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Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with mounting evidence implicating the gut microbiome in its pathogenesis. Among the microbial agents, Fusobacterium nucleatum has emerged as a prominent contributor, frequently detected in CRC tissues and associated with advanced disease stages and poor prognosis. This review highlights the complex interplay between F. nucleatum and host non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in modulating CRC biology. F. nucleatum influences the expression of several ncRNAs, which in turn regulate key signaling pathways such as Wnt/β-catenin (e.g., miR-1246, miR-135b), PI3K/AKT (e.g., miR-22, miR-135b), and TLR4/NF-κB (e.g., miR-31, lnc-NEAT1). Through these mechanisms, F. nucleatum contributes to tumor cell proliferation, immune evasion, metastasis, and chemoresistance. Additionally, its impact on ncRNA expression is implicated in reduced efficacy of standard chemotherapy. Emerging microbiota-based therapies, including probiotics and fecal microbiota transplantation, show promise in modulating gut flora and potentially reversing ncRNA dysregulation; however, their mechanistic effects on the F. nucleatum-ncRNA axis require further investigation. This review underscores the critical role of F. nucleatum-regulated ncRNAs in CRC and presents new opportunities for biomarker discovery and targeted therapeutics.
Zahra Sadeghloo and Sara Ebrahimi contributed equally to this work.
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CRC
Colorectal caner
IARC
International Agency for Research on Cancer
ncRNA
Non-coding RNA
miRNA
MicroRNA
lncRNA
Long non-coding RNA
circRNA
Circular RNA
F. nucleatum
Fusobacterium nucleatum
EMT
Epithelial-to-mesenchymal transition
SCFA
Short-chain fatty acid
GSK3β
Glycogen synthase kinase 3 beta
TCF4
Transcription factor 4
PTEN
Phosphatase and tensin homolog
VEGFA
Vascular endothelial growth factor A
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells
STX12
Syntaxin 12
eIF4EBP1/2
Eukaryotic translation initiation factor 4E-binding protein ½
CCL20
C-C motif chemokine ligand 20
MSI
Microsatellite instability
TGF-β
Transforming growth factor beta
FUT8
Fucosyltransferase 8
Smads
Mothers against decapentaplegic homologs
SHH
Sonic Hedgehog
GLI1
Glioma-associated oncogene homolog 1
MYC
Myelocytomatosis oncogene
m6A
N6-methyladenosine
MET
Mesenchymal-epithelial transition factor gene
MAP2K4
Mitogen-activated protein kinase kinase 4
KAT7
Lysine acetyltransferase 7
ENO1
Enolase 1
SP1
Specificity protein 1
YBX1
Y-box binding protein 1
RRBP1
Ribosome binding protein 1
ATF6p50
Activating transcription factor 6 p50
ER
Endoplasmic reticulum
5-FU
5-Fluorouracil
FMT
Fecal microbiota transplantation
LGG
Lactobacillus rhamnosus GG
H2O2
Hydrogen peroxide
CRA
Colorectal adenoma
Introduction
Colorectal cancer (CRC) represents a significant global health challenge, consistently identified as the third most prevalent and second deadliest neoplasm worldwide [1]. The International Agency for Research on Cancer (IARC)’s 2018 report indicated that CRC accounts for approximately 1.8 million new cases and 900,000 fatalities each year [2]. The significant public health impact of CRC underscores the need for a more comprehensive understanding of its underlying causes and the development of new treatment methods. Over the past few decades, research on migration and prospective cohort studies has demonstrated that diet and lifestyle significantly influence the development of CRC [3]. Nearly 50% to 60% of CRC cases in the United States are estimated to be linked to modifiable risk factors. These factors include smoking, excessive alcohol consumption, obesity, a sedentary lifestyle, a high intake of red and processed meats, and inadequate consumption of dietary fiber and essential nutrients [4].
Beyond lifestyle factors, the human gut harbors approximately 40 trillion microorganisms that make up the gastrointestinal microbiota [5]. In recent years, microbes have been implicated in 20% of cancers [6], including CRC [7]. The first study to demonstrate the effects of gut microbiota on the carcinogenic properties of cycasin in germ-free mice was published in 1967 [8]. Numerous studies have established a connection between dysbiosis of the gastrointestinal microbiota and the development of CRC [9‐11]. Gut dysbiosis is characterized by compositional and functional changes resulting from an imbalance between symbiotic and opportunistic microorganisms [12]. Research has indicated a connection between environmental factors and the imbalance of gut bacteria in relation to the development and prognosis of CRC [13, 14]. Changes in the gut microbiota can be triggered by factors including a lack of physical activity, antibiotics use, a Western-style diet, increasing age, and being overweight, potentially leading to a pro-inflammatory state [15]. Several bacterial species, specifically Fusobacterium nucleatum [16], E. coli [17], Bacteroides fragilis [18], Streptococcus bovis/gallolyticus [19], Clostridium septicum [20], Enterococcus faecalis [21], and Peptostreptococcus anaerobius [22], are frequently associated with the development of CRC.
