Integrated oral-gut microbiota therapy: a novel perspective on preventing bacterial translocation for systemic disease management

Traditionally, the gastrointestinal tract maintains physiological segregation between oral and gut microbiota through multiple defense mechanisms collectively termed the “oral-gut barrier”. This barrier system comprises chemical defenses (gastric acid and bile acids), host pattern recognition receptors, and colonization resistance conferred by indigenous gut microbiota. Within this paradigm, oral-to-gut microbiota translocation was historically viewed as a pathological aberration. However, emerging evidence challenges this notion, demonstrating that substantial quantities of oral microbiota—both as free-living organisms and within keratinocyte complexes—routinely enter the digestive tract through dietary intake. Salivary components (including water, lipids, and mucins) provide crucial protection, enabling these microorganisms to survive the harsh gastric environment and persist in the gastrointestinal tract. Abdelary et al.’s sodA sequence analysis definitively established the oral cavity as an endogenous source of gut microbiota, confirming that oral-gut microbiota translocation represents a widespread physiological phenomenon in healthy individuals (Schmidt et al., 2019; Abdelbary et al., 2022).

This translocation process becomes particularly pronounced when gastric acid and bile acid barriers are compromised or when microbiota develop resistance to these defenses, as demonstrated by Jackson and Boll’s research (Boll et al., 2012; Jackson et al., 2016). Clinical observations reveal significantly elevated levels of oral-derived bacteria (including Streptococcus, Veillonella, and Haemophilus spp.) in the intestines of long-term proton pump inhibitor users and inflammatory bowel disease (IBD) patients compared to healthy controls (Kitamoto et al., 2020b; Imai et al., 2021; Kitamoto and Kamada, 2022). Notably, the gut microbiota of IBD patients exhibits marked “oralization,” acquiring compositional features resembling oral microbiota. Certain oral pathogens (e.g., P.g) can survive the acidic gastric environment and traverse the gastric barrier (Walker et al., 2018). The oral microbiota may also disseminate to the gut via hematogenous or lymphatic routes. For instance, during dental procedures, increased oral epithelial permeability, or food ingestion, oral microbes may infiltrate and spread to extraoral sites. F.n, a Gram-negative oral anaerobe, exhibits strong binding affinity to vascular endothelium and modulates barrier permeability, potentially facilitating hematogenous dissemination—even transplacentally—and promoting co-invasion of commensal bacteria (e.g., Escherichia coli) into circulation. Finally, some oral pathogens carrying virulence factors that inhibit phagolysosome formation can invade dendritic cells and macrophages, hijacking these immune cells as “Trojan horses” for intestinal migration (Hajishengallis, 2015).

Bacterial translocation or their metabolites can disrupt the homeostasis of the gut microbiota and compromise intestinal barrier function, leading to dysbiosis (Kitamoto et al., 2020c; Mo et al., 2022). Oral microbiota colonize the gut by triggering intestinal inflammation, impairing colonization resistance of the gut microbiota, and enhancing resistance to the gastrointestinal chemical barrier, thereby disrupting host-microbiome homeostasis (Kim et al., 2017; Ducarmon et al., 2019). Intestinal inflammation is closely linked to gut dysbiosis, as inflammation provides an ecological niche for ingested oral bacteria while impairing pattern recognition receptors (PRRs) of gut immunity, resulting in reduced antimicrobial peptide production and diminished pathogen clearance (Larabi et al., 2020). Studies have found that periodontal pathogens (e.g.,P.g) produce an interspecies quorum-sensing signal called autoinducer-2 (AI-2), which modulates gut microbiota composition by promoting the growth of Firmicutes and increasing the Firmicutes/Bacteroidetes (F/B) ratio (Thompson et al., 2015; du Teil Espina et al., 2019). Certain oral microbes exhibit distinct metabolic pathways compared to gut commensals, enhancing their adaptability and competitive advantage in the inflammatory intestinal environment (Kitamoto et al., 2020a). Periodontal pathogens can further compromise the integrity and function of both the intestinal mucus barrier and epithelial barrier. They directly or indirectly reduce interepithelial adhesion, and may even invade and transmigrate across epithelial cells, thereby exacerbating intestinal “leakiness.” For instance, P.g employs its gingipains to directly degrade tight junction proteins (e.g., occludin) and adherens junction proteins (e.g., E-cadherin) (Tsuzuno et al., 2021). Certain pathogenic bacteria (e.g., P.g, A.a, and T.denticola) also downregulate E-cadherin expression on intestinal epithelial surfaces, disrupting adherens junctions and facilitating bacterial translocation (Devaux et al., 2019). Moreover, colonization by periodontal bacteria impairs the gut’s immune barrier. For example, P. gingivalis colonization increases pro-inflammatory cytokines (e.g., IL-6 and TNF-α) in the gut (Lee et al., 2022). In summary, periodontal pathogens disrupt the homeostasis of both the gut microbiota and immune barrier, potentially triggering excessive intestinal immune responses, damaging the intestinal barrier, and ultimately contributing to systemic diseases associated with altered gut immunity (Liu et al., 2021).

