AN INTEGRATED MULTI-OMIC APPROACH REVEALS A SHARED SIGNATURE OF IMMUNE ACTIVATION AND METABOLIC COLLAPSE IN ULCERATIVE COLITIS AND RHEUMATOID ARTHRITIS

Abstract BACKGROUND In recent years, extraintestinal manifestations in ulcerative colitis such as joint, skin, and neurologic complications have been recognized however remain poorly understood at the molecular level. Rheumatoid arthritis, a chronic autoimmune arthropathy, frequently coexists with ulcerative colitis and may share underlying inflammatory programs. Leveraging shared transcriptomic signatures across these diseases may illuminate cross-system mechanisms of immune dysfunction and identify novel biomarkers indicative of systemic impact. METHODS We analyzed RNA-sequencing datasets of colonic mucosal biopsies from UC patients and PBMCs from RA patients (GEO datasets GSE87473 and GSE15573). Differentially expressed genes (DEGs) were computed independently and intersected to identify co-upregulated and co-downregulated genes. To prioritize key mediators, we applied the machine learning methods LASSO and Weighted Gene Co-expression Network Analysis (WGCNA). Genes identified by ≥ 2 methods were assigned priority and functional enrichment was conducted via KEGG and Gene Ontology (ShinyGO). RESULTS We identified 4881 co-upregulated and 6987 co-downregulated differentially expressed genes (DEGs) across ulcerative colitis and rheumatoid arthritis . Upregulated DEGs were enriched for key proinflammatory pathways including TNF, IL-17, JAK-STAT, B cell receptor, and C-type lectin receptor signaling, consistent with mucosal immune activation and systemic autoimmunity. Importantly, pathways linked to osteoclast differentiation, focal adhesion, and relaxin signaling suggest shared remodeling programs. Conversely, downregulated DEGs aggregated on suppressed metabolic and neuroendocrine pathways, including TCA cycle, peroxisome, mTOR signaling, and thyroid hormone activity, suggesting systemic energy disruption. Notably, signaling pathways related to cardiac function and neuronal activity (e.g., adrenergic, dopaminergic, and calcium signaling) were also downregulated, supporting a molecular rationale for extra-intestinal manifestations such as arthropathy, fatigue, and neurologic symptoms in UC. CONCLUSION Using integrated machine learning and systems biology approaches, we identified a robust set of cross-disease transcriptomic features linking ulcerative colitis and rheumatoid arthritis. This dual signature of immune activation and metabolic suppression offers mechanistic insight into systemic inflammation and may guide future efforts in biomarker development, risk stratification, and multi-organ therapeutic strategies. The strength of this project lies within the co-analysis of tissue and serum data, allowing us to evaluate the impact of these diseases on a system wide basis.