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F. nucleatum is a Gram-negative anaerobic bacterium that is more prevalent in cases of CRC [23, 24]. F. nucleatum is considered a key architect of biofilms in the oral cavity and is believed to be a pioneer organism that facilitates the creation of a microenvironment conducive to the growth of other pathogenic microorganisms [25]. Various studies have demonstrated a significant increase in the colonization of F.nucleatum within tumor tissues, with levels reaching up to 400 times greater than those in the surrounding normal tissues [26]. The levels of F. nucleatum increase and correlate with adenoma progression to carcinoma [27, 28]. Furthermore, advanced CRC stages (III and IV) often exhibit high rates of metastasis, underscoring the aggressive nature of the disease in these stages [29, 30]. The association of F. nucleatum with both adenoma formation and metastasis highlights its multifaceted role in CRC progression and underpins its potential as a diagnostic and therapeutic target.
CRC is a complex disease characterized by genetic and epigenetic abnormalities contributing to its diverse features. The epigenetic changes associated with CRC are varied and extensive, affecting numerous genes and pathways involved in cell cycle regulation, programmed cell death, DNA repair mechanisms, and cell adhesion [31]. Their dysregulation can promote tumorigenesis by inactivating tumor suppressor genes or activating oncogenes, with significant implications for CRC’s clinical presentation and prognosis. Small non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are increasingly recognized for their roles in post-transcriptional gene regulation in CRC. These ncRNAs can act as either oncogenes or tumor suppressors and have been associated with various aspects of CRC pathogenesis, including epithelial-to-mesenchymal transition, angiogenesis, and immune evasion [32]. Recognizing the epigenetic profile of CRC has significant clinical implications. Epigenetic biomarkers can serve as diagnostic, prognostic, and predictive tools, providing valuable insights into patient stratification and potential responses to treatment. The reversible nature of epigenetic modifications presents a promising avenue for therapeutic intervention, with several epigenetic drugs currently in use or undergoing clinical trials for CRC treatment [33]. In summary, epigenetic regulation plays a crucial role in the biology of CRC, influencing the disease’s progression from its early stages to advanced malignancy. A comprehensive understanding of these regulatory mechanisms is essential for developing new diagnostic and therapeutic strategies aimed at improving patient outcomes.
Despite substantial research on various aspects of CRC, significant challenges persist concerning the interaction between F. nucleatum and ncRNAs in this disease. The interplay between F. nucleatum and ncRNAs adds another layer of complexity, potentially contributing to the disease’s heterogeneity and progression. Understanding this interaction is crucial for identifying novel therapeutic strategies aimed at improving patient outcomes. A comprehensive review of the latest data is likely to benefit researchers and medical professionals. For this review, a thorough examination of the most current available research was conducted to provide the most up-to-date information on the relationship between Fusobacterium and ncRNAs in CRC.
