Oral Dysbiosis and Neuroinflammation: Implications for Alzheimer’s, Parkinson’s and Mood Disorders

The human herpes virus and human papillomavirus families are responsible for the most common primary viral infections of the oral cavity [46]. Eight distinct human herpes virus types have been identified, each causing unique primary or recurrent oral infections [47]. These include herpes simplex viruses 1 and 2, varicella-zoster virus, Epstein–Barr virus, and cytomegalovirus, all of which are double-stranded DNA viruses [48]. These viruses possess a conserved structural organization: a linear double-stranded DNA genome encased within an icosahedral capsid, enveloped by tegument proteins and a host-derived lipid bilayer [49,50]. Epstein–Barr virus and cytomegalovirus, known for their associations with marginal periodontitis, are also implicated in the inflammatory processes leading to periapical bone destruction [46]. Further investigations link herpesviral lytic proteins to the activation of cellular signaling pathways, such as Notch signaling, and to increased expression of pro-inflammatory cytokines [46]. This biological response promotes the transcription of receptor activator of nuclear factor kappa-B ligand, which subsequently drives osteoclastogenesis and bone resorption [46]. The heightened production of pro-inflammatory cytokines further intensifies bone resorption in the periapical region [51].

Prokaryotic viruses, commonly referred to as bacteriophages, are the most prevalent biological entities identified to date [46,52]. Bacteriophages, which are viruses that infect bacteria, can either persist within host cells as parasitic deoxyribonucleic acid or harness bacterial metabolic machinery for their replication, culminating in the lysis of the host bacterium [53].

Notably, bacteriophages constitute a larger proportion of the human virome than their eukaryotic counterparts, despite their limited representation in current genomic databases [46]. Similarly to eukaryotic viruses, the taxonomic classification of bacteriophages is determined by various attributes, including the molecular composition of their viral genome, the structure of their capsid, the presence of a viral envelope, their host range, and shared genomic sequences [46]. Bacteriophages exhibit diverse morphologies and genomic compositions [53,54]. They can possess a proteinaceous capsid, which may be tailed and enclose a double-stranded deoxyribonucleic acid genome, or be non-tailed and accommodate either double-stranded DNA, single-stranded DNA, or ribonucleic acid genomes. Filamentous and pleomorphic phage types are also observed. Tailed bacteriophages constitute the majority (96%) of isolates and are classified into families based on their tail characteristics. For instance, large virions featuring a long contractile tail are classified under the families Myoviridae, Ackermannviridae, or Herelleviridae. Those with a long, flexible, but non-contractile tail belongs to the Siphoviridae family, while small virions with a short, non-contractile tail are assigned to the Podoviridae family. Phages with huge genomes are further grouped as jumbo phages and megaphages [53].

Elevated circulating pro-inflammatory cytokines, such as IL-1β and TNF-α, can cross the blood–brain barrier, exacerbating neurological deficits. These cytokines act as key signaling molecules in neuroinflammation, with TNF-α influencing central nervous system development, neuronal plasticity, cognition, and behavior [66]. In Alzheimer's disease, periodontal inflammation induces IL-1β, IL-6, IL-8, TNF-α, and CRP, promoting brain inflammation [67]. Pathogens like P. gingivalis may transport amyloid peptides from peripheral sites to the liver, exacerbating systemic pathology [68].

Periodontitis indirectly affects anxiety and depression via cytokines that activate TNF-α- and IL-1 receptor-expressing endothelial cells [69]. This stimulates perivascular macrophages and microglia, inducing neuroinflammation [69]. Compromised periodontal integrity also allows lipopolysaccharides to enter circulation, activating the hypothalamic–pituitary–adrenal axis and elevating stress hormones.

In PD, elevated gingival crevicular fluid IL-1β signals local inflammation, and poor oral health worsens progression [70]. α-synuclein (ASN) levels in saliva correlate with disease duration and severity, serving as a non-invasive biomarker. Periodontitis-driven systemic inflammation disrupts blood–brain barrier integrity, activates microglia, and promotes immune cell brain infiltration [67,71,72,73,74].

