Colorectal cancer (CRC) exhibits substantial heterogeneity in molecular subtypes and clinical outcomes. We performed an integrative analysis of multi-omics data from 274 CRC patients to investigate the impact of gut microbiota composition on prognosis, identify novel subtypes, and develop a machine learning-based prognostic model. Our microbiome analysis revealed significant differences between CRC and normal tissues. Multi-omics clustering identified two major CRC subtypes, CS1 and CS2, with distinct molecular characteristics and survival outcomes. We developed the Multi-Omics Integrative Clustering and Machine Learning Score (MCMLS) model, which demonstrated strong prognostic value in predicting patient survival and outperformed existing models. The MCMLS low-score group exhibited higher immune cell infiltration, increased metabolic pathway activity, and potentially better immunotherapy response. In contrast, the MCMLS high-score group showed higher mutation burden, fibroblast infiltration, and enrichment of cell adhesion and migration pathways. Bacterial analysis revealed differentially abundant bacteria associated with prognosis. Importantly, MCMLS consistently predicted immunotherapy response across six independent datasets. Our findings highlight the complex interplay between the gut microbiome, tumor microenvironment, and immune landscape in CRC, providing valuable insights for improving patient stratification and personalized treatment strategies.