The Oral–Gut–Brain Axis: From Periodontal Dysbiosis to Neuroinflammation—Mechanistic Pathways, Salivary and Intestinal Biomarkers, and Therapeutic Targets: A Narrative Review

“PD is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of alpha-synuclein ( α -syn) aggregates (Lewy bodies) in both the central and peripheral nervous systems [109,110].”

“The hypothesis that periodontal treatment can reduce systemic inflammatory burden is supported by multiple clinical studies demonstrating reductions in serum CRP, IL-6, and TNF-α after non-surgical periodontal therapy (scaling and root planing) [4,48,127,128].”

“…-secretases by pro-inflammatory cytokines intensifies amyloidogenic processing of amyloid precursor protein (APP), increasing A β production [93,95,97]; (2) microglial activation impairs phagocytic clearance of A β while simultaneously promoting the release of neurotoxic inflammatory mediators…”

“Excess adipose tissue produces adipokines and pro-inflammatory mediators that interact synergistically with inflammatory signals derived from the periodontium, creating a self-sustaining cycle of chronic inflammation [5,17].”

“…secretory phenotype (SASP), mitochondrial dysfunction generating excessive reactive oxygen species (ROS), deficient autophagy, persistent activation of the innate immune system through pattern recognition receptors (PRRs), and dysbiosis of mucosal-associated microbiomes [13,14].”

“…and the CNS. Vagal afferent neurons, whose cell bodies reside in the nodose ganglion, terminate in the nucleus tractus solitarius (NTS) of the brainstem and are capable of sensing luminal cytokines, bacterial metabolites, and neuroactive compounds produced by the intestinal microbiota [31,72,73].”

“Sub-antimicrobial dose doxycycline (SDD, 20 mg twice daily) is FDA-approved as an MMP inhibitor for periodontitis (Periostat ® ) and, at these doses, does not exert antibiotic selective pressure, making it an attractive candidate for long-term anti-inflammatory therapy along the axis [119,149].”

“The concept of inflammaging, introduced by Franceschi and colleagues, describes the chronic, sterile, low-grade inflammatory state that accompanies aging and predisposes individuals to a spectrum of age-related diseases [13].”

“…most prevalent form of dementia affecting approximately 55 million people worldwide, is characterized by extracellular amyloid-beta (A β ) plaques, intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein (Tau-P), synaptic loss, and progressive neuronal death [19,95,96].”

“In the context of oral pathogen-induced intestinal dysbiosis, reduced butyrate and altered butyrate/total SCFA ratios have been documented and correlate with intestinal permeability, systemic inflammation, and, indirectly, neuroinflammatory status [63–65].”

“…engaging microglial TLR4 [80]; pro-inflammatory cytokines traversing a disrupted BBB [77,81]; gingipains and other bacterial virulence factors potentially reaching the brain parenchyma [32,45]; and loss of butyrate-mediated HDAC inhibition that normally maintains microglial homeostasis [63,83,94].”

“…engaging microglial TLR4 [80]; pro-inflammatory cytokines traversing a disrupted BBB [77,81]; gingipains and other bacterial virulence factors potentially reaching the brain parenchyma [32,45]; and loss of butyrate-mediated HDAC inhibition that normally maintains microglial homeostasis [63,83,94].”

“…infection, through chronic stimulation of Toll-like receptors (TLR2, TLR4) by pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) and gingipains, contributes significantly to the systemic inflammatory burden and may accelerate the inflammaging process [5,15,16].”

“Prebiotics, including fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), and resistant starch, selectively stimulate the growth and metabolic activity of butyrate-producing commensals, thereby enhancing SCFA production and supporting intestinal barrier integrity [64,140–143].”

“Fourth, the reduction in butyrate consequent to intestinal dysbiosis removes the tonic protective signal that normally upregulates claudin-5 and occludin expression in cerebral endothelium [83,88].”

“Microglia, the resident innate immune cells of the CNS, serve as primary sentinels and effectors of neuroinflammatory responses [89–91].”

“Notably, the stability of phenolic compounds from fermented functional beverages under simulated gastrointestinal conditions has been confirmed, supporting their bioavailability for gut microbiome modulation and their potential role as dietary adjuncts in oral–gut axis interventions [144].”

