro. Correlation analysis identified the Akkermansia-derived tripeptide glycylprolylarginine (GPR) as a key metabolite strongly associated with DILI amelioration. Cellular experiments confirmed that GPR scavenges hydrogen peroxide and upregulates catalase expression in hepatocytes, thereby protecting liver cells. Collectively, these results suggest MBPS-02A as a promising natural polysaccharide candidate for DILI intervention via the gut-liver axis, and provide mechanistic insights into the hepatoprotective use of mulberry leaves.