The translocation of oral bacteria and their metabolic products into the circulatory system and central nervous system can adversely impact brain function by triggering a neuroinflammatory cascade. This response involves the upregulation of inflammatory signaling molecules, including pro-inflammatory cytokines, which can lead to a persistent, albeit potentially low-grade, immune reaction. Such systemic inflammation can compromise neurovascular integrity, leading to increased BBB permeability, diminished nutrient supply, and accumulation of toxic substances within the brain [2].

The aberrant localization of microorganisms within the host can precipitate disease, particularly when oral microbial communities exhibit dysbiosis. During such states, an overabundance of specific pathogenic microbes can arise. Subsequently, these oral microorganisms and their byproducts may disseminate via the bloodstream to various tissues, such as the cardiovascular system, to reach the brain, where they are implicated in impairing neurological functions and causing neurodegeneration through the accumulation of toxic substances [2].

The bacterium P. gingivalis has been observed to enter the bloodstream and migrate to the brain, where it establishes colonies and secretes neurotoxic enzymes known as gingipains [2]. These gingipains are implicated in the aberrant processing of the transmembrane protein amyloid precursor protein (APP), which plays a crucial role in maintaining synaptic stability, neuronal growth, and protection [2]. This disruption leads to the miscleavage of APP, resulting in the formation of amyloid beta protein plaques that subsequently trigger neuronal demise [2].

Growing transcriptomic and proteomic evidence shows an overlap in the molecular activities of PD, AD, and other dementias. Common differentially expressed genes have been identified across these diseases, linked to processes such as chemical synaptic transmission and nervous system development [75,76,77,78,79,80,81,82]. At the protein level, studies show similar dysregulation of proteins in AD brains and Tau pathologies, implicating new proteins in the disease process [83,84]. These similarities suggest a deep molecular convergence, even if the affected brain regions may vary clinically [79,85,86].

Fecal and oral microbiomes exhibit site-specific differences, with shared amplicon sequence variants primarily originating from the oral cavity, indicating primary oral-to-gut transmission [3]. In PD, alpha-diversity increases in stool and saliva compared to controls, characterized by an overabundance of Streptococcus mutans and Bifidobacterium dentium [89,90]. Beta-diversity significantly differs in PD gut and oral samples from controls, with gut depletion of short-chain fatty acid producers (Prevotella, Roseburia) and enrichment of Escherichia and Lactobacillus [91]. In Alzheimer's disease, oral microbiomes show increased levels of Firmicutes and Fusobacteria with greater cognitive decline, while Proteobacteria decrease; conversely, the gut microbiome shows a declining Firmicutes/Bacteroidetes ratio [92]. PD salivary and plaque microbiotas cluster separately from controls, often without changes in alpha-diversity [93]. Patterns of oral dysbiosis in neurodegenerative diseases mirror gut changes observed in AD and PD [3].

P. gingivalis enters circulation, colonizes the brain, and secretes gingipains that disrupt BBB and promote Aβ/tau pathology [1,94]. Gut dysbiosis worsens this via leaky gut, allowing microbial products to reach the brain through vagal/enteric pathways [95,96]. Gingipains are found in >90% of AD brains, correlating with tau tangles and cognitive decline [97,98]. They degrade proteins, evade immunity, and cleave APP to increase Aβ1–42 [1,3]. Secreted in vesicles, gingipains breach the BBB by degrading tight junctions, upregulating transcytosis, and activating inflammasomes, leading to Aβ plaques and neurodegeneration [1,99]. In PD, gingipains are found in the substantia nigra [100].

The overproduction of amyloid-beta, a normally soluble protein, is believed to trigger its self-assembly into oligomers and subsequently into highly ordered amyloid fibrils, which manifest as plaques observable in pathological specimens [106].

Evidence indicates that both soluble Aβ and amyloid plaques exert toxic effects. These impacts on cellular functions are thought to initiate secondary or downstream processes, including tau protein hyperphosphorylation, inflammation, oxidative stress, and excitotoxicity. Consequently, these events result in cell death and deficits in neurotransmitters, particularly acetylcholine, whose reduction contributes to certain symptoms of Alzheimer's disease [106].