A healthy gut microbiota plays a dual role in maintaining gut homeostasis and ameliorating oral dysbiosis, thereby contributing to periodontal disease control. Conversely, gut dysbiosis and inflammation can adversely affect the composition and stability of oral microbiota. Substantial evidence indicates that patients with IBD exhibit significant oral microbiota alterations that correlate with disease activity and increased susceptibility to oral pathologies (Zhou et al., 2023). Comparative analyses reveal distinct microbiota shifts in IBD patients, including elevated abundances of Veillonella and Prevotella in saliva (Abdelbary et al., 2022). Furthermore, Elmaghrawy et al. demonstrated IBD-associated perturbations in oral Firmicutes, characterized by decreased Clostridia and increased Bacilli-changes that directly correlate with disease severity (Elmaghrawy et al., 2023). Notably, therapeutic management of IBD can reverse these oral dysbiotic patterns, underscoring the dynamic interplay between gut health and oral microbiota. Emerging research elucidates multiple mechanisms through which gut microbiota and their metabolites influence periodontal pathogenesis: (1) Nutritional modulation: Enhanced Ca²⁺ and Mg²⁺ absorption promotes periodontal tissue integrity. (2) Osteogenic regulation: Direct activation of osteoblasts coupled with inhibition of osteoclast differentiation. (3) Anti-inflammatory effects: Lipocalin and vitamin D supplementation mitigate periodontal inflammation via gut repair. (4) Immunomodulation: Nagao et al. identified a gut-orchestrated immune pathway where oral P.g primes Th17 cell activation in Peyer’s patches, with subsequent migration to periodontal tissues (Nagao et al., 2022). The gut-oral axis is further evidenced by Th17/Treg dysregulation. Increased gut permeability and dysbiosis-induced inflammation disrupt bone marrow Th17/Treg homeostasis, exacerbating alveolar bone loss in periodontal and periapical diseases (Jia et al., 2024). Notably, probiotic administration can restore this balance and significantly attenuate bone resorption (Guo et al., 2023). These findings collectively highlight: Bidirectional communication between gut and oral ecosystems, the gut microbiota’s systemic immunomodulatory capacity, therapeutic potential of microbiota-targeted interventions and the critical importance of gut homeostasis for oral health maintenance (Figure 2).

AD is a progressive neurodegenerative disorder and the leading cause of cognitive and behavioral impairment worldwide. Its neuropathological hallmarks include amyloid-beta (Aβ) plaques and neurofibrillary tangles mediated by phosphorylated tau. Noble et al. (2009) analyzed data from the Third National Health and Nutrition Examination Survey (NHANES-III) and reported that individuals with elevated serum P.g IgG levels exhibited a higher likelihood of impaired speech memory and performance in subtraction tests (Noble et al., 2009). Furthermore, periodontal pathogens such as T.denticola, Tannerella forsythia, and P.g have been detected in postmortem brain tissue of AD patients (Poole et al., 2013; Dominy et al., 2019). The research findings by Lu et al. demonstrate that periodontitis-associated salivary microbiota may exacerbate the pathogenesis of Alzheimer’s disease (AD) through gut-brain axis crosstalk (Lu et al., 2022). Chen et al. investigated the composition of oral and gut microbiota across different stages of AD and observed a progressive increase in oral Firmicutes and Clostridiales abundance, while gut Firmicutes and Bacteroidetes levels declined from healthy controls to mild and moderate AD cases. Notably, the overlap between oral and gut microbiota intensified with AD severity, suggesting that moderate AD patients exhibit a higher propensity for oral-to-gut microbiota transmission compared to mild AD patients or healthy controls (Chen et al., 2022).