F. nucleatum: a key player in CRC pathogenesis
The biological profile of F. nucleatum
F. nucleatum is a non-spore-forming, fusiform rod-shaped bacterium belonging to the phylum Fusobacteriota. Its morphology is characterized by its elongated, tapered ends, often described as resembling a “fusiform” or spindle shape [34]. The bacterium ferments fructose and glutamate, producing butyric acid as a major metabolic byproduct [35]. The outer membrane of F. nucleatum plays a significant role in its interactions with the host and other bacteria, containing various proteins involved in adherence, invasion, and immune evasion [36, 37]. For instance, the outer membrane protein RadD is an arginine-inhibitable adhesin crucial for interspecies adherence and the structural integrity of multispecies biofilms [37]. F. nucleatum is ubiquitously found in the normal human oral flora, residing in subgingival plaques, particularly in individuals with poor oral hygiene [38, 39]. However, it’s important to note that this commensal bacterium contributes to maintaining oral microbial balance under normal conditions. The transition from commensal to pathogen involves a complex interplay of factors, including the host’s immune status, the presence of other microorganisms, and environmental conditions [40]. The ecological niches occupied by F. nucleatum extend beyond the oral cavity. It has been increasingly implicated in various extra-oral infections, including CRC, preterm birth, and other systemic diseases [41, 42]. The presence of F. nucleatum in the early stages of CRC, particularly through its association with the formation of various polyps, has garnered significant attention. Villous and tubulovillous adenomas, considered high-risk polyps, exhibit significant architectural distortion and abnormal epithelial proliferation, making them precancerous lesions with a strong potential for malignant transformation [43]. Elevated levels of this bacterium, especially in high-risk polyps such as villous or tubulovillous adenomas, suggest a potential role in promoting tumorigenesis [44]. Consistently, F. nucleatum is found in CRC tissues at significantly higher levels than in adjacent normal tissues, further implicating it in disease progression [45, 46]. Its higher prevalence in CRC tissues correlates with advanced tumor stages and poorer overall survival in patients [47, 48]. These findings highlight the potential of F. nucleatum as both a biomarker for early detection and a target for therapeutic intervention. However, the precise contribution of F. nucleatum to CRC initiation and progression remains a topic of ongoing research. It is important to distinguish between correlation and causation—while F. nucleatum is frequently found in CRC, further research is needed to fully understand its causal role in the disease process. The bacterium’s ability to interact with and modulate the host immune system, its secretion of various virulence factors, and its metabolic activities are all potential mechanisms through which it might influence CRC [49].
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Molecular mechanisms underlying F. nucleatum’s role in CRC
F. nucleatum’s contribution to CRC pathogenesis is multifaceted and involves several virulence factors and mechanisms (Fig. 1) [50]. One key player is FadA, a surface-associated adhesin that binds to E-cadherin on host cells. By binding to E-cadherin on the surface of intestinal epithelial cells, FadA triggers a cascade of signaling events that activate the Wnt/β-catenin pathway. This pathway is crucial for regulating cell growth and differentiation, and its dysregulation is a hallmark of many cancers, including CRC. Activation of the Wnt/β-catenin pathway by FadA promotes uncontrolled cell proliferation, contributing to tumor formation [51, 52]. Another significant virulence factor is Fap2, a type V-secreted autotransporter that facilitates F. nucleatum’s attachment to host cells by binding to D-galactose-β (1–3)-N-acetyl-D-galactosamine (Gal-GalNAc), and also plays a role in immune evasion. Fap2 directly interacts with the TIGIT immune receptor, suppressing the activity of T cells and natural killer cells. This immunosuppression allows the tumor to evade immune surveillance and destruction, thereby promoting its progression [53]. In addition to FadA and Fap2, other virulence factors are being explored, highlighting the complex nature of F. nucleatum’s interaction with the host [54]. The bacterium’s ability to produce short-chain fatty acids (SCFAs), such as acetate and butyrate, might also contribute to its pathogenic effects. These SCFAs act as neutrophil chemoattractants, potentially exacerbating the inflammation in oral infections. While direct evidence for this mechanism in the colorectal tumor microenvironment remains limited, it is plausible that similar SCFA-mediated recruitment of neutrophils could exacerbate inflammation and indirectly support CRC progression [55]. The production of hydrogen sulfide (H2S), another F. nucleatum metabolite, has also been linked to CRC progression. H2S promotes inflammation and alters the composition of the gut microbiota, creating a more favorable environment for tumor growth [49].
The inflammatory response is critical in CRC development, and F. nucleatum can actively modulate this process [56]. By inducing cytokine production and recruiting inflammatory cells, F. nucleatum creates a pro-tumorigenic microenvironment. It can also suppress host immune responses by interfering with the normal functions of macrophages, dendritic cells, T cells, and natural killer cells. This immune evasion contributes to the bacterium’s persistence and promotes tumor progression [57]. The interaction between F. nucleatum and the host immune system is complex and varies depending on the tumor microenvironment and the host’s genetic background. For instance, F. nucleatum has been linked to microsatellite instability (MSI), a condition characterized by defects in the DNA mismatch repair system. In MSI-high tumors, F. nucleatum may suppress immune responses, while in non-MSI-high tumors, it may enhance them [58]. This complex interplay highlights the need for further research to fully understand F. nucleatum’s role in immune modulation during CRC [58]. Studies using in vitro and in vivo models have demonstrated that F. nucleatum can directly influence cell apoptosis, affecting the development of CRC by altering the distribution of intestinal flora and metabolite concentrations [56]. Moreover, F. nucleatum can affect cell differentiation by triggering the expression of cancer-related genes in normal cells, further highlighting its potential contribution to the initiation and progression of CRC [59].