P. gingivalis can traverse the oral mucosal barrier to enter the bloodstream, potentially breaching the BBB and inducing the accumulation of beta-amyloid plaques and neurofibrillary tangles following experimental oral infection in mice [29,107]. Furthermore, P. gingivalis lipopolysaccharide has been detected in human brains affected by AD suggesting that P. gingivalis brain infection may be an essential factor in the development of AD [29]. Similarly, P. gingivalis DNA has been identified in Alzheimer's brains, as well as in the cerebrospinal fluid of living patients diagnosed with AD, suggesting its potential utility as a diagnostic marker [29]. Other bacterial species, such as Actinomycetes, Helicobacter pylori, and Chlamydia pneumoniae, as well as certain fungi and Herpes Simplex virus type 1 (HSV-1), have also been detected in post-mortem examinations of individuals with AD [108]. Perivascular spaces may enable bacteria and their products to access the brain [68] directly. Additionally, circumventricular organs might facilitate the entry of substances that typically cannot cross the BBB. Bacterial species can also reach the central nervous system (CNS) via peripheral nerves, following their pathways [108]. However, the presence of these bacteria in peripheral nerve fibers or in systemic circulation does not automatically guarantee their access to the CNS [67]. It is hypothesized that various cofactors, such as pro-inflammatory cytokines, concurrent infections, and the patient's age, may contribute to the entry of periodontal bacteria into the CNS [67] (Figure 2).

Oral pathogens such as P. gingivalis can translocate to AD brains, inducing amyloid-beta production and tau hyperphosphorylation [109,110]. Its LPS worsens amyloid-beta aggregation and contributes to AD-like pathology [98,111], while oral dysbiosis in AD patients triggers immune responses that sustain inflammation [3].

HSV-1, a neurotropic virus commonly detected in the oral cavity and trigeminal ganglion, has been increasingly recognized as a modulator of amyloidogenic pathways implicated in AD [112,113,114]. Upon neuronal entry via receptors such as nectin-1, HSV-1 is trafficked into early and late endosomal compartments, which coincide with the principal intracellular sites of APP cleavage [112,113,114,115]. Experimental evidence demonstrates that HSV-1 infection enhances the expression and enzymatic activity of β-site APP-cleaving enzyme 1 (BACE-1) and the γ-secretase complex, thereby favoring amyloidogenic APP processing and leading to intracellular accumulation of amyloid-β (Aβ), particularly the aggregation-prone Aβ1–42 isoform [112,113,114]. Importantly, Aβ accumulation is initially observed within neurons rather than extracellularly, indicating that HSV-1 promotes early intracellular amyloid pathology preceding plaque deposition [112,113]. Accumulating evidence indicates that intraneuronal Aβ exerts pronounced neurotoxic effects and represents a critical early event in AD pathogenesis, preceding extracellular plaque formation and neuronal loss [113,116] (Figure 3).

A key mechanism by which the periodontal pathogen P. gingivalis perturbs host cell function involves the release and cellular uptake of outer membrane vesicles (OMVs). These vesicles, which encapsulate virulence determinants such as LPS and gingipains, readily interact with epithelial and immune cells. Experimental evidence indicates that OMVs derived from P. gingivalis enter host cells through a lipid raft–dependent endocytic process that is independent of clathrin and caveolin but relies on Rac1-controlled micropinocytosis [117]. Once internalized, OMVs are transported through the endosomal system, initially localizing to EEA1-positive early endosomes and subsequently accumulating within LAMP1-positive late endosomes and lysosomes [117,118]. Notably, OMVs are not rapidly degraded within these compartments; instead, they persist intracellularly while retaining enzymatic activity of associated gingipains. Their prolonged residence within acidified vesicles suggests continuous disruption of endosomal–lysosomal integrity, a cellular network essential for proteostasis, autophagic flux, and controlled protein degradation [118,119].

Chronic systemic exposure to P. gingivalis LPS in murine models results in neuroinflammatory responses accompanied by intracellular accumulation of amyloid-β (Aβ) [120]. Importantly, this phenotype is dependent on cathepsin B activity, indicating that lysosomal protease dysregulation links inflammatory signaling to abnormal amyloid processing [120,121]. In addition to disrupting vesicular trafficking, P. gingivalis exerts strong effects on host redox signaling by inducing nitrosative stress. Infection with P. gingivalis or stimulation with its LPS markedly increases expression of inducible nitric oxide synthase (iNOS) in multiple cell types, including endothelial cells and macrophages [122].

