Probiotic Lactobacillus casei improves immune microenvironment in rheumatoid arthritis via gut microbiota-butyrate-HDAC/NF-κB signaling

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent synovial inflammation, progressive joint destruction, and functional disability. Emerging evidence indicates that gut microbiota dysbiosis and host protein glycosylation play essential roles in regulating immune signaling during RA progression. In this study, we demonstrate that the probiotic strain Lactobacillus casei (abbreviated as L. casei) modulates gut microbial composition and enhances butyrate production, consequently impacting HDAC/NF-κB signaling and O-GlcNAc glycosylation. The administration of L. casei significantly alleviated arthritis symptoms and synovial damage, reduced serum inflammatory cytokine levels, restructured the gut microbiota structure, and enhanced butyrate production. Moreover, L. casei markedly increased O-GlcNAcylation of key immune signaling proteins, such as STAB1, by downregulating O-GlcNAcase (OGA) activity. Importantly, L. casei also modulated histone deacetylase (HDAC) expression and inhibited NF-κB pathway activation, synergistically contributing to glycosylation-mediated anti-inflammatory effects. This study provides evidence that L. casei alleviates synovial inflammation and contributes to immune homeostasis in rheumatoid arthritis by collectively improving the joint immune microenvironment and mitigating inflammatory responses.