Fusobacterium nucleatum: a transboundary pathogen in host-microbiota networks
- Open Access
- 01.12.2025
- Review
Erschienen in:
Abstract
Introduction
Fusobacterium nucleatum (Fn) is a Gram-negative anaerobic bacterium that constitutes a normal component of the oral microbiota. In recent years, it has been found to be closely associated with various inflammatory diseases and cancers [1‐10]. Critically, Fn transcends its local niche to propagate systemic pathologies—a role inadequately addressed in prior syntheses. Most existing studies focused on Fn’s role in single diseases, such as colorectal cancer (CRC) and inflammatory bowel disease (IBD), overlooking its capacity as a unifier of multi-organ pathogenesis. Under disease conditions, Fn breaches mucosal barriers, enters the bloodstream, and colonizes distal tissues, where it exerts pathogenic effects. We thus propose Fn as a ‘transboundary pathogen’—bridging local dysbiosis (oral/gut) and systemic diseases via conserved mechanisms. Fn exhibits significant subspecies diversity, with distinct subspecies showing tissue-specific colonization preferences [11]. Its virulence factors (VFs; e.g., adhesins, outer membrane vesicles [OMVs]) enable adhesion, invasion, and immune evasion [5, 12, 13]. Critically, these shared molecular tools, individually or in synergy with other microbes, promote both Fn’s transboundary dissemination and pathogenicity, a link that has not been systematically delineated in prior reviews.
Beyond isolated virulence, Fn orchestrates pathologically significant polymicrobial interactomes [14‐19]. Synergistic alliances (e.g., with Porphyromonas gingivalis or Escherichia coli) enhance biofilm aggressiveness and barrier-breaching efficiency—a transboundary mechanism overlooked in single-pathogen paradigms [20]. Antagonistic cross-talk occurs where probiotics (e.g., Lactobacillus spp.) inhibit Fn colonization via competitive exclusion or bacteriocin production [15‐18].
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Its metabolites (e.g., Short-chain fatty acids [SCFAs], hydrogen sulfide [H₂S]) exhibit context-dependent effects: butyrate’s anti-inflammatory/barrier-protective roles vs. tumor-promotion at high concentrations [21‐26], but it can also induce DNA damage in CRC cells of different genotypes [24]. Butyrate at an average concentration of 32 mmol/L has shown cytotoxicity to Vero cells and in mice [25]. Similarly, H₂S can shift from cytoprotective at low concentrations to cytotoxic at high levels [27‐33]. Notably, non-steroidal anti-inflammatory drugs (NSAIDs) releasing low levels of H₂S have demonstrated significant anti-tumor effects in both mice [27] and humans [28]. Measuring H₂S levels in vivo remains challenging [30]. The concentration of H₂S in the human colon is approximately 250 µmol/L [32], and this level has been shown to cause significant genetic damage in mice [32]. Furthermore, an animal study found that even 1 µmol/L of sulfide can induce DNA damage in mice, potentially leading to the accumulation of mutations in CRC-related genes [31].
Critically, this synergism-antagonism duality (not merely co-existence) mediates Fn’s spatial dissemination: Cross-kingdom metabolic coupling (e.g., Fn’s acetate secretion promoting acid-tolerant pathogens) accelerates niche expansion [21‐24]; Metabolites like butyrate or H₂S exhibit context-dependent virulence modulation — their roles as collaborative facilitators or inhibitors remain unresolved in transboundary pathogenesis. We propose the unifying hypothesis of Fn as a ‘transboundary pathogen’—bridging local dysbiosis (oral/gut) and systemic diseases (e.g., CRC, IBD) via unique adhesion/invasion and immunomodulation. This perspective offers a novel framework for understanding microbiota-driven systemic pathologies.
Fn subspecies classification and pathogenic heterogeneity
Fn subspecies comprise five major subsp.: nucleatum (Fnn), animalis (Fna), polymorphum (Fnp), fusiforme (Fnf), and vincentii (Fnv)—the latter now recognized as phylogenetically identical to Fnp [11]. Each subspecies exhibits tissue-specific colonization patterns and distinct pathogenic mechanisms (Table 1), driven by differential VF expression: conserved VFs (e.g., Recombinase a direct-binding domain-containing adhesin [RadD] in Fnn/Fnp) versus subspecies-restricted VFs (e.g., Ferritin-like DNA-binding protein from Fn [Fn-Dps] exclusively in Fnn).