“The human oral cavity harbors one of the most complex and diverse microbial communities in the body, comprising approximately 700 cultivable species and an even greater number identified through culture-independent molecular techniques [34,35].”

“…systemic circulation through the ulcerated pocket epithelium (~8–20 cm 2 of ulcerated surface in moderate-to-severe periodontitis) constitutes a persistent source of endotoxemia that amplifies hepatic CRP production, activates endothelial cells, and contributes to the metainflammatory state [1,15].”

“Studies showing that vagotomy prevents the behavioral and neurochemical effects of probiotic administration [72] and attenuates the propagation of alpha-synuclein pathology from the gut to the brain in PD models [75,76] underscore the importance of this pathway.”

“GLP-1 receptor agonists (e.g., exenatide, liraglutide, semaglutide), initially developed for type 2 diabetes, have shown neuroprotective effects in animal models by reducing neuroinflammation, oxidative stress, and apoptosis [131–133].”

“The therapeutic rationale was based on the detection of gingipains in AD post-mortem brains and preclinical evidence that gingipain inhibition reduces A β production, neuroinflammation, and bacterial load in animal models [32].”

“…milieu through autocrine and paracrine amplification loops involving microglia–astrocyte crosstalk, where reactive astrocytes may further potentiate cytokine release and impair synaptic function, though these mechanisms have been established primarily in animal models and cell culture [87,90,93].”

“Endothelial activation by circulating LPS and pro-inflammatory cytokines has been associated with atherogenic processes, including upregulation of adhesion molecules (ICAM-1, VCAM-1, E-selectin), monocyte recruitment, foam cell formation, and plaque instability [4,8,70].”

“Although most episodes of bacteremia are rapidly cleared by the reticuloendothelial system, repeated and chronic exposure to oral pathogens and their products maintains a persistent state of low-grade systemic inflammation [4,5].”

“According to this model, P. gingivalis , although present in relatively low abundance, subverts host immune defenses through specific virulence mechanisms, thereby remodeling the commensal community into a dysbiotic one with enhanced inflammatory capacity [1,7,42].”

“…cytokines (IL-1 β , IL-6, TNF-α ), reactive oxygen and nitrogen species (ROS, NO), and chemokines, while the alternative M2 phenotype promotes tissue https://doi.org/10.3390/dj14050289 repair, anti-inflammatory cytokine production (IL-10, TGF-β ), and phagocytic clearance of debris [87,90,92,93].”

“Zonulin, a protein that modulates intestinal permeability through reversible disassembly of tight junctions, serves as a serological and fecal marker of intestinal barrier integrity (“leaky gut”) [59].”

“…most prevalent form of dementia affecting approximately 55 million people worldwide, is characterized by extracellular amyloid-beta (A β ) plaques, intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein (Tau-P), synaptic loss, and progressive neuronal death [19,95,96].”

“Microglia, the resident innate immune cells of the CNS, serve as primary sentinels and effectors of neuroinflammatory responses [89–91].”

“The dysbiotic shift is characterized by a proportional increase in Gram-negative, anaerobic, and proteolytic species at the expense of saccharolytic commensals, creating a microbial community with enhanced pathogenic potential [7,41].”

“…drug delivery systems for targeted anti-inflammatory therapy at the intestinal barrier or BBB, and theranostic nanoparticles combining diagnostic and therapeutic functions, represent a technological frontier with the potential to transform the management of axis-related diseases [159,160].”

“…cytokines (IL-1 β , IL-6, TNF-α ), reactive oxygen and nitrogen species (ROS, NO), and chemokines, while the alternative M2 phenotype promotes tissue https://doi.org/10.3390/dj14050289 repair, anti-inflammatory cytokine production (IL-10, TGF-β ), and phagocytic clearance of debris [87,90,92,93].”

