Structure-activity comparison of native larch arabinogalactan and its arabinose-depleted derivative in D-galactose-induced aging-like mice.

Abstract

Inflammaging is closely associated with gut microbiota dysbiosis, and structurally complex polysaccharides may provide microbiota-directed protection. This study compared the protective effects and gut microbiota-metabolite responses of native larch arabinogalactan (AG) and an acid-hydrolyzed arabinose-depleted derivative (DA) in D-galactose-induced aging-like mice. AG is a highly branched galactose (Gal)- and arabinose (Ara)-rich polysaccharide with a 1,3-linked Galp backbone and Galp/Ara-containing side chains. Acid hydrolysis markedly depleted Ara residues while largely retaining the Gal-rich branched framework, but also altered molecular size and solution-level properties. Both AG and DA alleviated oxidative-inflammatory responses, behavioral and multi-organ aging-like alterations, P53/P21-associated senescence-related responses, and colonic mucus barrier impairment. Direct dose-matched comparisons showed no significant AG-DA differences for most major host endpoints, while dose-response patterns varied across outcomes rather than showing a uniform monotonic trend. Cecal microbiota analyses revealed overlapping but treatment-biased responses, with AG associated with greater Bifidobacterium enrichment and DA with stronger Turicibacter enrichment. Exploratory metabolomic and pathway analyses further suggested partially convergent bile acid/lipid-related responses together with treatment-biased metabolic patterns. These findings suggest that Ara-depletion-associated structural changes are linked to treatment-biased microbiota-metabolite responses, whereas the retained Gal-rich branched framework may contribute to the protective effects observed with both treatments.