Fnn: orchestrating immune evasion through conserved virulence hubs
Fnn remains the best-characterized subspecies in gastrointestinal and oral pathologies (Table 1). Its immunosuppressive strategies involve: (1) RadD-Siglec-7 binding to inhibit natural killer cell (NK cell) cytotoxicity, promoting survival across CRC, pancreatic, and breast cancers [34‐38]; (2) Chitin-binding protein F (CbpF)-mediated carcino-embryonic antigen related cellular adhesion molecule1 (CEACAM1) engagement suppressing T/NK cell activity [39, 40]; (3) Fibroblast activation protein 2 - T cell immune receptor with Ig and ITIM domains (Fap2-TIGIT) interaction blocking immune activation [41].
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Critically, Fnn exploits shared VFs for gut barrier disruption. Fn adhesin A (FadA) binding to E-cadherin activates β-catenin/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, inducing DNA damage (↑Checkpoint kinase 2 [CHK2]), pro-inflammatory cytokine release, and colonic epithelial invasion—a mechanism exacerbating IBD-to-CRC progression [42‐45]. OMV-delivered FadA traffics to joints via circulation, exacerbating rheumatoid arthritis (RA) through Ras-associated binding protein 5a - Y-box binding protein 1 (Rab5a-YB1) axis activation [46]. Fusobacterial outer membrane protein A (FomA)-containing OMVs activate toll like receptor 2 (TLR2)/NF-κB in intestinal epithelial cells (IECs), reshaping gut innate immunity [47]. Fn-Dps (a novel VF) drives CRC metastasis by lysing erythrocytes via iron competition, enhancing macrophage survival via C-C motif chemokine ligand 2/C-C motif chemokine ligand 7 (CCL2/CCL7) upregulation, and inducing epithelial-mesenchymal transition (EMT) [48].
Fna: dominant CRC driver via genomic adaptation
Fna demonstrates distinct strain-level genomic adaptations that potentiate its role in colorectal carcinogenesis [49]. Mechanistically, Fna infection activates pro-inflammatory monocytes within the colonic mucosa, thereby fueling microenvironmental inflammation conducive to tumor development [10]. Critically, its OMVs deliver lipopolysaccharide (LPS) capable of binding the immunoreceptor Siglec-7, directly implicating bacterial immune subversion in CRC progression [50]. Genomic stratification further resolves Fna into two functionally specialized clades: C1, enriched in oral colonization genes (radD/ami1/fadA2), and C2, predominating in CRC tumors and harboring fap2/cmpA/fusolisin—a suite of virulence factors hypothesized to facilitate intestinal niche colonization and persistence [51]. Collectively, these genomic and functional adaptations position Fna as a paradigm of subspecies evolution dedicated to gut-specific pathogenicity.
Fnp/Fnv: bridging oral dysbiosis to systemic inflammation
Compared to the more extensively studied Fnn and Fna, research on Fnp is relatively limited. Fnp serves as a critical mediator of oral-gut axis crosstalk. Its RadD adhesin binds Streptococcus mutans SpaP protein, facilitating the formation of oral biofilms that act as reservoirs for bacterial translocation to the gut [20, 52]. Crucially, Fnp-derived OMVs transport LPS, DNA, and adhesins to intestinal sites, where they activate the toll like receptor 4 (TLR4)/extracellular signal-regulated kinase (ERK)/cAMP response element-binding protein (CREB)/NF-κB signaling cascade in gut epithelial cells, thereby amplifying systemic inflammatory responses [52]. Furthermore, Fnp dynamically modulates sulfur metabolism through its cysteine synthase-PLP system, generating H₂S—a key mediator implicated in both periodontal tissue destruction and gut barrier dysfunction [53]. Additionally, emerging evidence links Fnp to Yes-associated protein (YAP)-driven oncogenic signaling, suggesting a direct role in oral carcinogenesis [54]. However, the precise mechanisms underlying this oncogenic process remain to be elucidated. Recent genomic analyses have reclassified Fnv as synonymous with Fnp [11]. However, clinical isolates from neurological cases suggest a potential neuropathogenic role: LPS-induced systemic inflammation may contribute to reported associations with cerebral edema [55]. Further mechanistic studies are needed to elucidate how oral/gut-colonizing strains translocate to neural tissues. As synthesized in Table 1, Fn subspecies exhibit distinct pathogenic specialization. Importantly, shared mechanisms—such as OMV trafficking and VF dissemination from oral/gut reservoirs—unify these subspecies as transboundary pathogens. Future studies should prioritize mapping cross-subspecies VF distribution through pangenome analysis, developing VF-targeted inhibitors (e.g., anti-FadA) for barrier-specific therapies, and elucidating gut-to-neural trafficking routes of Fnp/Fnv clinical isolates.
