The alleviating mechanism of Lycium barbarum polysaccharide on rheumatoid arthritis mediated by Romboutsia lituseburensis

Our previous studies have shown that Lycium barbarum polysaccharide (LBP) alleviates rheumatoid arthritis (RA) symptoms in gut microbiota-dependent manner, with the key bacterium and the underlying mechanism remain unidentified. In this study, LBP was fermented in vitro by Romboutsia lituseburensis , Lactobacillus johnsonii , or a combination of both strains, and were administered to pseudo-germ-free RA rats. Only R. lituseburensis- fermented LBP significantly alleviated RA and markedly enriched osteoclast differentiation pathway-related genes. Twenty-six metabolites produced by R. lituseburensis , including glutamic acid-proline-glutamine (EPQ), that reduced inflammation and inhibited osteoclast differentiation by downregulating Rankl expression and its downstream factors. Notably, EPQ was also proposed to bind RANKL and potentially interfere with the RANKL/RANK pathway, thereby suppressing the expression of osteoclastogenesis-related genes. These findings identify R. lituseburensis as the key bacterium mediating the anti-RA effects of LBP, with its fermentation products, particularly EPQ, serving as critical active substances that inhibit inflammation and modulate osteoclast differentiation via the RANKL-RANK signaling.