Integrative microbiome–methylome analysis links bacterial taxa to colorectal cancer histological subtypes

Vollständiger Abstract

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ABSTRACT Colorectal cancer (CRC) arises through distinct molecular and histological routes that may be shaped by interactions between the mucosa-associated microbiota and host epigenetic regulation. We analyzed paired tumor and adjacent non-tumor colorectal mucosa from CRC patients stratified by histological subtype (conventional vs serrated-pathway groups). Microbiota composition was profiled by Illumina sequencing, and host DNA methylation was assessed using genome-wide CpG arrays with targeted validation. Alpha diversity showed modest tumor–non-tumor differences, with variation by anatomical location driven by distal tumors. Differential abundance testing identified tumor-associated genera, and linear discriminant modeling highlighted taxa with high discriminatory power, including Bacteroides , Eubacterium , Fusobacterium , and Acinetobacter . Methylome ordination separated tumor from non-tumor samples and revealed prominent contributions of zinc finger (ZNF) loci. Integrative latent-variable modeling (PLS/sparse partial least squares and multi-block sparse partial least squares discriminant analysis) supported coordinated microbiome–methylome variation distinguishing tumor from non-tumor mucosa, prioritized a limited set of bacterial and methylation signals, and suggested partial discrimination between conventional and serrated tumor profiles, particularly in the methylome block. Focusing on Fusobacterium , methylation changes in selected host loci were associated with its abundance, and qPCR-based quantification of Fusobacterium nucleatum correlated with CpG methylation at ZNF788. F. nucleatum levels were also associated with serrated/microsatellite instability-related CRC features and more advanced disease. These findings identify subtype-aware microbiome–methylome signatures in CRC and highlight ZNF788 methylation as a candidate epigenetic correlate of intratumoral F. nucleatum burden. IMPORTANCE Colorectal cancer does not develop in a single way, and different tumor types may interact differently with bacteria living on the bowel lining. This study examined both tissue-associated bacteria and DNA methylation, an epigenetic mark that helps regulate genes, in paired tumor and nearby non-tumor tissue from patients with colorectal cancer. By analyzing these two layers together, we identified microbial and host methylation patterns linked to tumor tissue and to serrated-pathway cancers. In particular, Fusobacterium nucleatum was associated with serrated/microsatellite instability-related features, more advanced disease, and methylation of the host gene ZNF788 . These findings suggest that combining microbiome and epigenetic information may help explain why colorectal cancer subtypes behave differently and may support future subtype-aware biomarkers.