Papel de Fusobacterium nucleatum e outras bactérias periodontopatogênicas na carcinogênese, progressão e prognóstico do câncer colorretal: Uma síntese das evidências

Abstract

Growing evidence indicates that periodontopathogenic bacteria exert a relevant influence on the carcinogenesis, progression, and prognosis of colorectal cancer (CRC). Among these microorganisms, Fusobacterium nucleatum has been consistently identified in tumor tissues and associated with inflammatory, immunological, and molecular alterations that may impact disease evolution. This thesis aimed to critically synthesize the available evidence on the role of periodontopathogenic bacteria in CRC, integrating mechanistic experimental findings with prognostic evidence from observational studies in humans. The thesis was structured into two scientific articles. The first consisted of a systematic review with meta-analysis of observational studies, conducted according to the PECO strategy, assessing the association between the presence of periodontopathogenic bacteria and survival outcomes in patients with CRC. Searches were performed in PubMed/MEDLINE, Embase, Scopus, and Web of Science, covering the last ten years. Only cohort studies reporting adjusted risk estimates for prognostic outcomes, expressed as hazard ratios (HR), were included. The second article comprised a systematic review of experimental in vitro, in vivo, and organoid studies aimed at elucidating the cellular and molecular mechanisms activated by periodontopathogenic bacteria within the colorectal tumor microenvironment. In Article 1, five observational studies met the eligibility criteria, of which four were included in the quantitative synthesis. The meta-analysis demonstrated a significant association between the presence of periodontopathogenic bacteria and worse survival outcomes in CRC, with a pooled HR of 1.84 (95% CI 1.38–2.46). This association was particularly consistent for Fusobacterium nucleatum, with low heterogeneity across studies. In Article 2, experimental evidence demonstrated that Fusobacterium nucleatum, especially lineages adapted to the colorectal tumor niche, modulates key inflammatory and oncogenic pathways, including NF-κB, β-catenin, and epithelial–mesenchymal transition (EMT), while promoting immune evasion, tumor microenvironment remodeling, and therapeutic resistance through ferroptosis suppression. These mechanisms contribute to tumor progression, metastatic potential, and poorer clinical outcomes. Taken together, the findings of this thesis support the role of periodontopathogenic bacteria as active modulators of colorectal cancer progression and prognosis, highlighting Fusobacterium nucleatum as an emerging prognostic biomarker and potential therapeutic target. The evidence reinforces the importance of integrating microbiome research with inflammation and oncology and underscores the need for prospective studies incorporating microbiological, molecular, and clinical data to develop more personalized strategies for prevention, risk stratification, and treatment of CRC.