“…goal, with no currently validated instrument capable of simultaneous multi-compartment measurement [116,117,126]. https://doi.org/10.3390/dj14050289 Intestinal barrier integrity (“leaky gut”) marker; associated with metabolic syndrome, autoimmune and [58] https://doi.org/10.3390/dj14050289”

“Although most episodes of bacteremia are rapidly cleared by the reticuloendothelial system, repeated and chronic exposure to oral pathogens and their products maintains a persistent state of low-grade systemic inflammation [4,5].”

“Studies showing that vagotomy prevents the behavioral and neurochemical effects of probiotic administration [72] and attenuates the propagation of alpha-synuclein pathology from the gut to the brain in PD models [75,76] underscore the importance of this pathway.”

“From the NTS, signals are transmitted to higher brain centers, including the hypothalamus, amygdala, and prefrontal cortex, through ascending projections that modulate emotion, cognition, and neuroendocrine function [74].”

“In the context of periodontal disease, resolvins have demonstrated efficacy in reducing alveolar bone loss, promoting tissue regeneration, and attenuating systemic inflammatory responses in preclinical models [137].”

“Tryptophan–kynurenine axis modulators, including IDO1 inhibitors and kynurenine amino-transferase (KAT) modulators, represent additional novel targets for restoring neurotransmitter balance disrupted by intestinal dysbiosis [18,82,85].”

“This symbiotic equilibrium involves complex inter-species interactions, including metabolic cooperation, quorum sensing, and competitive exclusion of potential pathogens [28,37].”

“…milieu through autocrine and paracrine amplification loops involving microglia–astrocyte crosstalk, where reactive astrocytes may further potentiate cytokine release and impair synaptic function, though these mechanisms have been established primarily in animal models and cell culture [87,90,93].”

“This metabolic endotoxemia has been proposed as a contributor to the insulin resistance and dyslipidemia observed in periodontitis patients, representing a plausible mechanistic link in the bidirectional relationship between periodontal disease and type 2 diabetes [48,68,69].”

“CRP, an acute-phase protein synthesized primarily by hepatocytes in response to IL-6, enters saliva through gingival crevicular fluid transudation and, to a lesser extent, through salivary gland secretion [114].”

“In the context of oral pathogen-induced intestinal dysbiosis, reduced butyrate and altered butyrate/total SCFA ratios have been documented and correlate with intestinal permeability, systemic inflammation, and, indirectly, neuroinflammatory status [63–65].”

“Salivary biomarker panels, tailored to individual patient profiles (age, comorbidities, microbiome composition, genetic risk), could enable personalized risk stratification and targeted preventive interventions [117,126,153].”

“Multiple sclerosis (MS), an autoimmune demyelinating disorder, has been linked to alterations in gut microbiota that skew T cell differentiation toward Th17 and away from Treg phenotypes [110–112].”

“Systemic LPS, derived from the increased intestinal permeability described above, activates cerebral endothelial TLR4, inducing local production of inflammatory mediators and recruitment of peripheral immune cells into the CNS [77,80].”

“Gingipain Inhibitors COR388 (atuzaginstat), developed by Cortexyme, represented the first small-molecule gingipain inhibitor to advance to Phase II/III clinical trials for AD [32,134].”

“Studies showing that vagotomy prevents the behavioral and neurochemical effects of probiotic administration [72] and attenuates the propagation of alpha-synuclein pathology from the gut to the brain in PD models [75,76] underscore the importance of this pathway.”

“…reported in AD patients, including reductions in butyrate producers and increases in LPS-producing species, partially overlap with the dysbiotic patterns observed following oral pathogen colonization in animal models, though a causal relationship has not been established in humans [8,104–108].”

“…cell (Treg) differentiation, while simultaneously promoting Th17 polarization and exacerbating the Th17/Treg imbalance that characterizes chronic mucosal inflammation, although the extent to which oral pathogen colonization specifically drives these changes in humans remains unclear [21,62,63,66].”

“BBB integrity depends on the proper expression and assembly of tight junction proteins, particularly claudin-5, occludin, and ZO-1, which restrict paracellular permeability to ions and macromolecules [78,79].”

“PD is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of alpha-synuclein ( α -syn) aggregates (Lewy bodies) in both the central and peripheral nervous systems [109,110].”

