Integrative multi-omics analysis of bile acid metabolism as a prognostic determinant in colorectal cancer

Metabolic reprogramming is a hallmark of colorectal cancer (CRC), yet the prognostic role of the bile acid metabolism pathway, regulated by host genetics and gut microbiota, remains poorly understood. We utilized an integrative multi-omics framework, combining bulk transcriptomics, single-cell, and spatial transcriptomics with microbiome data, to systematically dissect the prognostic significance of this pathway. The analysis was validated by experimental qRT-PCR on paired patient tumor and normal tissues. The pathway exhibited widespread transcriptional suppression in CRC tumors, a finding confirmed by the development of a 15-gene prognostic signature that demonstrated consistent prognostic association with overall survival across five independent cohorts. Single-cell analysis demonstrated that bile acid activity is suppressed across epithelial tumor subsets. Crucially, spatial transcriptomics provided cellular context, revealing that the pathway’s activity is distinctly enriched in metastatic stromal and CMS3 tumor microenvironment (TME) niches. Furthermore, the pathway’s activity was significantly correlated with gut microbiota composition, identifying key associated taxa ( Clostridiales positive, Dorea longicatena negative). Collectively, these integrated findings suggest that suppression of the bile acid metabolism pathway is associated with prognosis in CRC and support further investigation of this pathway as a prognostically relevant feature of CRC. This comprehensive multi-omics analysis, supported by qRT-PCR validation of the significant downregulation of representative pathway genes (including ABCA8 and ABCD2 ), provides a framework for hypothesis-driven biomarker discovery and future investigation of therapeutic strategies targeting bile acid metabolism.