Integrated Multi‐Omics Analysis of Polygonatum odoratum Polysaccharide in D‐Galactose‐Treated Mice Reveals Changes in Oxidative Stress Markers and Gut Microbiota

ABSTRACT Age‐related changes are associated with oxidative stress, metabolic dysregulation, and alterations in the gut microbiota. Although Polygonatum odoratum polysaccharide (POP) has shown antioxidant and neuroprotective effects, its associations with gut bacterial composition, circulating metabolites, and tissue gene expression remain unclear. Using a D‐galactose‐treated mouse model, we assessed hippocampal histology and oxidative stress markers and performed bacterial 16S rRNA sequencing, untargeted serum metabolomics, and hippocampal and colonic transcriptomic analyses. POP treatment was associated with improved hippocampal histology, reduced malondialdehyde levels, and increased glutathione levels and superoxide dismutase activity. It was also associated with changes in selected gut bacterial taxa and serum lipid metabolites, lower expression of NF‐κB‐related genes ( Btk , Lat , and Tnfrsf13c ) in the colon, and lower Ninj2 expression in the hippocampus. Cross‐omics analysis identified correlations among these bacterial, metabolite, and gene‐expression features. These findings identify candidate gut–serum–tissue associations accompanying the effects of POP in D‐galactose‐treated mice. Functional studies are needed to determine whether any of these changes mediate its effects.