Table 1
Variations in VFs among Fn subspecies
Subspecies | VF | Clinical associations | Pathogenic roles |
|---|---|---|---|
Fnn | FadA | CRC, Ulcerative colitis, RA | 2) FadA exacerbates RA via the Rab5a-YB1 axis [46] |
Fnn | Fap2 | Cancer | Fap2 binds to human inhibitory receptor TIGIT to protect tumors from immune cell attack [41] |
Fnn | CbpF | Cancer | |
Fnn | FomA | Gut diseases | FomA + OMVs activate TLR2/NF-κB in IECs [47] |
Fnn | Fn-Dps | CRC | It enhances Fn retention in macrophages via CCL2/CCL7 upregulation [48] |
Fnn | RadD | Pan-cancer, Oral disease | RadD-Siglec-7 axis inhibits NK cell function to enhance tumor survival [38] S. mutans SpaP binds to RadD of the Fnp subspecies to form a biofilm [20] |
Fnp | H₂S | Halitosis | Fnp dynamically regulates H₂S synthesis via its cysteine synthase-PLP system [53] |
Fnp | OMVs | Inflammation | Fnp-OMVs activate TLR4/ERK/CREB/NF-κB axis to drive pro-inflammatory cytokine production [52] |
Fna | LPS | CRC | LPS-OMVs bind Siglec-7 to modulate immunity and promote CRC [50] |
Fnv | LPS | Cerebral swelling | Fnv releases LPS, triggering systemic inflammation [55] |
Fn: transboundary routes to systemic pathologies
Beyond its enrichment in hypoxic oral niches (e.g., periodontal pockets, gingival sulci), Fn secretes VFs such as adhesins to interact with epithelial cells, driving oral inflammatory diseases [56‐58]. Critically, Fn exhibits transboundary colonization, invading distant sites like the gastrointestinal tract (esophagus, stomach, colorectum, liver) and associating with related systemic pathologies [42, 45, 59‐67]. This ubiquitous localization and trans-barrier migration establish Fn as a pivotal “microbiota-host-disease” mediator [46, 68‐77] (Fig. 1).
Fig. 1
Systemic pathologies associated with Fn infection: A transboundary pathogen perspective
Key spatial features of Fn:
(1) Colonization and Migration:
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As a Primary resident in oral/GI mucosa [56], Fn translocates across barriers to distal organs [71] via hematogenous routes.
(2) Tissue-Specific Pathogenesis:
(3) Systemic Pathogenesis:
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(i)
Atherosclerosis: Hepatic lipid dysregulation via phosphatidylinositol 3-kinase/ AKT threonine kinase/mechanistic target of rapamycin (PI3K/Akt/mTOR) → plaque formation [71].
(ii)
(iv)
(v)
Joints: OMVs deliver FadA to synovium → autoreactive B cells → anti-citrullinated protein antibodies (ACPAs) in RA [46].
(vi)
Breast: Fap2 → Gal-GalNAc → cancer stem cell (CSC) enrichment; synergizes with programmed death-ligand 1 (PD-L1) → immune evasion [77].
(4) Molecular Drivers:
Adhesins (FadA, RadD, Fap2, FomA), biofilm formation, immune evasion, metabolic adaptation (glycolysis/SCFAs), and OMV-mediated effector delivery enable Fn’s tissue tropism and trans-barrier migration. Targeting these mechanisms offers therapeutic potential against multiple Fn-linked diseases.
Mechanisms of Fn-mediated drug resistance in cancer therapy
Anti-PD-1 monoclonal antibody (mAb) blockade is pivotal in CRC treatment, yet therapeutic resistance persists. Accumulating evidence reveals that Fusobacterium nucleatum (Fn) orchestrates therapy resistance through multifaceted mechanisms across cancer types (Fig. 2).