Fig. 1
F. nucleatum in CRC pathogenesis. F. nucleatum promotes CRC by binding to epithelial cells through FadA and Fap2 adhesins. FadA activates the Wnt/β-catenin pathway, driving cell proliferation and tumor growth. Fap2 binds to Gal-GalNAc and suppresses immune cells via the TIGIT receptor. Bacterial metabolites also trigger neutrophil recruitment and inflammation, leading to gut dysbiosis and reduced anti-tumor immunity
Interplay between F. nucleatum and non-coding RNAs in CRC
Beyond the direct effects of F. nucleatum virulence factors and metabolic byproducts on the tumor microenvironment and host immune response, an increasing body of evidence indicates a crucial role for ncRNAs in mediating the bacterium’s influence on CRC pathogenesis. These ncRNAs are involved in various cellular processes, and their dysregulation is frequently observed in cancer. F. nucleatum infection may alter the expression profiles of these ncRNAs, contributing to the disruption of cellular pathways and promoting tumor development [60, 61]. This complex interaction will be explored in detail in the following sections (Fig. 2).
ncRNAs, including miRNAs, lncRNAs, and circRNAs, are critical regulators of gene expression that don’t encode proteins. miRNAs are approximately 22 nucleotides in length and regulate gene expression post-transcriptionally by binding to the 3′ untranslated regions (UTRs) of target mRNAs, thereby influencing key processes such as differentiation, proliferation, and apoptosis [62]. lncRNAs, which exceed 200 nucleotides in length, modulate gene expression at multiple levels and are increasingly recognized for their roles in cancer progression and metastasis [63]. circRNAs form stable, covalently closed-loop structures and have been implicated in processes such as cell proliferation and chemoresistance [64]. In CRC, dysregulation of these ncRNAs is common, and they can function as either oncogenes or tumor suppressors by targeting key signaling pathways, including Wnt/β-catenin, TGF-β, and PI3K/AKT [65, 66].
The presence of F. nucleatum—a bacterium frequently found in CRC tissues—adds another layer of complexity by influencing the expression of ncRNAs, thereby shaping the molecular landscape of CRC. This regulatory influence disrupts key cellular processes, including proliferation, metastasis, and chemoresistance, fostering a tumor-promoting microenvironment [67]. The intricate relationship between F. nucleatum and ncRNAs highlights its critical role in CRC progression, with significant implications for downstream signaling cascades [68]. It should be noted that many of the ncRNAs reported in relation to F. nucleatum have previously been described as CRC-associated biomarkers independent of microbial influence. Current evidence indicates that the bacterium may contribute by further modulating or amplifying their dysregulation, which could in turn exacerbate tumor progression and therapy resistance. Table 1 summarizes ncRNAs regulated by F. nucleatum in CRC The following sections will explore the specific molecular pathways through which F. nucleatum-driven alterations in ncRNA contribute to CRC development.
Table 1
The role of NcRNAs regulated by F. nucleatum in CRC
Signaling mechanisms of F. nucleatum in tumor progression and metastasis. This schematic highlights the pivotal role of miRNAs and lncRNAs in mediating the effects of F. nucleatum on host cells, influencing a broad spectrum of signaling pathways including Wnt/β-catenin signaling, NF-κB activation, autophagy regulation, EMT processes, pro-inflammatory responses, and other regulatory mechanisms, thereby promoting tumor progression, metastasis, persistent infection, and inflammation. Upregulated ncRNAs (blue) and downregulated ncRNAs (red) are indicated. This image was created on BioRender.com
The Wnt/β-catenin signaling pathway plays a crucial role in the development of CRC by promoting cell proliferation and tumor growth. F. nucleatum enhances this pathway by modulating ncRNAs expression, particularly miRNAs. It increases the levels of miR-1246, miR-92b-3p, and miR-27a-3p in exosomes derived from infected CRC cells. These miRNAs target glycogen synthase kinase 3 beta (GSK3β), a negative regulator of β-catenin. Consequently, β-catenin accumulates in the nucleus, leading to the activation of transcription of genes involved in migration, invasion, and epithelial-mesenchymal transition (EMT)—critical steps in metastasis [69]. Furthermore, miR-135b is upregulated through the TCF4/β-catenin complex, which binds to its promoter. The elevated levels of miR-135b suppress KLF13, leading to increased resistance to cisplatin [70]. These findings underscore the role of miRNAs in amplifying Wnt/β-catenin signaling during infection with F. nucleatum.