“…indole derivatives, modulates astrocyte and microglial function, while the balance be-tween neuroprotective (kynurenic acid) and neurotoxic (quinolinic acid) metabolites of the kynurenine pathway is disrupted in dysbiosis, potentially contributing to excitotoxicity and neurodegeneration [82,85,86].”

“Sun et al. (2018) reported that FMT from healthy donors to MPTP-induced PD mice was associated with restored gut microbiota diversity, reduced microglial activation, and attenuated dopaminergic neurodegeneration through modulation of TLR4/TNF-α signaling in an animal model [146].”

“BBB integrity depends on the proper expression and assembly of tight junction proteins, particularly claudin-5, occludin, and ZO-1, which restrict paracellular permeability to ions and macromolecules [78,79].”

“Studies in AD transgenic mice have reported that ligature-induced periodontitis or oral administration of P. gingivalis was associated with exacerbated A β deposition, tau pathology, and cognitive decline in rodent models [100–103].”

“…shift moved the field from the classical specific plaque hypothesis toward a more nuanced understanding of polymicrobial synergy and community-level pathogenesis [37,43] Gingipains are cysteine proteases produced by P. gingivalis that represent the bac-terium’s most potent virulence arsenal.”

“This phenomenon is characterized by persistently elevated levels of pro-inflammatory cytokines (IL-6, TNF-α , interleukin-1 β [IL-1 β ]), acute-phase proteins (CRP, fibrinogen), and activated innate immune cells, in the absence of overt infection [10,13].”

“…consistent with oral-to-gut microbial translocation comes from 16S rRNA sequencing studies demonstrating enrichment of oral cavity-associated taxa in the fecal microbiome of patients with periodontitis; however, these associations do not establish active translocation or causality [51,52,56].”

“Point-of-care testing for aMMP-8 has been commercialized (e.g., the PerioSafe ® test, Dentognostics GmbH, Solingen, Germany)), enabling chair-side assessment of periodontal disease activity within minutes [117,122].”

“The hypothesis that periodontal treatment can reduce systemic inflammatory burden is supported by multiple clinical studies demonstrating reductions in serum CRP, IL-6, and TNF-α after non-surgical periodontal therapy (scaling and root planing) [4,48,127,128].”

“GLP-1 receptor agonists (e.g., exenatide, liraglutide, semaglutide), initially developed for type 2 diabetes, have shown neuroprotective effects in animal models by reducing neuroinflammation, oxidative stress, and apoptosis [131–133].”

“Additionally, age-associated cognitive decline, even in the absence of manifest neurodegenerative disease, is accelerated by chronic neuroinflammation (inflammaging), and the oral–gut–brain axis provides a continuous source of inflammatory stimulation that may hasten this process [13,26,81,113].”

“Two classes exist: arginine-specific gingipains (RgpA and RgpB) and lysine-specific gingipain (Kgp) [44].”

“Tryptophan–kynurenine axis modulators, including IDO1 inhibitors and kynurenine amino-transferase (KAT) modulators, represent additional novel targets for restoring neurotransmitter balance disrupted by intestinal dysbiosis [18,82,85].”

“Modifiable risk factors include smoking, poorly controlled diabetes mellitus, obesity, psychological stress, inadequate oral hygiene practices, and dietary factors [3,38,39].”

“Tryptophan–kynurenine axis modulators, including IDO1 inhibitors and kynurenine amino-transferase (KAT) modulators, represent additional novel targets for restoring neurotransmitter balance disrupted by intestinal dysbiosis [18,82,85].”

“Challis et al. (2020) refined this model by demonstrating that α -syn fibrils seeded in the gut promote brain pathology specifically in aged mice, highlighting the intersection of aging, intestinal dysbiosis, and neurodegeneration [111].”

“The primary route of oral bacterial translocation to the gastrointestinal tract is saliva swallowing, which occurs approximately 600 times per day, delivering an estimated 1.5 L of saliva containing approximately 10 9 bacteria daily to the stomach and intestines [51–53].”

“Hazan (2020) reported cognitive improvement after FMT in a single patient with AD; this observation cannot be generalized and should be considered anecdotal evidence only [147].”

