Distinct structural features of neutral and acidic flaxseed gum polysaccharides confer complementary anti-hyperuricemic effects via multi-dimensional regulation of urate metabolism.

This study characterized flaxseed gum (FG) and its fractions, neutral (NFG) and acidic (AFG), elucidating their structure-activity relationships in hyperuricemia (HUA) mitigation. Monosaccharide, methylation, and NMR analyses identified NFG as a highly branched (1 → 4)-β-D-xylan, with its O-2/O-3 positions substituted with α-L-arabinofuranosyl, α-d-glucopyranosyl, and α-D-galactopyranosyl residues, while AFG exhibited a rhamnogalacturonan-I architecture comprising a repeating →2)-α-L-Rhap-(1 → 4)-α-D-GalpA-(1→ core. In HUA mice, oral administration of FG significantly decreased serum urate levels, alleviating renal tubular dilation, glomerular atrophy, and systemic inflammation (IL-1β, IL-6, TNF-α). Mechanistically, both fractions shared inhibitory effects on urate reabsorption by downregulating renal URAT1 and GLUT9 transcription. However, their specific regulatory pathways diverged: NFG effectively suppressed hepatic xanthine oxidase activity and upregulated renal OAT1 expression, whereas AFG facilitated urate elimination by specifically enhancing ABCG2 expression in both renal and colonic tissues. 16S rRNA sequencing revealed that NFG enriched Bacteroidetes and Actinomycetota while AFG restored Firmicutes/Bacteroidetes ratios and promoted Roseburia. Their complementary interaction within the total FG fraction uniquely enriched the beneficial genus Akkermansia and enhanced colonic short-chain fatty acid production, particularly butyrate and propionate. Overall, FG and its fractions mitigate HUA via gut-kidney axis modulation, establishing these flaxseed polysaccharides as high-efficiency natural dietary supplements for multi-targeted urate management.