Comprehensive multi-omics analysis reveals the core role of glycerophospholipid metabolism in rheumatoid arthritis development.

ABSTRACT

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic autoimmune disease with complex causes and recurrent attacks that can easily develop into chronic arthritis and eventually lead to joint deformity. Our study aims to elucidate potential mechanism among control, new-onset RA (NORA) and chronic RA (CRA) with multi-omics analysis. METHODS: A total of 113 RA patients and 75 controls were included in our study. Plasma and stool samples were obtained for 16S rRNA sequencing, internally transcribed spacer (ITS) sequencing and metabolomics analysis. And PBMCs were obtained for RNA sequencing. We used three models, logistic regression, least absolute shrinkage and selection operator (LASSO), and random forest, respectively, to distinguish NORA from CRA, and finally we validated model performance using an external cohort of 26 subjects. RESULTS: Our results demonstrated intestinal flora disturbance in RA development, with significantly increased abundance of Escherichia-Shigella and Proteobacteria in NORA. We also found that the diversity was significantly reduced in CRA compared to NORA through fungi analysis. Moreover, we identified 29 differential metabolites between NORA and CRA. Pathway enrichment analysis revealed significant dysregulation of glycerophospholipid metabolism and phenylalanine metabolism pathways in RA patients. Next, we identified 40 differentially expressed genes between NORA and CRA, which acetylcholinesterase (ACHE) was the core gene and significantly enriched in glycerophospholipid metabolism pathway. Correlation analysis showed a strong negatively correlation between glycerophosphocholine and inflammatory characteristics. Additionally, we applied three approaches to develop disease classifier models that were based on plasma metabolites and gut microbiota, which effectively distinguished between new-onset and chronic RA patients in both discovery cohort and external validation cohort. CONCLUSIONS: These findings revealed that glycerophospholipid metabolism plays a crucial role in the development and progression of RA, providing new ideas for early clinical diagnosis and optimizing treatment strategies.