Polygonatum cyrtonema Polysaccharides-Derived Metabolic Meta Alleviates ALD via a Gut–Liver Axis–Mediated, Bifidobacterium pseudolongum–Driven Suppression of the AA Metabolism–MAPK Signaling Network

Abstract

Polygonatum cyrtonema, a traditional Chinese medicinal and edible herb, possesses potential liver-protecting activities. Its primary active component is fermented polysaccharides (PCP), which exhibit gut microbiota–modulating activity. However, the key metabolites derived from PCP under gut microbiota mediation, along with their hepatoprotective bioactivity and mechanism of action, remain to be elucidated. Our findings demonstrated that microbial fermentation of PCP generated specifically elevated levels of indoleacetic acid, indole-3-carbinol, and β-hydroxybutyrate. The PCP metabolic meta alleviated typical alcohol-related liver disease symptoms and reduced hepatic lipid accumulation. Meanwhile, it restored gut microbiota dysbiosis, specifically elevating the abundance of Bifidobacterium pseudolongum, which was negatively correlated with liver injury indices. Mechanistic studies demonstrated that the PCP metabolic meta reduced intestinal levels of arachidonic acid (AA) metabolites such as 3R-HETE, 12-HEPE, and PGE1 and suppressed hepatic AA metabolism via the gut–liver axis, thereby inhibiting the phosphorylation of JNK and p38 mitogen-activated protein kinase (MAPK), downregulating downstream transcription factors c-Jun and activating transcription factor 2 (ATF2), and attenuating inflammation. B. pseudolongum alone recapitulated these protective effects, inhibiting hepatic AA metabolism and MAPK signaling. Collectively, these findings provide a fresh perspective for investigating the interactions between natural bioactive polysaccharides and the gut microbiota in the context of liver protection.