PI3K/AKT pathway
The PI3K/AKT pathway is another central driver of CRC, orchestrating inflammation, cell proliferation, and tumor progression. F. nucleatum promotes the activation of PI3K/AKT pathway by upregulating miR-21, which inhibits PTEN, a critical negative regulator of this pathway, thereby enhancing tumor cell proliferation [67, 68]. Clinical evidence further supports this connection, demonstrating an increased abundance of F. nucleatum in colorectal adenoma (51.8%) and CRC (72.1%) tissues, accompanied by elevated miR-21 expression in colorectal adenoma lesions, particularly in tumors harboring KRAS mutations, which are known to potentiate PI3K/AKT signaling. Beyond miR-21, F. nucleatum infection also modulates other ncRNAs involved in CRC progression. miR-135b, which is significantly upregulated in both colorectal adenomas (CRA) and CRC tissues colonized by F. nucleatum, has been implicated in activating oncogenic pathways, including PI3K/AKT signaling pathway. Conversely, miR-22 and miR-28-5P, which are exclusively downregulated in CRC tumors, typically exert tumor-suppressive effects, partly by inhibiting PI3K/AKT activity; their loss correlates with increased F. nucleatum loads. Moreover, the upregulation of miR-34a via a TLR2/TLR4-dependent response to F. nucleatum further integrates microbial signals into the regulation of ncRNA networks that influence CRC progression [67].
Additionally, recent studies highlight the role of lncRNAs in this context. Yan et al. [71] demonstrated that lnc-NEAT1, induced by F. nucleatum, enhances PI3K/AKT signaling and promotes VEGFA expression, thereby supporting angiogenesis and EMT in CRC. This effect is mediated partly through lnc-NEAT1’s interaction with miR-374a-5p, which regulates VEGFA, revealing a novel mechanism by which F. nucleatum-driven lncRNA-miRNA networks amplify oncogenic signaling.
NF-κB signaling pathway
F. nucleatum activates the NF-κB signaling pathway, a key regulator of inflammation and tumorigenesis, by modulating specific miRNAs and lncRNAs. Tang et al. [60] demonstrated that F. nucleatum induces miR-31 expression by promoting the binding of phosphorylated p65 to the miR-31 promoter. This upregulation of miR-31 suppresses STX12, inhibiting autophagy, and targets eIF4EBP1/2, thereby enhancing CRC cell proliferation, and establishing a positive feedback loop that favors bacterial persistence. Additionally, Xu et al. [72] reported that F. nucleatum also upregulates miR-1322, leading to the downregulation of CCL20 and modulation of the inflammatory response. Notably, pharmacological inhibition of NF-κB signaling using Bay11-7082 was found to reverse these effects, further confirming the critical role of this pathway. Wang et al. [73] found that F. nucleatum upregulates miR-155-5p through NF-κB, targeting MSH6’s 3’UTR to promote microsatellite instability and CRC progression. Additionally, a recent study revealed that F. nucleatum infection, through NF-κB activation, increases the expression of lncRNA Keratin7-antisense (KRT7-AS) and Keratin7 (KRT7) in CRC cells, thereby promoting cell migration and lung metastasis. By enhancing KRT7 expression, KRT7-AS further drives metastatic progression [74]. Collectively, these findings illustrate how F. nucleatum manipulates miRNAs and lncRNAs via NF-κB signaling to create a pro-inflammatory, tumor-promoting microenvironment that favors its survival.
TGF-β/Smads signaling pathway
The TGF-β/Smads signaling pathway plays a crucial role in regulating EMT and metastasis in CRC. According to findings by Zhang et al. [75], F. nucleatum downregulates miR-122-5p, a miRNA that typically targets and suppresses the expression of fucosyltransferase 8 (FUT8). The reduction of miR-122-5p leads to the upregulation of FUT8, which subsequently enhances TGF-β1/Smads signaling, as evidenced by increased phosphorylation of Smad2/3 proteins. This activation promotes EMT and accelerates metastatic progression. Moreover, experimental overexpression of miR-122-5p has been shown to inhibit the TGF-β/Smads pathway, highlighting its potential as a therapeutic target. Overall, these findings emphasize the intricate regulatory network through which F. nucleatum manipulates miRNA expression to drive CRC progression via TGF-β/Smads signaling.