Oral microbiota may reach the brain through several potential pathways. First, via direct oral-brain communication, where periodontal pathogens and their virulence factors can compromise the blood-brain barrier (BBB) integrity by increasing its permeability, thereby gaining access to and damaging central nervous system tissue (Sansores-España et al., 2021). Second, through trigeminal nerve translocation, as demonstrated by Santiago Tirado et al., showing that certain periodontal pathogens like P.g employ virulence factors to evade phage lysosome formation, enabling intracellular survival and subsequent axonal/dendritic migration via Trojan horse mechanisms or vesicular transport (Santiago-Tirado et al., 2017). Third, the oral-gut-brain axis provides another route, wherein AD-associated gut dysbiosis increases gut barrier permeability, facilitating microbiota metabolite transfer into circulation. These circulating factors can then activate central nervous system(CNS) immune cells, triggering neuroinflammation and neuronal loss characteristic of AD (Bello-Corral et al., 2023). Enhanced gut leakage through this axis allows systemic dissemination of virulence factors and pro-inflammatory mediators either through circulation or via vagus nerve fibers (Sansores-España et al., 2021). The gut microbiota further modulates BBB function through multiple mechanisms, including secretion of hormones, metabolic cofactors, GI-derived small molecules, and inflammatory mediators like cytokines that influence BBB permeability through oxidative stress pathways. Chronic periodontal disease driven by dysbiosis promotes neuroinflammation and cognitive impairment through partial activation of the TLR4/MyD88/NF-κB signaling cascade, providing mechanistic support for the oral-gut-brain axis (Xue et al., 2020; Li et al., 2022). Compellingly, recent murine studies demonstrate that oral P.g inoculation induces both cognitive deficits and gut dysbiosis, offering direct experimental evidence for this pathway (Chi et al., 2021). In summary, oral bacteria can achieve ectopic colonization in the central nervous system through the oral-brain bidirectional communication and the oral-gut-brain axis pathways (Figure 4).

Current research reveals that ectopically colonized oral pathogens in the CNS can trigger excessive β-amyloid (Aβ) accumulation. These BBB-penetrating oral microbita activate neuroimmune responses, which not only enhance Aβ production but may also induce Aβ cascade amplification, thereby accelerating AD pathogenesis (Weaver, 2020). Taking P.g as an example, this pathogen stimulates aberrant β-amyloid generation through activating the cathepsin B (CatB)/NF-κB signaling pathway while upregulating TLR-2 and IL-1β expression (Nie et al., 2019). Furthermore, P.g-derived outer membrane vesicles (OMVs) containing gingipains not only boost Aβ production but also generate LPS via TLR4-mediated NF-κB and MAPK pathway activation, directly contributing to Aβ plaque formation (Zhao et al., 2017; Dominy et al., 2019). Beyond amyloid pathology, periodontal pathogens promote tau hyperphosphorylation, another hallmark of AD progression (Narengaowa et al., 2021). These microbiota also exacerbate neuroinflammation through neuromodulatory mechanisms: P.g-derived LPS elevates IL-17A levels in splenic mononuclear cells, and this cytokine can breach the blood-brain barrier to activate microglia-mediated neuroinflammation and cognitive impairment (Sun et al., 2015). Feng et al. demonstrated that serum IL-17A promotes neuronal apoptosis through IL-17RA interaction in P.g-exposed R1441G mice while in vitro studies confirm IL-17A’s capacity to activate microglia and accelerate dopaminergic neuron degeneration (Chen et al., 2020; Feng et al., 2020). Supporting these findings, Dominy et al. identified P.g DNA and gingipain antigens in AD mouse cerebrospinal fluid, confirming that periodontal pathogens induce neuroinflammation and neurodegeneration through neuronal pyroptosis and caspase-1 activation, resulting in elevated neuroinflammatory cytokines IL-1β and IL-18. Notably, small-molecule gingipain inhibitors have shown therapeutic potential by blocking P.g-induced neurodegeneration, providing neuroprotection and significantly reducing cerebral P.g burden in murine models (Dominy et al., 2019).

Emerging evidence highlights a strong association between disruptions in the oral and gut microbiota and various health conditions, including breast cancer (BC), adverse pregnancy outcomes (APOs), and gynecological disorders (GDs) such as preterm labor, spontaneous abortion, endometriosis, bacterial vaginosis (BV), and ovarian and cervical cancers (CC) (Ghosh et al., 2024) (Figure 5).