Macrophage-based models further demonstrate that P. gingivalis LPS induces sustained iNOS expression and prolonged NO release via Toll-like receptor–mediated signaling pathways [123]. Under inflammatory conditions, elevated NO readily reacts with superoxide radicals to form peroxynitrite (ONOO⁻), a highly reactive nitrogen species capable of inducing protein nitration, mitochondrial damage, and lipid oxidation. Peroxynitrite-driven post-translational modification of neuronal proteins has been strongly implicated in neurodegenerative cascades, providing a mechanistic link between chronic periodontal inflammation, nitrosative stress, and neuronal vulnerability [124] (Figure 4).

The emerging field of metabolic biochemistry links oral bacteria to AD, focusing on microbial metabolites that influence neuroinflammation and neurotransmission [37]. Oral bacteria produce metabolites that modulate inflammation, immune responses, and neurotransmitters, including tryptophan metabolism, which alters serotonin levels implicated in AD [125]. Some bacteria generate short-chain fatty acids with anti-inflammatory effects, though dysbiosis may promote systemic inflammation [126]. Oral pathogens also trigger vascular inflammation and oxidative stress, contributing to neurodegeneration [3].

Genetic factors are considered to play an essential role in the predisposition to these diseases; however, non-genetic risk factors such as trauma, poor upbringing or lifestyles, and current exposure to stress are also associated with the development of depression and anxiety [130]. Modern living, with its associated high stress, reliance on processed foods, overemphasis on hygiene, and prevalent antibiotic use, coupled with environmental shifts such as elevated pollution, climate instability, and urban expansion, has contributed to a transformation of the human microbiota into an industrialized pattern [69]. These modifications in microbial composition, in conjunction with a decline in particular functional capabilities, could foster microbial communities that are less effective at preventing disease and more prone to promoting it, thereby exacerbating existing mental health issues [69].

Recent studies have linked periodontal pathogens to the etiology and pathophysiology of depression and anxiety disorders [131]. In a survey of self-reported anxiety and depressive symptoms among adolescents, no significant differences were observed in oral microbiome diversity between the anxiety or depression groups and controls. Nonetheless, these symptoms correlated with altered relative abundances of specific taxa, including a positive association of Spirochaetaceae with both anxiety and depression, as well as positive correlations of Actinomyces, Fusobacterium, and Leptotrichia spp. with depression. Additionally, Leptotrichia spp. relative abundance positively correlated with cortisol levels [132,133]. Furthermore, in a non-clinical adult population, the overall composition of the oral microbiome, together with diurnal fluctuations in the relative abundance of bacterial taxa, varied with psychological distress and affective state [129].

Interestingly recent evidence suggests that specific alterations in the oral microbiome are associated with depressive symptoms during pregnancy [134]. In particular, studies examining pregnant cohorts have reported significant reductions in the relative abundance of Neisseria, Fusobacterium, Capnocytophaga, and Streptococcus in women exhibiting clinically relevant depressive symptoms [134]. Conversely, increased abundance of the phyla Firmicutes and Spirochaetes has been observed among participants with more severe depressive profiles [134]. These findings indicate that pregnancy-related depression may be linked not to overall microbial diversity but rather to shifts in key bacterial genera, which could reflect underlying immunological, metabolic, or inflammatory processes unique to the perinatal period [134].

Periodontal bacteria can directly access and affect the brain through multiple routes [69,131] (Figure 5).

The oral microbiome affects anxiety and depression through systemic inflammation, direct neural pathways such as the trigeminal nerve and the olfactory system, and the oral–gut–brain axis [59]. The oral microbiota also dysregulates the hypothalamic–pituitary–adrenal axis: stress alters the microbial composition and virulence of periodontitis-related species [2] while salivary cortisol levels associate with psychological symptoms and bacterial abundance [135]. Notably, specific changes include lower Neisseria elongata and higher Oribacterium asaccharolyticum in anxiety [3], increased Prevotella nigrescens and Neisseria spp., and decreased Rothia and Streptococcus in depression [129]. Genome-wide studies also reveal interactions between salivary-tongue microbiota and these disorders [3].