Other pathways
F. nucleatum influences several miRNA-mediated pathways critical to CRC progression, including autophagy, Sonic Hedgehog (SHH) signaling, m6A RNA methylation, and c-Met receptor signaling, which respectively drive chemoresistance, cancer cell stemness, proliferation, and tumor growth. In regulating autophagy, F. nucleatum downregulates miR-18a and miR-4802, both of which normally suppress autophagy-related proteins ULK1 and ATG7. This downregulation occurs via the activation of the TLR4/MYD88 signaling pathway in infected CRC cells, leading to impaired autophagy and increased resistance to chemotherapy [76]. In the SHH signaling axis, F. nucleatum reduces the expression of miR-361-5p, a miRNA that targets SHH and GLI1, through a MYC-dependent mechanism. The resulting activation of the SHH pathway enhances CRC stemness and chemoresistance [77]. Moreover, F. nucleatum promotes CRC cell proliferation through the modulation of epigenetic marks. It increases the expression of miR-4717 by inducing METTL3-mediated m6A RNA methylation, which in turn targets and downregulates the tumor suppressor MAP2K4, thereby driving tumor growth in CRC [78]. Furthermore, F. nucleatum upregulates miR-4717 and miR-4474 to target CREBBP mRNA, promoting CRC progression by enhancing proliferation and activating the Wnt/β-catenin pathway [61]. Additionally, F. nucleatum further promotes CRC cell proliferation by upregulating the c-Met receptor, encoded by the MET gene, which is frequently overexpressed in colorectal tumors. This regulation is mediated by miR-139-5p (in both its intracellular and extracellular forms), which normally suppresses c-Met translation. Reducing F. nucleatum levels restores the inhibitory function of miR-139-5p on c-Met, thereby restraining CRC growth. Interestingly, miR-139-5p also directly impairs F. nucleatum itself, potentially through interaction with a complementary site on its 16 S rRNA, thereby limiting both bacterial proliferation and its pro-tumorigenic effects [79]. Collectively, these findings highlight F. nucleatum’s multifaceted role in hijacking miRNA-dependent pathways to orchestrate chemoresistance, stemness, proliferation, and tumor growth, contributing to CRC progression and therapy resistance.
Beyond miRNAs, F. nucleatum orchestrates CRC progression by fine-tuning lncRNAs and circRNAs. F. nucleatum activates lncRNA ENO1-IT1 by enhancing SP1 binding to its promoter, which promotes glucose metabolism and oncogenesis via KAT7-mediated histone acetylation of ENO1 [80]. Similarly, lncRNA EVADR, which is upregulated by F. nucleatum, acts as a scaffold for YBX1, enhancing the translation of EMT factors such as Snail, Slug, and Zeb1. This process drives metastasis by altering the levels of E-cadherin, N-cadherin, and vimentin [81]. Additionally, F. nucleatum induces the formation of circRNA hsa_circ_0004085, which stabilizes GRP78 mRNA by binding RRBP1. This interaction facilitates the nuclear translocation of ATF6p50, alleviating endoplasmic reticulum (ER) stress and conferring resistance to oxaliplatin and 5-fluorouracil (5-FU) chemotherapy [82]. Collectively, these findings underscore the multifaceted role of F. nucleatum’s in hijacking miRNA, lncRNA, and circRNA-dependent pathways to orchestrate chemoresistance, stemness, proliferation, metastasis, and tumor growth, thereby contributing to CRC progression and therapy resistance (Fig. 3).
Fig. 3
Chemoresistance mechanisms in CRC mediated by F. nucleatum. This diagram illustrates the intricate network of molecular pathways influenced by F. nucleatum in cancer cells, emphasizing its interaction with Toll-like receptors and Sonic Hedgehog signaling. Key regulators include miRNAs (e.g., miR-135b, miR-18a), lncRNAs (e.g., ENO1-IT1), circularRNA (e.g., circ-0004085), which collectively contribute to resistance to cisplatin, oxaliplatin and 5-fluorouracil. Upregulated ncRNAs (blue) and downregulated ncRNAs (red) are indicated. This image was created on BioRender.com
The presence of F. nucleatum in CRC tissues has significant clinical implications, particularly concerning prognosis and treatment response. Studies have consistently shown a correlation between high levels of F. nucleatum and poorer patient outcomes, including an increased risk of cancer recurrence and reduced survival rates [83‐85]. However, this association is not universal, however, and the strength of the correlation may vary depending on factors such as tumor stage, location, and genetic characteristics [84, 85]. A large-scale investigation of intra-tumoral bacteria in CRC conducted by Hullar et al. revealed that the inclusion of pathogenic intra-tumoral microbiomes may enhance survival predictions and identify patients who could benefit from targeted therapies that modulate the tumor microbiome. Specifically, F. nucleatum-positive tumors were associated with shorter survival in non-hypermutated tumors [85]. Further research is needed to determine the causal relationship between F. nucleatum abundance and adverse clinical outcomes.