Petricevic et al. demonstrated that 80% of pregnant women and 40% of postmenopausal women shared identical lactic acid bacteria (LAB) isolates between their vaginal and rectal microbiota. Furthermore, 53% of pregnant women and 33% of postmenopausal women exhibited overlapping LAB strains in oral and rectal samples, suggesting that the oral and gut tracts may serve as reservoirs for vaginal colonization (Petricevic et al., 2012). Adolescent women with suboptimal vaginal microbiota exhibited a higher prevalence of periodontal pathogens—including Prevotella intermedia and P.g—in their supragingival microbiota, alongside enriched Pseudomonas aeruginosa and Pseudomonas intermedia in saliva (Balle et al., 2020). Notably, Prevotella copri, a gut microbe associated with a healthy microbiota, was found exclusively in vaginal samples of women without BV. Wei et al. investigated the vaginal and oral microbiota in women with a history of abortion, HPV infection, or CC, revealing a significant increase in periodontal pathogens among CC patients. Shared pathogens such as Porphyromonas spp. and Prevotella spp. were identified as oral biomarkers for CC. Their findings underscore that vaginal and oral microbiota are interconnected, with microbiota translocation between body sites potentially influencing systemic metabolism (Zhang et al., 2024). Huang et al. quantified F.n levels in tumor tissues from 112 CC patients using qPCR, revealing significantly elevated F.n in CC tissues, particularly in recurrent cases. A multi-omics study by Maarsingh et al. further demonstrated that F.n infection exacerbates HPV persistence and cervical neoplasia by inducing pro-inflammatory responses, upregulating cell cycle metabolism, and modulating oxidative stress and lipid metabolism—key drivers of tumorigenesis. Additionally, CC cells with high intratumoral F.n exhibited cancer stem cell (CSC)-like properties, implicating oral and gut microbiota in CC progression (Maarsingh et al., 2022).

Large-scale epidemiological studies support a link between PD and BC. A U.S. cohort study of 65,869 postmenopausal women found that PD significantly increased BC risk (adjusted hazard ratio [aHR] = 1.13, 95% CI: 1.03–1.23) (Nwizu et al., 2017). A meta-analysis of 16,811 participants further confirmed this association (RR = 1.18, 95% CI: 1.11–1.26, I² = 17.6%) (Shi et al., 2018). Parhi et al. discovered that oral F.n can translocate hematogenously to colonize breast tissue milk ducts. BC tissues express high levels of D-galactose-beta [1-3]-N-acetyl-D-galactosamine (Gal-GalNAc, or T-antigen), which facilitates F.n adhesion via its surface lectin Fap2. F.n may drive tumor growth and metastasis by suppressing T-cell infiltration and upregulating matrix metalloproteinase-9 (MMP-9). Notably, metronidazole treatment attenuated breast tumor metastasis in murine models, highlighting Fap2 as a potential therapeutic target (Narengaowa et al., 2021). Clinical studies report elevated F.n abundance in breast tumors, with bacterial load correlating positively with tumor size and disease progression (Parhi et al., 2020; Parida and Sharma, 2020; Li et al., 2023; Baima et al., 2024b). Recent in vivo work confirmed that F.n-derived small extracellular vesicles (F.n-EVs) promote BC cell proliferation, migration, and invasion, accelerating tumor growth and metastasis. The gut microbiota also influences BC pathogenesis. Multiple studies implicate gut microbiota and their metabolites in BC initiation and progression through mechanisms including: epithelial-mesenchymal transition (EMT), invasive phenotype acquisition, DNA damage and epigenetic modifications, microenvironmental inflammation, estrogen and short-chain fatty acid (SCFA) production (Haque et al., 2022; Wang N. et al., 2022; Álvarez-Mercado et al., 2023; Yang et al., 2023). Zheng et al. observed marked dysbiosis in the oral and gut microbiota of dogs with canine mammary tumors (CMTs), characterized by elevated Bacteroidetes—a microbial signature shared among oral, gut, and intratumoral microbiota. These findings suggest a potential pathway for microbiota dissemination from the oral cavity to the gut and, ultimately, to distant breast tumors (Zheng et al., 2022).