“Daily activities such as toothbrushing, mastication, and professional dental procedures in patients with periodontitis lead to translocation of oral bacteria into the bloodstream through the ulcerated sulcular epithelium [8,47].”

“The activated form (aMMP-8) has been proposed as a more specific indicator of active disease, as it reflects ongoing collagenolysis [117,121,122].”

“Czesnikiewicz-Guzik et al. (2019) provided causal evidence from a Mendelian randomization study and a randomized trial showing that periodontal therapy reduces blood pressure in hypertensive patients [49].”

“FMT, established as first-line therapy for recurrent Clostridioides difficile infection [145], has shown promising preclinical results in neurodegenerative disease models.”

“In particular, miR-146a and miR-155, which modulate NF-κ B signaling and inflammatory gene expression, are differentially expressed in the saliva of periodontitis patients and represent potential biomarkers of inflammatory regulation [115,125].”

“This metabolic endotoxemia has been proposed as a contributor to the insulin resistance and dyslipidemia observed in periodontitis patients, representing a plausible mechanistic link in the bidirectional relationship between periodontal disease and type 2 diabetes [48,68,69].”

“…toward the pro-inflammatory M1 phenotype: circulating LPS engaging microglial TLR4 [80]; pro-inflammatory cytokines traversing a disrupted BBB [77,81]; gingipains and other bacterial virulence factors potentially reaching the brain parenchyma [32,45]; and loss of butyrate-mediated HDAC…”

“…systemic circulation through the ulcerated pocket epithelium (~8–20 cm 2 of ulcerated surface in moderate-to-severe periodontitis) constitutes a persistent source of endotoxemia that amplifies hepatic CRP production, activates endothelial cells, and contributes to the metainflammatory state [1,15].”

“Wearable biosensors capable of continuous or semi-continuous monitoring of salivary biomarkers (pH, cortisol, inflammatory cytokines) are under development and could rev-olutionize disease monitoring by providing real-time data on inflammatory status [154].”

“Most clinical evidence is correlational or cross-sectional, and although preclinical models provide mechanistic plausibility, translation to human pathophysiology requires confirmation through prospective longitudinal cohort studies and interventional trials [1,5,38].”

“…human cohorts have consistently demonstrated alterations of the Firmicutes-to-Bacteroidetes ratio, with a relative decrease in butyrate-producing species ( Faecalibacterium prausnitzii , Roseburia spp., Eubacterium rectale ) and an increase in pro-inflammatory Gram-negative species [22,54,56,61].”

“The clinical development program was terminated due to hepatotoxicity signals and the failure to meet primary efficacy endpoints, and no gingipain inhibitor is currently approved or in active late-phase clinical development for any neurodegenerative indication [134,138].”

“Population aging in both developed and developing countries acts as an amplifying factor, as the prevalence of both periodontitis and neurodegenerative diseases increases exponentially with advancing age [11,12].”

“P. gingivalis gingipains have been shown in experimental models to cleave tight junction proteins through their proteolytic activity, reducing occludin and claudin-1 expression at the protein level [55,56,60].”

“The capsule provides additional resistance against phagocytosis and complement-mediated killing, contributing to bacterial persistence in periodontal lesions and potentially at distant sites [7].”

“MCC950 and related NLRP3-specific inhibitors have shown efficacy in preclinical models of periodontitis, IBD, and AD, suggesting the potential for a single pharmacological intervention to modulate inflammation simultaneously across oral, intestinal, and cerebral compartments [151,154].”

“P. gingivalis gingipains have been shown in experimental models to cleave tight junction proteins through their proteolytic activity, reducing occludin and claudin-1 expression at the protein level [55,56,60].”

“…(3) this neuroinflammatory milieu has been associated in preclinical models with A β aggregation, tau hyperphosphorylation, and alpha-synuclein propagation; and (4) biomarkers measurable in saliva and feces may reflect the inflammatory status across all three compartments of the axis [23,25,27,32].”

“Existing reviews have typically addressed individual segments of this axis in isolation: periodontal disease and systemic inflammation, gut–brain communication in neurodegeneration, or oral microbiome translocation to the gut [24,29–31].”

