Lipid metabolism dysregulation in rheumatoid arthritis: from multi-omics discovery to adjunctive therapy with conjugated linoleic acid

This study aims to comprehensively analyze the role of metabolic signatures in rheumatoid arthritis (RA). A total of 599 samples, including fecal (n = 206), plasma (n = 206), and peripheral blood mononuclear cell (PBMC) samples (n = 187), were collected from 443 individuals with RA, systemic lupus erythematosus, and controls. Fecal, plasma and PBMC samples were subjected to 16S rRNA sequencing, liquid chromatography-tandem mass spectrometry, RNA sequencing and 4D DIA proteomics, respectively. A collagen-induced arthritis mouse model was used to investigate the role of the metabolite conjugated linoleic acid (CLA) in experimental arthritis. An RA clinical cohort (n = 26) was recruited to validate the potential role of CLA as an adjunct to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) therapy. Multi-omics analysis revealed comprehensive alterations in metabolic signatures (metabolism-related molecules, metabolites, and metabolic pathways) in RA. Lipid metabolism pathways, particularly linoleic acid metabolism, appear to play a significant regulatory role in RA progression. Metabolites and molecules involved in linoleic acid metabolism were significantly associated with clinical phenotypes in RA patients. In animal experiments, CLA reduced arthritis scores, swollen joint counts, histopathological scores, and inflammatory levels. Finally, CLA supplementation accelerated the reduction of inflammatory levels in RA patients receiving csDMARDs therapy. These findings reveal lipid metabolism as a druggable axis, position dietary CLA as an adjunct to improve outcomes in RA, and offer a new avenue to enhance remission rates.