The gut microbiome as a biomarker and modifiable risk factor in Lynch Syndrome

Lynch Syndrome (LS) is the most prevalent hereditary colorectal cancer syndrome, driven by germline mutations in DNA mismatch repair genes. Despite intensive colonoscopy surveillance, cancer risk among LS carriers remains highly variable, suggesting additional modifiers beyond genetics. Emerging evidence implicates the gut microbiome as a potential biomarker and modifiable risk factor in LS-associated carcinogenesis. This review synthesizes current findings on taxonomic and functional microbiome alterations in LS carriers, highlighting early dysbiosis characterized by depletion of butyrate-producing taxa and enrichment of virulent species such as pks+ Escherichia coli, Fusobacterium nucleatum, and enterotoxigenic Bacteroides fragilis. These oncogenic microbes promote DNA damage, inflammation and epithelial hyperproliferation in the mismatch repair deficient context, accelerating tumorigenesis. Functional signatures such as colibactin genotoxicity appear more predictive than taxonomic diversity. However, methodological heterogeneity, small cohorts and lack of longitudinal data limit biomarker validation. Finally, we outline future research that should integrate multi-omics, spatial profiling and genotype-stratified designs to identify clinically actionable microbial signatures. Understanding microbiome and host interactions in LS could assist in improved risk stratification beyond current standard surveillance guidelines.