The metabolic biochemistry linking oral bacteria to anxiety and depression involves neuroactive metabolites and modulation of host pathways. Oral bacteria produce or break down neurotransmitters like serotonin, dopamine, GABA, and others, helping maintain neurochemical balance even in small amounts [59]. Tryptophan metabolism, common in oral species, produces serotonin, a mood regulator, with lower plasma levels found in symptomatic groups [3,69,125]. Additionally, pathways involved in tyrosine metabolism, glutamate-glutamine, and glutamatergic synapses influence reward circuits linked to mood disorders [2].

The etiology of PD remains unknown in the vast majority of cases, but is believed to involve a complex interaction between genetic predisposition, environmental factors, and age-related processes [95]. Furthermore, certain ecological and behavioral factors, potentially amenable to modification, have been identified as contributing to the development of PD across diverse populations [136]. A conclusive diagnosis of PD necessitates the post-mortem identification of characteristic neuropathological alterations within the brain [137]. Pathologically, the disease is characterized by the aggregation of ASN into Lewy bodies and Lewy neurites, a process associated with a dense cellular environment rich in membranes, vesicular structures, malformed organelles such as mitochondria, and a high lipid content [137]. Emerging research indicates that comparable pathological changes occur in peripheral organs, such as the skin, colon, and salivary glands, even at the earliest stages of the disease, suggesting that PD affects multiple bodily systems [137]. Aggregates of phosphorylated ASN, the hallmark histopathological feature of PD, have been found not only in the central nervous system but also within neurons of the olfactory bulb and in the peripheral autonomic nervous system of the upper aerodigestive and gastrointestinal tracts, at a very early stage of the disease, even before motor symptoms appear [95].

Inflammation is a critical component of PD [138]. In post-mortem examinations, microglial cells within the substantia nigra of individuals with PD exhibit heightened activation compared to those in healthy brains [70]. Elevated levels of inflammatory cytokines have been detected in the blood, cerebrospinal fluid, colon, and saliva of PD patients compared with healthy controls [70]. Microglial activation leads to the secretion of inflammatory mediators that can damage the central nervous system and contribute to neurodegeneration [138]. Evidence from multiple research works indicates that PD correlates with a dysbiosis in the host-microbiota relationship within both the oral cavity and the intestinal tract [70].

Recent research has established a connection between oral microbiota and PD, revealing distinct oral bacterial compositions in individuals with PD compared to healthy subjects [70,139,140]. Although the oral microbiota of early-stage PD patients was comparable to that of control groups, patients exhibited higher proportions of Firmicutes, Negativicutes, Lactobacillaceae, Lactobacillus, Scardovia, Actinomyces, Veillonella, Streptococcus mutans, and Kingella oralis [70]. Conversely, Lachnospiraceae and Treponema were found in lower quantities. The major periodontitis pathogens, including Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Prevotella intermedia, and Fusobacterium nucleatum, may induce neurodegeneration by directly invading the brain or by colonizing other organs, leading to systemic inflammation [138] (Figure 6).

ASN is highly susceptible to nitrosative post-translational modification due to its intrinsically disordered structure and exposed tyrosine residues. Nitrated forms of ASN have been consistently detected in dopaminergic neurons and Lewy body inclusions in PD and related synucleinopathies, supporting a pathogenic role for nitrosative stress in disease progression [141,142,143]. Experimental evidence indicates that these modifications are predominantly mediated by peroxynitrite rather than nitric oxide (NO) alone, leading to altered protein conformation and impaired clearance [144].

ASN nitrosation typically arises under conditions of sustained inflammation, where inducible nitric oxide synthase (iNOS) is upregulated, resulting in prolonged NO production [145]. Simultaneously, inflammatory oxidative stress increases superoxide generation. The rapid reaction between NO and superoxide produces peroxynitrite, a highly reactive nitrogen species that nitrates tyrosine residues within ASN [146]. Nitrated ASN exhibits increased resistance to proteasomal and lysosomal degradation and shows an enhanced tendency to form stable oligomeric and fibrillar assemblies, which are widely considered neurotoxic [143,147].

