Cardiovascular-kidney-metabolic syndrome stages and risk of diverse gastrointestinal diseases: a prospective cohort study and integrative proteomic analysis.

[BACKGROUND] The systemic influence of cardiovascular-kidney-metabolic (CKM) syndrome on gastrointestinal (GI) pathologies remains largely unexplored. We evaluated the impact of CKM stages on incident GI diseases and underlying proteomic mechanisms.

[METHODS] We analyzed 354,444 UK Biobank participants (CKM stages 0-4) free of baseline GI diseases. Cox proportional hazards models evaluated incident functional, inflammatory, and malignant GI diseases. High-throughput plasma proteomics (N = 38,031) and mediation modeling explored intermediate pathways.

[RESULTS] Over a median follow-up of 13.2 years, 81,168 GI cases occurred. Advanced CKM stages robustly increased overall GI risk (Stage 4 vs. 0 adjusted HR, 1.91; 95% CI, 1.84-2.00), consistent across sensitivity analyses. CKM stages 1-4 yielded a 27.1% population attributable fraction. Associations were stronger in females and individuals < 60 years, except for higher male susceptibility to colorectal cancer. Mediation modeling identified distinct plasma proteins linking CKM to these risks: immune-inflammatory networks underpinned functional and inflammatory diseases, whereas GI cancers were enriched in pro-proliferative pathways. Crucially, HGF, GDF15, and PLAUR emerged as core shared targets.

[CONCLUSIONS] Advanced CKM stages significantly elevate the risk of diverse GI diseases. Specific circulating proteomic signatures underlie these systemic associations. Integrating cardiometabolic profiling into GI risk stratification holds early preventive potential, requiring external validation before clinical implementation.