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Fn exhibits bidirectional immunoregulation, modulating checkpoint efficacy in both CRC and head/neck cancers:
(i)
Negative regulation in CRC: Fn-derived succinate suppresses the cyclic MP-AMP synthase - interferon-β (cGAS–IFN-β) axis (Fig. 2A), reducing cluster of differentiation 8⁺ (CD8⁺) T-cell infiltration and blunting anti-PD-1 responses [80]. C-X3-C motif chemokine receptor 1⁺ (CX3CR1⁺)PD-L1⁺ phagocytes transfer intracellular Fn to tumor cells, recruiting polymorphonuclear neutrophils (PMNs)/immunosuppressive macrophages (MΦs) via C-X-C motif chemokine ligand 2/8 - C-X-C chemokine receptor type 2 (CXCL2/8-CXCR2) and C-C motif chemokine ligand 5 - C-C chemokine receptor 5 (CCL5-CCR5) axes → metastatic progression → immunotherapy resistance (Fig. 2D) [81].
(ii)
Positive regulation: Fn activates stimulator of interferon genes (STING) signaling → PD-L1 upregulation → enhances IFN-γ⁺CD8⁺ tumor-infiltrating lymphocytes.
(iii) Head and neck squamous cell carcinoma (HNSCC)-specific mechanism:
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In HNSCC, Fn-OMVs deliver tryptophanase (TnaA) to tumor-associated macrophages (TAMs) → activates tryptophan 2,3-dioxygenase 2/aryl hydrocarbon receptor (TDO2/AHR) pathway → upregulates IL-10 and checkpoint molecules → promotes immune evasion (Fig. 2C) [83].
Fig. 2
Fn-driven immunotherapy resistance mechanisms. (A) Fn metabolite succinate suppresses the cGAS–IFN-β pathway, impairing CD8⁺ T cell infiltration into the TME; (B) Fn activates the STING signaling pathway to induce PD-L1 expression; (C) TAMs internalize TnaAfrom Fn-derived OMVs, activating the TDO2/AHR axis and triggering IL-10 production; (D) CX3CR1⁺PD-L1⁺ phagocytes translocate intracellular Fn to tumor cells. This process recruits PMNs/MΦsg via CXCL2/8-CXCR2 and CCL5-CCR5 chemokine axes, promoting CRC metastasis and diminishing immunotherapy efficacy
Fn drives chemoresistance through metabolic reprogramming and epigenetic silencing. Fn selectively suppresses miR-18a and miR-4802 expression via the TLR4/myeloid differentiation primary response 88 (MyD88) pathway, inducing tumor autophagy and thereby conferring chemoresistance in CRC [84]. Furthermore, this bacterium mediates chemotherapeutic resistance through upregulated expression of anti-apoptotic protein baculoviral IAP repeat containing 3 (BIRC3) and chloride channel ANO1.136 [85]. To counteract Fn-induced drug resistance [86], the recently developed MPLO@HA nanodrug—constituted by covalent conjugation of oligomeric methyleneimine with metformin, oxaliplatin, and lauric acid, followed by surface-coating with hyaluronic acid—demonstrates therapeutic potential by concurrently targeting bacterial infection, chemoresistance, and immunosuppression in Fn-associated CRC [87].
The dual-faced nature of Fn in cancer therapeutics necessitates precision intervention strategies: Targeted microbiota modulation (selective Fn depletion without disrupting commensal flora) and combinatorial approaches dynamically balancing microbial and TME represent pivotal keys to overcoming emerging cancer resistance paradigms.
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Multilayered barrier disruption and bidirectional immunomodulatory role of Fn in the gut
Paracellular and apoptotic breaching of epithelial defense
The intestinal barrier constitutes an innate defense system comprising multiple protective layers, including mechanical, chemical, microbial, and immunological barriers. Pathogenic gut bacteria primarily compromise this barrier through three mechanisms: the paracellular pathway, transcellular pathway, and apoptotic pathway [88]. Fn induces barrier damage predominantly through the paracellular pathway and apoptotic pathway (Fig. 3). Intercellular junctions, including tight junctions (TJs), adherens junctions (AJs), and desmosomes, form protein complexes that regulate paracellular passage of molecules and pathogens to maintain intestinal homeostasis [89]. Fn compromises intestinal barrier integrity through two primary mechanisms: Disruption of TJ proteins (e.g., zonula occludens-1 [ZO-1] and occludin), enabling deeper invasion into subjunctional structures (e.g.,AJs). Direct induction of IECs apoptosis or autophagy.
