Rethinking Colorectal Cancer Microbiome: From Universal Biomarkers to Patient-Stratified Signatures

The gut microbiome has emerged as one of the most promising sources of non-invasive biomarkers for colorectal cancer (CRC). Over the past decade, fecal metagenomic studies have consistently identified a core CRC-associated signature enriched with oral-typical, biofilm-forming species, most notably Fusobacterium nucleatum, Parvimonas micra, Peptostreptococcus stomatis, and Bacteroides fragilis. The recent landmark pooled analysis by Piccinno et al., which combined 3741 metagenomes from 18 international cohorts, offers the most methodologically solid confirmation of this signature to date. It achieved a leave-one-dataset-out area under the curve (AUC) of around 0.85 and expanded resolution to previously unclassified species-level genome bins (SGBs) and strain-level phylogenies. In this narrative review, we critically evaluate the evidence supporting current universal CRC microbiome signatures, explore the mechanistic basis of the oral-to-gut microbial axis and the immunometabolic tumor microenvironment, and argue that increasing evidence indicates the field is nearing a point where investigating patient-level heterogeneity could be the most valuable next step. Because a strong average CRC signal has been convincingly established, an important next direction is to examine how much these signatures’ impact varies among individual patients, considering tumor molecular subtype, immune environment, metabolic profile, and host genetics. We review emerging evidence of such patient-level heterogeneity, outline analytical methods to assess it, and discuss its importance for developing microbiome-based screening, prognostics, and therapeutic strategies in CRC.