Periodontal disease and gastric and colorectal cancers: mechanisms and therapeutic perspectives

Abstract

Periodontal disease (PD) is one of the most prevalent chronic oral diseases globally, characterized by chronic inflammatory responses in the gingiva and supporting periodontal tissues. Recent epidemiological and mechanistic studies have indicated that PD not only adversely affects oral health but is also significantly associated with gastric and colorectal cancers. This article reviews the potential link between PD and these gastrointestinal malignancies, exploring the underlying pathogenic mechanisms and potential strategies for preventing and treating gastric and colorectal cancers through the management of PD. Periodontal health management may represent an adjunct avenue for the prevention and control of gastrointestinal cancers; however, high-quality longitudinal and interventional studies are needed to clarify causality.

Keywords: colorectal cancer; gastric cancer; immune evasion; inflammation; oral – gut microbiome axis; periodontal disease; therapeutic strategies.

Figure 1

Transmission pathways and colonization mechanisms of periodontal pathogens in the gastrointestinal tract. Periodontal pathogens spread through three main routes: (i) hematogenous dissemination, where a compromised gingival barrier and increased capillary permeability allow bacterial translocation into the bloodstream during daily stimuli; (ii) digestive tract transfer, as bacteria with acid resistance, adhesion, and immune evasion capabilities cross oral, gastric, and bile salt barriers to colonize the stomach and intestines; and (iii) co-colonization, where co-migration with other microbes and multispecies symbiotic networks enhance pathogenicity and carcinogenicity. F. nucleatum promotes colonization via FadA-mediated binding to VE-cadherin and E-cadherin, increasing endothelial permeability and facilitating epithelial invasion, while its surface lectin Fap2 specifically recognizes Gal-GalNAc on CRC cells, enabling targeted enrichment in tumor tissues. F. nucleatum, Fusobacterium nucleatum; pre-FadA, precursor FadA; mFadA, mature FadA; VE-cadherin, vascular endothelial cadherin.

Figure 2

PD-driven inflammation in gastric and colorectal carcinogenesis. F. nucleatum induces systemic low-grade chronic inflammation and tumor progression through multiple pathways. By binding to E-cadherin via FadA, it activates Wnt/β-catenin, MAPK, and TLR4/MyD88/NF-κB signaling, leading to increased expression of oncogenes (c-Myc, Cyclin D1), pro-inflammatory cytokines (IL-8, IL-10, TNF-α), and anti-apoptotic genes, thereby enhancing proliferation, inhibiting apoptosis, and remodeling the tumor microenvironment. F. nucleatum also promotes neutrophil extracellular trap (NET) formation through ROS- and NOD1/2-mediated pathways. P. gingivalis contributes to tumor-associated inflammation via virulence factors (gingipains, capsule, Pg-LPS), activation of PAR2 and NF-κB signaling, induction of Th17/IL-17, suppression of Tregs/IL-10, and increased release of TNF-α, IL-6, and IL-1β, collectively fostering a pro-tumor inflammatory microenvironment. PD, Periodontal disease; P. gingivalis, Porphyromonas gingivalis; LPS, lipopolysaccharide; MyD88, Myeloid differentiation factor 88; TLR4, Toll-like receptor 4; PTK, protein tyrosine kinase; NF-κB, Nuclear factor kappa B; NETs, neutrophil extracellular traps; ROS, reactive oxygen species; Pg-LPS, porphyromonas gingivalis lipopolysaccharide; iNOS, inducible nitric oxide synthase; PAD, peptidylarginine deiminase; Tregs, regulatory T cells.

Figure 3

Mechanisms of immune evasion mediated by periodontal pathogens. F. nucleatum induces immune suppression by recruiting MDSCs that block TCR signaling, activate PD-L1/CTLA-4, and impair T-cell migration and function; by attracting TANs, TAMs, DCs, and NK cells to remodel the tumor microenvironment; by driving M2 macrophage polarization through IL-6/STAT3/c-MYC; and by activating PI3K/AKT and ERK pathways with IDO-dependent inhibition of T-cell proliferation and cytotoxicity. It also directly suppresses T/NK cell activity via Fap2–TIGIT and CbpF–CEACAM1 interactions, reducing cytotoxicity and IFN-γ secretion. P. gingivalis promotes immune evasion through fimbriae-mediated TLR modulation, IRAK-1 downregulation, PD-L1 upregulation in macrophages, and impaired iNKT cell activity, collectively enhancing immune tolerance and reducing anti-tumor responses. MDSCs, myeloid-derived suppressor cells; NO, nitric oxide; PNT, peroxynitrite; TCR, T-cell receptor; TAMs, tumor-associated macrophages; TANs, tumor-associated neutrophils; DCs, dendritic cells; IDO, indoleamine 2,3-dioxygenase; TILs, tumor-infiltrating lymphocytes; PAMPs, pathogen-associated molecular patterns; iNKT, invariant natural killer T.

Figure 4

Clinical strategies for managing PD to reduce gastrointestinal cancer risk. Potential approaches include (1) cessation of unhealthy lifestyle habits such as smoking and alcohol consumption, (2) improvement of oral hygiene through regular brushing and interdental cleaning, (3) surgical treatment of periodontitis to remove infected tissues and restore periodontal structure, (4) use of antibiotics to control pathogenic bacteria, and (5) oral administration of probiotics to restore microbial homeostasis. These strategies aim to control periodontal inflammation and may contribute to lowering the risk of gastrointestinal tumor development.