“Importantly, elevated aMMP-8 has been associated with metabolic syndrome parameters and systemic inflammatory markers, suggesting its potential as a screening tool for systemic inflammatory burden beyond the oral cavity [117,122,123].”

“…dysbiosis, obesity, and metainflammation has been proposed, whereby each component may exacerbate the others, including periodontal disease severity, through altered immune function and metabolic disruption, suggesting a self-sustaining but not yet causally proven inflammatory cascade [5,15,71].”

“…reported in AD patients, including reductions in butyrate producers and increases in LPS-producing species, partially overlap with the dysbiotic patterns observed following oral pathogen colonization in animal models, though a causal relationship has not been established in humans [8,104–108].”

“Additionally, age-associated cognitive decline, even in the absence of manifest neurodegenerative disease, is accelerated by chronic neuroinflammation (inflammaging), and the oral–gut–brain axis provides a continuous source of inflammatory stimulation that may hasten this process [13,26,81,113].”

“…drug delivery systems for targeted anti-inflammatory therapy at the intestinal barrier or BBB, and theranostic nanoparticles combining diagnostic and therapeutic functions, represent a technological frontier with the potential to transform the management of axis-related diseases [159,160].”

“Metabolomic profiling of saliva, including analysis of fatty acids, amino acids, and organic acids, is emerging as a high-throughput approach for capturing the metabolic signature of oral–systemic disease interactions [115,116].”

“LPS-mediated activation of the TLR4/MyD88/NF-κ B signaling cascade induces the production of pro-inflammatory cytokines (IL-1 β , IL-6, TNF-α ), chemokines (CXCL8/IL-8, CCL2/MCP-1), and prostaglandins (PGE2) by macrophages, dendritic cells, and epithelial cells [6,7].”

“Meta-analyses have confirmed that salivary IL-1 β and IL-6 levels are significantly elevated in periodontitis patients compared with healthy controls and correlate with clinical parameters including probing depth, clinical attachment loss, and bleeding on probing [114,118].”

“Lu et al. (2022) reported that periodontitis-related salivary microbiota was associated with exacerbated AD pathology through gut–brain axis crosstalk in animal models, though translation to human disease remains speculative [27].”

“Existing reviews have typically addressed individual segments of this axis in isolation: periodontal disease and systemic inflammation, gut–brain communication in neurodegeneration, or oral microbiome translocation to the gut [24,29–31].”

“This symbiotic equilibrium involves complex inter-species interactions, including metabolic cooperation, quorum sensing, and competitive exclusion of potential pathogens [28,37].”

“Evidence associating periodontal pathogens with AD neuropathology includes the detection of P. gingivalis DNA and gingipains in the post-mortem brain tissue of AD patients, with gingipain load correlating with tau and ubiquitin pathology [32,99].”

“Recent meta-analyses have confirmed that salivary MMP-8 levels are significantly higher in periodontitis patients, with a standardized mean difference of approximately 2.71 compared with healthy controls [120].”

“Sub-antimicrobial dose doxycycline (SDD, 20 mg twice daily) is FDA-approved as an MMP inhibitor for periodontitis (Periostat ® ) and, at these doses, does not exert antibiotic selective pressure, making it an attractive candidate for long-term anti-inflammatory therapy along the axis [119,149].”

“…strictly investigational: challenges of donor standardization, microbiota engraftment variability, safety concerns (including serious adverse events reported in immunocompromised recipients), and the absence of controlled clinical trials preclude any current clinical recommendation [148].”

“Haririan et al. (2022) reported reduced salivary BDNF levels in periodontitis patients in a single study, suggesting a possible link between oral inflammation and neurotrophic factor depletion; however, this finding has not been independently replicated and must be interpreted with caution [124].”

“…of Lactobacillus reuteri , L. brevis , L. rhamnosus , and Bifidobacterium species, have demonstrated efficacy as adjuncts to non-surgical periodontal therapy, reducing probing depth, clinical attachment loss, and salivary pathogen load in meta-analyses of randomized clinical trials [139–141].”

“Studies in AD transgenic mice have reported that ligature-induced periodontitis or oral administration of P. gingivalis was associated with exacerbated A β deposition, tau pathology, and cognitive decline in rodent models [100–103].”