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F. nucleatum has also been associated with chemoresistance in CRC. Patients with elevated levels of F. nucleatum in their tumors may exhibit reduced sensitivity to chemotherapy, potentially leading to treatment failure. The mechanisms underlying this chemoresistance are not yet fully understood, but they may involve the bacterium’s modulation of the tumor microenvironment or its direct interactions with cancer cells [83, 86]. Targeting F. nucleatum with specific therapies, such as antibiotics or other anti-bacterial agents, could improve the efficacy of chemotherapy and enhance patient outcomes. However, developing of effective and safe anti-F. nucleatum therapies remain a significant challenge. The complexity of the interactions between F. nucleatum, the host immune system, and the tumor microenvironment necessitates a multifaceted approach to developing new therapies that target this bacterium and its influence on CRC progression [83, 86, 87]. More research is necessary to establish the clinical utility of F. nucleatum as a biomarker for CRC prognosis and to develop effective strategies for targeting this bacterium in the treatment of CRC [83‐85].
Targeting F. nucleatum: probiotic and fecal microbiota transplantation strategies for CRC prevention
Building on the established link between the role of F. nucleatum in dysbiosis and its impact on host ncRNAs, strategies targeting this pathogen, such as probiotic interventions and fecal microbiota transplantation (FMT), could offer promising avenues for prevention. These approaches aim to restore microbial balance and potentially mitigate the influence of F. nucleatum on host ncRNA expression, thereby reducing CRC risk. Probiotics, by introducing beneficial bacteria into the gut, can help rebalance the microbiome and suppress the growth of pathogenic species like F. nucleatum. Similarly, FMT has gained attention as a possible effective method for restoring gut health by transferring a diverse array of microorganisms from healthy donors to patients [88, 89].
These beneficial microorganisms exert various mechanisms to improve gut health, including promoting the repair of the gut barrier, strengthening immune responses, reducing inflammation, and balancing the intestinal microbiome. Specifically, probiotics can directly compete with F. nucleatum for resources and attachment sites within the gut, thereby possibly limiting its colonization and diminishing its pathogenic effects. This competition for niche occupancy could not only reduces the abundance of F. nucleatum but also minimizes its oncogenic impact on the host. Additionally, probiotics produce a range of metabolites, such as SCFAs, which exhibit anti-inflammatory and anti-proliferative properties. These combined effects appear to contribute to the regulation of metabolic pathways, the mitigation of gut dysbiosis, and the potential reduction of cancer development risk [90, 91].
A study demonstrated that certain probiotic strains isolated from kimchi, specifically strains identified as Kimchi 44 and Kimchi 71, exhibited significant antibacterial activity against F. nucleatum. These strains were found to be more effective in inhibiting F. nucleatum than the well-known probiotic strain Lactobacillus rhamnosus GG (LGG) [92]. In a study conducted by Mann S, et al. [93], the probiotic strain Lactobacillus gasseri HHuMIN D significantly reduced the in vitro binding of F. nucleatum by 89% compared to its binding in the absence of probiotics. The hydrogen peroxide (H2O2) production by L. gasseri HHuMIN D effectively targets F. nucleatum, serving as a powerful antimicrobial agent. This highlights the potential of probiotics in targeting and reducing the attachment of harmful bacteria such as F. nucleatum. Additionally, a study by Bae et al. [94] demonstrated that the culture supernatant of Lactobacillus reuteri AN417 effectively inhibits the growth of F. nucleatum. They found that a 40% (v/v) concentration of the supernatant resulted in significant suppression of F. nucleatum, with the inhibitory effect sustained for up to 48 h.
