Achyranthes bidentata polysaccharides alleviates rheumatoid arthritis via the gut microbiota-barrier-metabolite axis in vitro and in vivo.

The mechanisms by which Achyranthes bidentata polysaccharides (ABPs) ameliorate rheumatoid arthritis (RA) via the gut-joint axis remain poorly understood. By combining in vitro digestion-fermentation models with a collagen-induced arthritis (CIA) murine model, this study dissected ABPs' therapeutic pathways through gut microbiota-barrier-metabolite network. Structurally, ABPs resisted simulated digestion, with molecular weight slightly decreasing from 2026 Da to 1989 Da, and were efficiently metabolized by RA-derived gut microbiota during in vitro fermentation. This resulted in microbial remodeling, marked by a significant expansion of short-chain fatty acid (SCFAs)-producing Bacteroides and suppression of pro-inflammatory Fusobacterium, leading to an increase in total SCFAs from 120 mmol/L to 151 mmol/L. In CIA mice, ABPs intervention reduced arthritis indices, improved trabecular bone volume, and restored joint receptor activator of nuclear factor kappa-B ligand/osteoprotegerin (RANKL/OPG) balance. Concurrently, ABPs repaired intestinal barrier integrity by 2.8-fold upregulation of tight junction proteins Zonula Occludens-1, Occludin, activated the kynurenine pathway of tryptophan metabolism and the 12/15-hydroxy-eicosatetraenoic acid (12/15-HETE) pathway of arachidonic acid metabolism, and downregulated serum pro-inflammatory cytokines tumor necrosis factor-αpha reduced by 37.1 %, Interleukin-6 by 42.3 %. This suppressed systemic inflammation through microbiota-SCFAs-metabolite interactions. Thus, ABPs ameliorate RA by remodeling the gut microbiota-SCFAs-metabolite axis. They enhance SCFA-producing bacteria, repair the intestinal barrier, suppress inflammation via kynurenine/12/15-HETE activation, and rebalance joint RANKL/OPG. This provides a paradigm for targeting the gut-joint axis in phytotherapy.