Beyond toxic metabolite production, Fusobacterium employs various molecular strategies to sustain infection within periodontal tissues81,82,83. Adhesins such as FadA facilitate bacterial adherence to and invasion of host epithelial cells, enabling deeper tissue colonization13,84. Furthermore, Fusobacterium modulates host immune responses by secreting enzymes and factors that degrade host tissues and immune components, thereby promoting bacterial survival and persistence. These toxins, while not directly cytotoxic, significantly impair fibroblast proliferation, delaying wound healing and contributing to chronic inflammation85,86,87. This interplay between bacterial virulence factors and host immune modulation highlights Fusobacterium's pivotal role in the pathogenesis of periodontal disease, including gingivitis88.
The genus Fusobacterium exhibits a multifaceted role in gastrointestinal pathologies, spanning neoplastic and non-neoplastic diseases. Accumulating evidence implicates Fusobacterium, particularly F. nucleatum, not only in colorectal carcinogenesis but also in other gastrointestinal malignancies and inflammatory conditions, underscoring its systemic pathogenic potential.
The Fusobacterium detected in colorectal cancer tissues is genetically identical to strains from the oral cavity, suggesting microbial translocation via hematogenous or enteric routes. Whole-genome sequencing studies support this oral-gut axis, positioning Fusobacterium as a mediator of distal carcinogenesis. Clinically, meta-analyses demonstrate significantly higher Fusobacterium DNA detection rates in colorectal tumor tissues compared to adjacent healthy tissues or controls, with a less pronounced but still significant enrichment observed in precancerous polyps, particularly those with high-grade dysplasia. Fecal microbiome analyses reveal elevated F. nucleatum abundance in colorectal cancer patients, with pooled odds ratios indicating stronger associations in colorectal cancer than in healthy controls or polyp-bearing individuals. Beyond colorectal cancer, F. nucleatum has been detected in pancreatic, esophageal, and gastric cancers, suggesting broad oncogenic relevance.
CpG islands are regions of DNA rich in cytosine and guanine dinucleotides, often located near gene promoters. In cancer, hypermethylation of these regions, frequently catalyzed by DNA methyltransferases (DNMTs), can silence tumor suppressor genes, contributing to tumorigenesis. The CpG Island Methylator Phenotype (CIMP) and Microsatellite Instability (MSI) are hallmark epigenetic and genetic alterations, respectively, in colorectal and gastric cancers, both of which have been linked to Fusobacterium presence. Specifically, studies demonstrate that Fusobacterium infection enhances DNMT-mediated CpG island methylation, which silences tumor suppressor genes such as MLH1 and CDKN2A, thereby driving cancer progression. Moreover, Fusobacterium triggers MSI through inflammatory responses that impair DNA mismatch repair proteins, further promoting genetic mutations. Mechanistic studies also show that F. nucleatum interacts with host cells via its FadA adhesin protein and E-cadherin, activating the β-catenin signaling pathway to promote tumor cell proliferation and invasion. Additionally, F. nucleatum can inhibit the function of NK cells, diminishing immune surveillance and creating favorable conditions for tumor metastasis.
Moreover, multiple studies associate intratumoral Fusobacterium with poorer survival outcomes in colorectal cancer. Fusobacterium presence correlates with adverse clinicopathological features, such as larger tumor size, increased depth of invasion, poor differentiation, lymph node or distant metastasis, and advanced tumor stages.
In summary, genomic analyses of the colorectal cancer microbiome consistently show significant enrichment of Fusobacterium species, particularly strains closely related to F. nucleatum, F. mortiferum, and F. necrophorum. These species have been identified in various clinical settings and are increasingly recognized for their potential role in human health and disease. This enrichment is corroborated by molecular analyses, such as fluorescence in situ hybridization (FISH), quantitative PCR, and sequencing-based methods, that identify Fusobacterium DNA within primary tumor tissues and colorectal metastases, highlighting its potential involvement in tumor progression and metastasis.
Recent studies reveal that beyond its established role in colorectal cancer, Fusobacterium is intricately linked to a spectrum of other gastrointestinal tumors, notably showing high prevalence in esophageal, gastric, and pancreatic cancers (Table 1). Pan-cancer analyses demonstrate an increased abundance of Fusobacterium in both primary tumors and adjacent normal tissues across gastrointestinal cancers, contrasting with non-gastrointestinal malignancies. Specifically, a significant prevalence of Fusobacterium species in gastric cancer patients suggests a potential contributory role in the pathogenesis of this cancer. The enrichment of F. nucleatum in esophageal cancer has been correlated with poor prognosis; however, direct mechanistic evidence remains limited.
CCL20 (C-C motif chemokine ligand 20) is a chemokine critically involved in inflammatory responses by recruiting immune cells, especially dendritic cells and Th17 cells, into inflamed tissues and tumor microenvironments. This association may be driven by F. nucleatum's ability to activate chemokines such as CCL20, intensifying inflammatory responses within the tumor microenvironment (Table 1). Such an inflammatory milieu fosters a favorable environment for tumor progression.
Additionally, METTL3 (Methyltransferase-like 3) is an enzyme involved in m6A methylation, which plays a significant role in regulating RNA stability and splicing. Enhanced METTL3 activity has been associated with increased tumor metastasis and progression. Specifically, F. nucleatum infection has been shown to enhance METTL3-mediated m6A methylation, promoting metastasis in esophageal squamous cell carcinoma (ESCC) (Table 1).