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Recently, FMT has emerged as an innovative treatment method that utilizes processed donor stool, which is freeze-dried in a laboratory setting and delivered directly into a patient’s intestinal tract to achieve therapeutic effects [95]. F. nucleatum, particularly its virulence factor FadA, is a key target in this approach. Studies have demonstrated that FMT can reduce the abundance of F. nucleatum and its virulence, highlighting its potential in CRC prevention, though clinical validation is still limited [96]. Similarly, the research conducted by Li DH et al. showed that FMT effectively reduced both F. nucleatum levels and the expression of its virulence factor, FadA, further reinforcing the therapeutic potential of this strategy [97]. Dan et al. [98], showed in a murine CRC model induced by azoxymethane/dextran sodium sulfate that combining fecal microbiota transplantation with salinomycin corrected microbial dysbiosis, restored microbial diversity, and reduced tissue damage, resulting in improved survival and enhanced anti-cancer activity. The treatment also elevated anti-inflammatory SCFAs, such as propionic and butyric acids, while increasing CD8⁺ T-cell and neutrophil infiltration and lowering macrophage recruitment. Moreover, in a study employing CLA-producing Bifidobacterium strains (B. breve CCFM683 and B. pseudocatenulatum MY40C) in a spontaneous CRC mouse model, FMT from treated mice validated the preventive benefits by restoring microbial diversity, boosting beneficial bacteria such as Odoribacter splanchnicus for butyric acid production, and strengthening gut barrier function via tight junction proteins. These effects addressed dysbiosis-related imbalances, including those involving oncogenic pathogens like F. nucleatum, through CLA-driven PPAR-γ activation, NF-κB inhibition, and enhanced tumor cell apoptosis [99]. Furthermore, a recent investigation using FMT from CRC patients to germ-free mice showed that it induces hypermethylation and downregulation of PHLPP1, a key tumor suppressor gene, alongside increased levels of virulent bacteria such as F. nucleatum, reduced commensals, and heightened inflammation. This microbiota-driven epigenetic alteration correlates with poorer outcomes, particularly in IBD-associated CRC, suggesting that FMT from healthy donors could reverse such dysbiosis-induced effects and support CRC prevention [100]. Clinical investigations have reported that in CRC, FMT combined with immune checkpoint blockade improved microbial diversity and CD8⁺ T-cell infiltration, thereby enhancing antitumor immunity. Similarly, in microsatellite-stable metastatic CRC, FMT administered alongside PD-1 and VEGFR inhibitors slowed tumor progression and reshaped the gut microbiota toward beneficial taxa, including Proteobacteria and Lachnospiraceae [101, 102].
While current studies have demonstrated the potential of probiotics and FMT in reducing F. nucleatum levels and improving gut health, there is currently no direct mechanistic evidence linking these interventions to the modulation of F. nucleatum-related ncRNAs in CRC. Future research should prioritize understanding the interactions between F. nucleatum and host ncRNAs, as well as identifying the specific molecular pathways through which probiotics and FMT exert their effects.
Conclusion
The dynamic interplay between F. nucleatum and ncRNAs in CRC reveals a sophisticated molecular network that drives disease onset, progression, and resistance to therapy. This review highlights F. nucleatum’s transformation from a commensal bacterium to a key player in CRC pathogenesis, mediated by its virulence factors (e.g., FadA and Fap2) and metabolites, which orchestrate oncogenic pathways such as Wnt/β-catenin, PI3K/AKT, and NF-κB. These pathways are intricately regulated by ncRNAs, including miRNAs, lncRNAs, and circRNAs, which serve as critical modulators of tumor-promoting processes, including proliferation, metastasis, and chemoresistance. However, significant knowledge gaps hinder the translation of these insights into clinical applications. The precise mechanisms by which F. nucleatum selectively alters ncRNA expression and the impact of these changes across diverse patient cohorts remain unclear. Additionally, while probiotics and FMT show potential in reducing F. nucleatum abundance, their ability to restore ncRNA balance and mitigate CRC risk lacks direct evidence. These uncertainties prompt compelling questions: Can we design therapies that specifically target F. nucleatum-ncRNA interactions without disrupting the gut microbiome? How do host genetic variations, such as KRAS mutations, shape this axis and inform personalized treatments? To address these challenges, future research should prioritize longitudinal multi-omics studies to map the temporal dynamics of F. nucleatum-ncRNA interactions, advanced models such as patient-derived organoids to unravel molecular mechanisms, and clinical trials to evaluate probiotics and FMT as modulators of ncRNA profiles. Developing targeted inhibitors, such as small molecules against FadA or RNA-based therapies silencing oncogenic ncRNAs, offers a promising path for precision medicine. The F. nucleatum-ncRNA axis stands as a pivotal frontier in CRC research, and by tackling these gaps through interdisciplinary efforts, we can pave the way for innovative diagnostics and therapies to improve patient outcomes.
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