Fig. 3
Fn-mediated multimodal disruption of the intestinal barrier: Molecular pathways targeting tight junction integrity and epithelial homeostasis. (A) Myosin light chain (MLC) signaling pathway regulation; (B) Fn-OMV-mediated miR-574-5p downregulation leading to caspase recruitment domain family member3 (CARD3) pathway activation; (C) Signal transducer and activator of transcription 3 (STAT3) activation induced by acetyl-CoA accumulation; (D) TNF-α secretion via Fn-OMVs triggering receptor-interacting protein kinase 1/receptor-interacting protein kinase 3 (RIPK1/RIPK3) kinase modulation; (E) IL-8-dependent neutrophil recruitment through TLR2/ERK signaling. The red arrows and green arrows indicate upregulation and downregulation of expression
Elucidating Fn-mediated TJ dysregulation and epithelial cell death pathways represents a promising therapeutic strategy for IBD (Table 2). Notably, maintaining the stability of the intestinal mucin layer has emerged as a promising research focus in understanding the pathogenesis of IBD in recent years [90]. Paneth cells secrete antimicrobial peptides into the mucosa, contributing to the support of the stem cell niche within the crypts [91]. Goblet cells serve as critical therapeutic targets for IBD intervention [92]. However, Fn damages goblet cells and disrupts the mucus barrier by stimulating MUC2 expression and secretion in the IECs line Caco-2 [93]. Under antibiotic treatment, Fn-OMVs can induce IL-8 and TNF production, leading to irreversible damage and depletion of goblet cells [52]. Conversely, certain probiotics (e.g., Saccharomyces cerevisiae) and kefir supernatant [94] have been demonstrated to ameliorate Fn-induced goblet cell injury. The molecular mechanisms by which Fn impairs goblet cells to exacerbate host infections remain relatively underexplored and warrant further investigation.
Table 2
Experimental evidence of Fn-mediated paracellular pathway via TJ disruption and apoptotic pathway through epithelial cell death
Mechanisms | Pathway |
|---|---|
1. Paracellular pathway | 1). MLC signaling pathway activation [95] |
2). CARD3 expression and ER stress [96] | |
3) En-OMVs-mediated regulation (miR-574-5p expression⬇) [79] | |
4). Induces ZO-1/occludin degradation through RIPK1/RIPK3 signaling [97] | |
5). Fn induces IL-8 secretion via TLR2/ERK [2] | |
6). Acetyl-CoA accumulation activates STAT3 [1] | |
2. Apoptotic pathway | 1). Fn-secreted LPS induces autophagic cell death in IECs, exacerbating intestinal inflammation [98] |
2). Acetyl-CoA accumulation activates STAT3 [1] | |
3). Fn-OMVs downregulate miR-574-5p [79] | |
4). Fn-OMVs trigger RIPK1/RIPK3-mediated necroptosis and oxidative stress [97] |
Bidirectional immunomodulatory role of Fn in the gut
Fn exhibits strain-specific and microenvironment-driven duality in gut immunity regulation, reconciling seemingly contradictory Th17/Treg responses. In inflammatory contexts (e.g., established colitis or CRC), Fn dominates and secretes FadA adhesin, which hyperactivates STAT3 signaling to expand pro-inflammatory Th1/Th17 populations; this is exacerbated by formate-driven free fatty acid receptor 2 (FFAR2) stimulation that overproduces IL-17, further compromising barrier integrity [78, 95]. Conversely, in localized microenvironments with preserved epithelial function, Fn preferentially engages TLR4 via unique LPS structures, inducing forkhead box P3⁺ (Foxp3⁺) Treg differentiation and IL-10 secretion to resolve inflammation [99].