Furthermore, NOD1 (nucleotide-binding oligomerization domain-containing protein 1) is an intracellular pattern-recognition receptor (PRR) that senses bacterial components, activating downstream signaling pathways involving the adaptor protein RIPK2 (receptor-interacting serine/threonine-protein kinase 2). F. nucleatum further invades ESCC cells, activating the NF-κB pathway via the NOD1/RIPK2 signaling axis, thereby facilitating tumor progression (Table 1). Collectively, these findings suggest that F. nucleatum contributes to cancer advancement through diverse mechanisms, including chemokine activation, epigenetic modifications, and inflammatory signaling.
In gastric cancer, the enrichment of bacterial taxa including Fusobacterium, Lactobacillus, and Veillonella underscores the significance of microbiome composition alterations in tumorigenesis (Table 1). Notably, F. nucleatum and other Fusobacterium species have emerged as potential diagnostic biomarkers for gastric cancer. High expression of the Gal-GalNAc antigen, a carbohydrate structure serving as a binding target for specific bacterial adhesins, in gastric and esophageal cancers may facilitate increased adherence and enrichment of F. nucleatum within the tumor microenvironment, thereby influencing disease progression.
In pancreatic cancer, while Fusobacterium spp. have been detected in pancreatic tumor tissues (Table 1), other studies have not consistently confirmed its involvement. However, the presence of Fusobacterium within pancreatic ductal adenocarcinoma (PDAC) tumors correlates with a poorer prognosis in PDAC patients. This observation suggests that Fusobacterium may serve as a prognostic biomarker for PDAC, indicating potentially variable roles of Fusobacterium across gastrointestinal cancers, possibly mediated by distinct mechanisms.
In summary, the extensive presence of Fusobacterium across gastrointestinal tumors, particularly its dominance in the colorectal cancer microenvironment, highlights the complex and multifaceted relationship between F. nucleatum and gastrointestinal cancers. However, the evidence linking Fusobacterium to non-colorectal gastrointestinal cancers, such as pancreatic and esophageal cancer, remains largely correlative, and further mechanistic studies are needed to clarify its causal role in these contexts.
The relationship between Fusobacterium and inflammatory bowel disease (IBD) is particularly noteworthy within the broader context of digestive system disorders. IBD, which includes ulcerative colitis (UC) and Crohn's disease (CD), is characterized by chronic intestinal inflammation. Recent research has increasingly focused on the genus Fusobacterium, especially F. nucleatum, due to its association with IBD. Studies have demonstrated that both the frequency and abundance of F. nucleatum in the intestines of IBD patients are significantly elevated compared with healthy individuals, correlating closely with disease severity.
F. nucleatum appears to drive UC progression by promoting a shift toward pro-inflammatory M1-type macrophages. Mechanistically, this occurs in part through activation of the AKT2 signaling pathway, an intracellular serine/threonine kinase pathway that regulates diverse cellular processes including proliferation, survival, metabolism, and inflammation. Targeting F. nucleatum or its AKT2-mediated inflammatory signaling could therefore represent a promising therapeutic approach for UC. Furthermore, F. nucleatum exacerbates intestinal inflammation, epithelial barrier dysfunction, dysbiosis, and metabolic disruption, thereby worsening UC through its capacity to adhere to and invade host epithelial cells.
The association between Fusobacterium and IBD underscores its broader role in digestive disease pathogenesis. Its high invasiveness and positive correlation with disease activity suggest that F. nucleatum may promote inflammation and disease progression by modulating host immune responses and destabilizing the intestinal microenvironment. Recent studies have further implicated Fusobacterium in functional gastrointestinal disorders, such as irritable bowel syndrome (IBS) and functional dyspepsia. In these conditions, F. nucleatum can exacerbate symptoms by altering intestinal microbiota composition, disrupting the mucosal barrier, increasing intestinal permeability, and facilitating the release of inflammatory mediators. Interactions between Fusobacterium and abnormalities in the enteric nervous system may also contribute to visceral hypersensitivity and motility disorders in IBS. These findings suggest that rebalancing the intestinal microbiota, particularly by controlling Fusobacterium overgrowth, could offer a potential strategy for managing functional gastrointestinal diseases.
Although direct studies on the association between Fusobacterium and liver diseases are limited, emerging research has begun to explore its potential impact. In liver diseases, especially non-alcoholic fatty liver disease (NAFLD) and liver fibrosis, recent findings indicate a close link with gut microbiota dysbiosis. Fusobacterium may exacerbate liver damage by directly influencing hepatocyte function and structure through its virulence factors.
Fusobacterium species are also implicated in various gastrointestinal infections. They have been isolated from intra-abdominal abscesses, liver abscesses, and colonic lesions. F. nucleatum, in particular, has been linked to colorectal cancer, where it promotes tumor growth and metastasis through interactions with host immune cells and the tumor-associated infectious microenvironment.
In summary, the genus Fusobacterium demonstrates complex and multifaceted associations with a variety of non-tumoral digestive diseases. These connections enhance our understanding of the pathogenesis of these conditions and suggest potential avenues for novel therapeutic strategies.