Integrative Multi-Omics Analysis Reveals Host Regulatory and Immune Networks with Inferred Dysbiosis Relevance in Colorectal Cancer
TL;DR
The findings provide a system-level framework describing the associations between dysbiosis-relevant host pathways, CRC-related regulatory networks, and immune responses and represent hypothesis-generating host candidates for further mechanistic and clinical validation.
Abstract
Background: Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Increasing evidence suggests that intestinal microbial dysbiosis contributes to colorectal tumorigenesis by reshaping host molecular signaling and the tumor immune microenvironment. However, the molecular mechanisms linking microbiome-associated alterations to host regulatory networks and disease progression remain incompletely understood. Objective: This study aimed to identify the microbiome-associated molecular regulators and immune modulators involved in colorectal cancer through an integrative multi-omics systems biology approach. Methods: Publicly available transcriptomic datasets were analyzed to identify differentially expressed genes, followed by functional enrichment, protein-protein interaction network construction, hub gene prioritization, immune infiltration profiling, survival analysis, and multi-omics characterization. Results: The identified hub genes represent hypothesis-generating host candidates for further mechanistic and clinical validation. These genes occupied key positions within host regulatory networks and were significantly associated with adverse clinical outcomes and altered CD8+ T-cell infiltration, suggesting their involvement in immune remodeling within the tumor microenvironment. Multi-omics characterization demonstrated that PTEN and SMAD4 alterations were predominantly associated with genomic deletions, whereas SMAD2 dysregulation was associated with transcriptomic and gene-dosage variation. Although the overall mutational burden of the identified hub genes was not significantly associated with disease-free survival (p = 0.878), these molecular regulators showed associations with immune-cell infiltration and CRC-related pathways. Conclusions: Collectively, our findings provide a system-level framework describing the associations between dysbiosis-relevant host pathways, CRC-related regulatory networks, and immune responses.