Despite SCFAs’ established anti-inflammatory properties [26], Fn-derived fermented butyrate/isovalerate exhibit diminished bactericidal capacity [100, 101] yet act as potent chemoattractants: butyrate binding to FFAR2 triggers neutrophil chemotaxis and calcium influx, amplifying inflammation at damaged sites [102]. Fn depletes commensal butyrate producers (Lachnospira, Roseburia, Faecalibacterium), suppressing protective butyrogenesis and AMP-activated protein kinase (AMPK)-mediated proliferation control - an effect exacerbated by antibiotics [103]. In TME, Fn-derived butyrate alleviates CD8⁺ TIL exhaustion by suppressing PD-1 through the histone deacetylase 3/T-box transcription factor 21 (HDAC3/TBX21) axis, increasing PD-1 sensitivity in microsatellite-stable CRC [104]; Fn-synthesized 3-indolepropionic acid (IPA) activates the aryl hydrocarbon receptor to drive macrophage M2 polarization and promote tumor immunosuppression [105].
Thus, the Th17/Treg paradox hinges on three determinants: (1) Microbial competition: Commensal-derived butyrate favors Tregs, whereas dysbiosis permits Fn-driven Th17 bias; (2) Spatial localization: Ulcerated sites with TLR2/ERK activation enable FFAR2-mediated neutrophil recruitment; (3) SCFA structural specificity: Fn-produced iso-butyrate (C4) vs. commensal n-butyrate (C6) alters FFAR3 affinity for IL-17 induction. The immunological impact of Fn is therefore a function of strain virulence factors, metabolite gradients, and host-tissue crosstalk - reconciling its dual role in inflammation and cancer. Consequently, the “double-edged sword” effects of Fn-derived SCFAs have become a research focus, revealing their pathogenic contributions to inflammation and tumorigenesis [106].
Therapeutic implications: targeting strain heterogeneity and microbial networks
The colonization dynamics and pathogenic potential of Fn are critically regulated by bidirectional interactions within polymicrobial ecosystems. Compelling evidence reveals that specific commensals and probiotics—notably Lactobacillus rhamnosus, Akkermansia muciniphila, Streptococcus salivarius, Parabacteroides distasonis, Enterococcus faecalis, and Bifidobacterium animalis—antagonize Fn through three synergistic mechanisms: (1) Direct antimicrobial secretion (e.g., bacteriocins, SCFAs); (2) Host signaling modulation (e.g., PI3K/AKT/mTOR, TLR/NF-κB); and (3) Restoration of cellular defense pathways (e.g., autophagy). Collectively, these actions suppress Fn proliferation, adhesion, and inflammatory cascades (Fig. 4; Table 3).
Conversely, Fn forms synergistic consortia with pathobionts including Clostridioides difficile, Pseudomonas aeruginosa, Tannerella forsythiais, Parvimonas micra, and S. mutans via: (1) Adhesin-mediated biofilm co-aggregation (e.g., RadD-pili binding); and (2) Immunomodulatory cross-talk that enhances reciprocal colonization (Fig. 4; Table 3). Such alliances exacerbate tissue damage and drive progressive inflammation.
Fig. 4
Interacting network of Fn within the gut microbial ecosystem. The light green shaded areas represent antagonism; the light purple shaded areas represent synergism; red arrows and green arrows indicate upregulation and downregulation of expression, respectively; the red X symbol denotes blocking
Notably, the established synergy between periodontal pathogens P. gingivalis and Fn correlates with advanced carcinogenesis in OSCC, CRC, and pancreatic ductal adenocarcinoma (PDAC). However, the precise molecular mechanisms underlying these cooperative networks remain largely undefined [19]. Thus, dissecting Fn’s polymicrobial interplay represents a pivotal frontier for targeted therapeutic development. Fundamentally, the equilibrium between microbial antagonism and synergism dictates Fn’s net pathogenicity and clinical disease trajectories.