Experimental studies have demonstrated that P. gingivalis and its LPS induce robust iNOS expression and sustained NO release in endothelial and immune cells [122]. When sustained over time, such a peripheral inflammatory environment may intersect with brain regions already vulnerable to oxidative stress, thereby promoting conditions favorable for ASN nitrosation and aggregation. Importantly, this mechanism does not require direct bacterial invasion of the CNS; instead, oral pathogens may act indirectly by amplifying systemic inflammatory and nitrosative pathways that drive pathological protein modification [148,149] (Figure 7).

Bacteriophages, abundant in the oral and gut virome, regulate prokaryotic composition through lysis and lysogeny, affecting permeability, inflammation, and metabolite production [150,151,152]. In PD, gut phagobiota shows altered diversity and abundance, for example, increased levels of Siphoviridae and Myoviridae, correlating with ASN pathology and the loss of dopaminergic neurons [152,153,154]. Phages may directly induce ASN misfolding or do so by influencing pathogens such as P. gingivalis, whose gingipains interact with ASN aggregates in Parkinson's brains [100,155]. Oral–gut transmission enhances this process, as salivary phages alter downstream microbiota, perpetuating neurotoxic cascades [91,156].

The relationship between oral bacteria, their metabolic pathways, and neurotransmitter synthesis is an emerging research area. Like gut bacteria, oral microbes encode pathways that produce or degrade neurotransmitters such as dopamine, glutamate, tryptophan, and GABA, though in vivo biosynthesis remains to be investigated [125]. Tryptophan metabolism impacts serotonin synthesis, which is reduced in PD [157]. Oral microbial pathways are enriched in tyrosine metabolism and glutamate production, influencing brain reward circuits and overall function [2]. Notably, Streptococcus mutans-derived imidazole propionate promotes dopaminergic neuronal loss and motor deficits in PD models [158].

The dopamine D1 receptor, found in the midbrain and forebrain, regulates motor control, reward, motivation, and cognition, with dysfunction linked to PD [159,160]. Changes in the gut microbiome influence dopaminergic signaling and DRD1 expression, such as through Clostridioides difficile infection [161], microbiome composition shifts associated with impulsivity [162]. Oral pathogens worsen neuroinflammation, promote dopaminergic neuron loss [138], and exacerbate PD motor and non-motor symptoms through microbiome-driven inflammation and neurotransmitter alterations [3].

The Food and Agriculture Organization of the United Nations and the World Health Organization define probiotics as "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host [164]. Probiotic microorganisms supply essential nutrients, facilitate host digestion of food, and compete with potential pathogens for adhesion sites and resources. Moreover, probiotics modulate the host immune system, inducing local and systemic responses that regulate inflammatory processes throughout the body [165]. This immunomodulatory potential, along with their direct antimicrobial activity against pathogens, establishes probiotics as a promising therapeutic strategy for diverse inflammatory conditions, including those associated with brain disorders [166] (Table 2).

Prebiotics are recognized as functional foods due to their significant role in promoting health and preventing disease [177,178]. These approaches collectively aim to counteract the "oralization" of the gut microbiota and subsequent translocation of toxic bacterial proteases to the brain, which contribute significantly to neuroinflammation and cognitive dysfunction. This intricate interplay between the oral and gut microbiomes underscores the critical importance of maintaining microbial homeostasis for systemic and neurological health, suggesting that therapeutic interventions targeting oral dysbiosis may offer significant neuroprotective benefits [3,179].

A synbiotic is defined by its composition, which includes a live microorganism and a selectively utilized substrate [180]. For synbiotics classified as complementary, their individual components must satisfy the requisite evidence and dosage criteria established for both probiotics and prebiotics [180]. Furthermore, the combined formulation must empirically demonstrate a health benefit in the target host, substantiated by an appropriately designed trial [180]. In addition to microbiome-focused interventions, growing attention has been directed toward phytogenic natural compounds as complementary strategies for AD. Preclinical evidence suggests that several plant-derived bioactive molecules can modulate neuroinflammatory signaling, particularly through the nuclear factor kappa B (NF-κB) pathway, acting in coordination with pathways such as Nrf2 and MAPK [181]. Although these approaches remain largely experimental, they underscore the therapeutic relevance of targeting shared inflammatory mechanisms across neurodegenerative disorders (Table 3).