“Non-modifiable risk factors include genetic susceptibility, advancing age, and sex-related differences in immune response [3,40].”

“Existing reviews have typically addressed individual segments of this axis in isolation: periodontal disease and systemic inflammation, gut–brain communication in neurodegeneration, or oral microbiome translocation to the gut [24,29–31].”

“Statins (HMG-CoA reductase inhibitors), beyond their established lipid-lowering effects, exhibit anti-inflammatory properties through inhibition of isoprenoid synthesis, reduction in NF-κ B activation, and suppression of pro-inflammatory cytokine production [4,130].”

“…consistent with oral-to-gut microbial translocation comes from 16S rRNA sequencing studies demonstrating enrichment of oral cavity-associated taxa in the fecal microbiome of patients with periodontitis; however, these associations do not establish active translocation or causality [51,52,56].”

“Point-of-care testing for aMMP-8 has been commercialized (e.g., the PerioSafe ® test, Dentognostics GmbH, Solingen, Germany)), enabling chair-side assessment of periodontal disease activity within minutes [117,122].”

“…(3) this neuroinflammatory milieu has been associated in preclinical models with A β aggregation, tau hyperphosphorylation, and alpha-synuclein propagation; and (4) biomarkers measurable in saliva and feces may reflect the inflammatory status across all three compartments of the axis [23,25,27,32].”

“Synbi-otics combining probiotic strains with prebiotic substrates offer the potential for synergistic effects in both oral and intestinal compartments [142].”

“Subsequent experimental studies suggested that gingipains may degrade BBB tight junction proteins, facilitate bacterial invasion of endothelial cells, and activate neuroinflammatory cascades in microglial cells, though these findings derive primarily from in vitro and animal models [45,46].”

“…critical role in modulating the severity of periodontal tissue destruction and its systemic consequences; both endogenous and exogenous sources of ROS contribute to this redox imbalance, and plant-derived antioxidants have been proposed as adjunctive modulators of the oral inflammatory milieu [50].”

“In particular, miR-146a and miR-155, which modulate NF-κ B signaling and inflammatory gene expression, are differentially expressed in the saliva of periodontitis patients and represent potential biomarkers of inflammatory regulation [115,125].”

“Mechanistically, oral probiotics compete with periodontal pathogens for adhesion sites, produce antimicrobial substances (bacteriocins, hydrogen peroxide), and modulate local immune responses toward anti-inflammatory profiles [140,141].”

“…cell (Treg) differentiation, while simultaneously promoting Th17 polarization and exacerbating the Th17/Treg imbalance that characterizes chronic mucosal inflammation, although the extent to which oral pathogen colonization specifically drives these changes in humans remains unclear [21,62,63,66].”

“Prebiotics, including fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), and resistant starch, selectively stimulate the growth and metabolic activity of butyrate-producing commensals, thereby enhancing SCFA production and supporting intestinal barrier integrity [64,140–143].”

“Lyu et al. (2025) demonstrated that periodontal infection with P. gingivalis was associated with aggravated nonalcoholic steatohepatitis through intestinal barrier disruption and hepatic inflammatory activation in animal models [67].”

“This example illustrates both the dominant direction of the interaction, a drug that reshapes the microbiota with downstream clinical consequences, and the role of the oral–gut axis as an anatomical–microbiological interface through which this remodelling is manifested [9].”

“The oral compartment, where berberine reaches its highest concentrations of all, is unexamined and belongs in the same program [103–108].”

“…of oral dysbiosis, oral–gut interactions, or the microbiota–gut–brain axis, the present review specifically integrates these domains within a pediatric developmental framework, while distinguishing direct pediatric evidence from findings extrapolated from adult and preclinical studies [148–150].”

“Together, these mechanisms can promote glial activation and amplify inflammatory responses in the CNS (Hajishengallis and Chavakis, 2021; Li et al., 2022; Dumitru et al., 2026; Tessarin et al.).”

“Coupling with individual microbiome profiling would open the way to person-alised delivery, a natural bridge toward pharmacomicrobiomics [3,112–114].”