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Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide.1 While genetic mutations have long been recognised as key drivers of CRC development, the substantial role of environmental factors, particularly the gut microbiome, in shaping cancer phenotypes has emerged as a critical area of investigation. In recent years, mounting evidence has linked gut microbial dysbiosis to CRC by modulating the mucosa through the reprogramming of host gene expression, promoting inflammatory pathways and contributing to barrier dysfunction.2 The interplay between microbiome, host immunity and epigenetic regulation is now recognised as a central axis in host gene reprogramming and predisposition to CRC.3 However, the molecular mechanisms underlying these interactions remain incompletely understood.Aberrant methylation patterns—especially the hypermethylation of tumour suppressor gene promoters—are a hallmark of CRC, exemplified by the CpG island methylator phenotype (CIMP).4 Microbial metabolites, along with microbial virulence factors, have been shown to directly impact the host epigenome and contribute to the CIMP.5 For example, short-chain fatty acids (SCFAs) produced by commensal bacteria can inhibit histone deacetylases, thereby contributing to genomic stability.6 In contrast, pathogenic bacteria like Fusobacterium nucleatum promote DNA hypermethylation of tumour suppressor genes, accelerating carcinogenesis.7The study by Sobhani et al8 advances this field by linking CRC-associated microbiota to the epigenetic regulation of the tumour suppressor gene PHLPP1, offering novel insights into microbial contributions to disease progression and patient outcomes. PHLPP1 is a phosphatase that negatively regulates key oncogenic signalling pathways, including Akt/mTOR, ERK1/2 and STAT1, thereby modulating cell survival, inflammation and tumour progression. By integrating analyses of 97 patient tumour tissues, microbial profiling and faecal microbiota transfer (FMT) experiments in germ-free mice, the authors demonstrate that CRC-associated microbial dysbiosis—characterised by an overabundance of virulent bacteria and loss of commensals—predicts hypermethylation and transcriptional downregulation of PHLPP1 in the colonic mucosa. Notably, PHLPP1 downregulation was most pronounced in inflammatory subtypes of CRC, such as those associated with inflammatory bowel disease, and correlated with increased tumour inflammation, immune cell infiltration and poor patient outcomes. FMT from CRC patients into mice recapitulated these findings, inducing PHLPP1 hypermethylation, reduced gene expression and heightened mucosal inflammation. The study further identifies a microbial signature enriched in virulent taxa (eg, Fusobacterium) and depleted in commensals (eg, butyrate producers), underscoring the microbiota’s role in shaping tumour epigenetics.While these findings provide valuable insights, certain limitations should be acknowledged. The relatively small cohort size (n=97) and focus on European populations limit generalisability of results to broader ethnic groups and geographical regions, which may have diverse dietary profiles and, consequently, distinct microbiota features. Additionally, the murine FMT model, while informative, may not fully capture the complexity of human microbial–host interactions. The complexity of the microbiome and its interactions with host genetics and immunity also poses challenges for pinpointing specific bacterial taxa or metabolites responsible for the observed effects. While the study demonstrates associations between particular bacterial species and PHLPP1 methylation patterns, the underlying causal mechanisms driving these relationships remain to be elucidated.The findings open several promising avenues for future CRC research and management. First, PHLPP1 methylation has potential as a prognostic biomarker, enabling the identification of patients with aggressive, inflammation-driven tumours who may benefit from intensified monitoring or targeted therapeutic strategies. Second, interventions aimed at modulating the gut microbiota (such as probiotics, dietary modifications or FMT) could help restore PHLPP1 expression and reduce carcinogenesis risk. For example, Sobhani et al8 reported that CRC-associated dysbiosis leads to reduced levels of butyrate, a SCFA metabolite essential for maintaining barrier function. Strategies to replenish butyrate-producing bacteria through prebiotics or microbial therapeutics may help reverse epigenetic silencing. Strategies to replenish butyrate-producing bacteria through prebiotics or microbial therapeutics may help reverse epigenetic silencing, a concept supported by previous studies demonstrating that butyrate-promoting interventions by prebiotics can enhance mucosal immunity and barrier function and ameliorate colon carcinogenesis in CRC models.9 Nonetheless, further research is required to pinpoint the specific microbial species and metabolites responsible for PHLPP1 silencing and to determine its therapeutic potentials in sporadic and inflammation-associated CRCs.In summary, Sobhani et al8 provide compelling evidence that the gut microbiome can epigenetically silence a key tumour suppressor gene, PHLPP1, thereby driving inflammation and contributing to poor outcomes in CRC. These findings underscore the importance of the microbiota-epigenome axis in cancer biology and highlight new opportunities for biomarker discovery and therapeutic innovation in CRC.