Table 3
Mechanisms classification of Fn-gut microbiota interactions
Bacterium | Disease | Mechanism |
|---|---|---|
Antagonist | ||
L. rhamnosus | IBD | Inducing the reduction of p-mTOR, p-p85 and p-AKT protein levels and effectively restoring the damaged autophagic flux [15] |
A. muciniphila | Periodontitis | Inhibiting the inflammatory effect of Fn on GECs by inhibiting TLR/MyD88/NF-κB pathway modulation and secretion of inflammatory factors [107] |
S. salivarius | CRC | Secreting of a novel antimicrobial peptide nisin G [16] |
P. distasonis | CRC | It is speculated that it is the function of some metabolites of P. dielii [17] |
B. animalis | CRC | Secreting acidic metabolites (such as lactic acid, acetic acid, propionic acid and butyric acid) to inhibit the growth of Fn [18] |
L. reuteri | Periodontitis | |
E. faecalis | Endodontic Infections | Producing an acidic microenvironment and hydrogen peroxide, showing a strong ability to kill Fn, thereby invading and dominating the pre-established in vitro Fn biofilm [110] |
S. gordonii | Inflammation | Coagulation can inhibit the adhesion and invasion of Fn to human gingival epithelial cells (hGECs). On the contrary, it can enhance the pathogenicity of S. gordonii [111] |
Synergist | ||
C. difficile | C. difficile Infection | Fn can bind to the pili of C. difficile through RadD, thereby promoting the formation of biofilm in intestinal mucus and increasing the colonization ability [14] |
P. aeruginosa | Respiratory diseases | Fn and P. aeruginosa aggregated to form more complex biofilms and invaded respiratory epithelial cells together, effectively increasing the levels of IL-13, TNF-x and IL-6 in the lungs [73] |
P. micra | Periodontitis | Having a synergistic biofilm formation effect [112] |
T. forsythiais | Periodontitis | |
S. mutans | Others | Its adhesin SpaP can specifically recognize the adhesin RadD of Fn, thereby enhancing their colonization in the oral cavity [20] |
Conclusion and prospective
Research on the pathogenic mechanisms of Fn and its microbial interactions is profoundly reshaping our understanding of the microbiota-host-disease axis. This review systematically integrates the subspecies heterogeneity, spatial colonization characteristics, pathogenic mechanism network, and synergistic-antagonistic relationships of Fn within microbial communities, revealing its complex biological behaviors as a “transboundary pathogen.” Although breakthroughs have been made in Fn research, several critical questions warrant deeper exploration. Current therapeutic strategies targeting Fn, such as antibiotics and nanoparticle-mediated treatments (e.g., MPLO@HA), lack subspecies specificity and could inadvertently disrupt commensal flora. Key unresolved issues include: How can we dynamically monitor the concentration thresholds of key metabolites within local microenvironments? Would targeted modulation of specific metabolic pathways (e.g., butyryl-CoA transferase inhibition) prove superior to directly eradicating Fn populations? Furthermore, while Fn forms synergistic oncogenic alliances with bacteria like P. gingivalis and streptococci, the molecular mechanisms underlying these interactions remain largely a “black box.” Deciphering metabolite exchange, signaling dialogues within biofilms, and exploring ecological niche competition through multi-omics integration is essential.
Notably, Fn exists as a commensal bacterium in the oral cavity of healthy individuals but transforms into a pathogen under specific host genetic backgrounds (e.g., subjects with CEACAM1 mutations) [115, 116] or microenvironmental conditions (e.g., the hypoxic core of CRC tumors). This highlights that its pathogenesis fundamentally reflects “dysbiosis” rather than “foreign invasion”.
Future research should integrate advanced host gene-microbiota interaction models, such as organoid co-culture systems combined with clustered regularly interspaced short palindromic repeats (CRISPR) screening, to dynamically model the transition from microbial symbiosis to pathogenicity. Employ Fna-specific genomic markers, such as fap2 and fusolisin, in fecal DNA testing to enable non-invasive CRC screening. Develop anti-FadA monoclonal antibodies or Fn-Dps inhibitors to inhibit metastasis while preserving commensal microbiota. Engineer localized delivery systems for butyrate-scavenging nanoparticles or H₂S-neutralizing compounds to suppress procarcinogenic microenvironments. Investigate metabolite exchange between Fn and P. gingivalis, such as heme/iron sharing, using spatial transcriptomics in biofilms. Prioritize CRISPR-based editing of Fn subspecies in organoid systems, the development of real-time metabolite biosensors, and the clinical validation of comprehensive Fn biomarker panels across diseases.
Fn serves as a prism, refracting the complex nature of microbes as both destructive agents and potential modulators in human disease. To harness the power of the microbiota and achieve a medical paradigm shift from confrontation to coexistence, a deeper deconstruction of its survival logic is imperative.
Declarations
Competing interests
The authors declare no competing interests.
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