Oral microbiome dysbiosis, neuroinflammation, and psychiatric disorders: A review of current progress

Abstract

The oral microbiome, as the largest and most diverse microbial community in the human body, has emerged as a potential contributor to brain health. However, the mechanistic pathways by which oral dysbiosis influences the pathogenesis of psychiatric disorders remain incompletely integrated, and its translational implications for clinical practice have yet to be fully elucidated. This minireview aims to systematically synthesize current evidence on the role of oral microbiome dysbiosis in psychiatric disorders, with a particular focus on neuroinflammation as the key mediating mechanism, and to discuss the clinical and translational implications of these findings. In contrast to prior reviews that have largely centered on the gut-brain axis or individual diagnostic categories, the current minireview synthesizes evidence on three neuroinflammatory pathways: Hematogenous, retrograde neural, and the oral-gut-brain axis by which oral dysbiosis may contribute to psychiatric outcomes. By consolidating findings across major psychiatric disorders and emphasizing neuroinflammation as a core mediating process, we propose an integrative framework that unites oral microbiology with psychiatric pathophysiology.

Key Words: Psychiatric disorders; Neuroinflammatorty diseases; Oral microbiota; Oral-gut-brain axis; Periodontitis; Major depressive disorder; Schizophrenia; Autism spectrum disorder; Cytokines

Core Tip: Oral microbiome dysbiosis can drive neuroinflammation and contribute to psychiatric disorders via three key pathways: Direct bloodstream invasion, neural retrograde transport along trigeminal and olfactory nerves, and disruption of the oral-gut-brain axis. Recent animal evidence showing that Lactobacillus supplementation alleviates anxiety- and depression-like behaviors reinforces the translational potential of targeting the oral microbiota. This minireview integrates these mechanisms and highlights the oral cavity as an accessible, modifiable target for novel diagnostic and adjunctive therapeutic strategies in psychiatry.

INTRODUCTION

A recent study was published in the World Journal of Psychiatry by Chang et al[1] showed that Lactobacillus supplementation ameliorated hypobaric hypoxia-induced anxiety- and depression-like behaviors in mice, offering exploratory experimental evidence in an animal model that supports the biological plausibility of an oral-gut-brain axis relevant to psychiatric symptoms, though direct translation to human psychiatric disorders requires caution. Psychiatric disorders, including major depressive disorder, schizophrenia, bipolar disorder, and autism spectrum disorder, collectively rank among the leading causes of global disability, imposing a substantial socioeconomic burden and often following a chronic or relapsing course with limited treatment response[2,3].

The oral microbiome, the largest and most taxonomically diverse microbial niche in the human body, comprising over 700 bacterial species predominantly from the phyla Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria, which has traditionally been studied in the context of caries and periodontitis[4,5]. There is now growing evidence that this microbial community plays a vital, yet still overlooked, role in brain health[6]. It is important to distinguish between oral microbial dysbiosis and periodontitis. Oral microbial dysbiosis denotes a compositional or functional shift in the microbial community, which can occur without clinical disease. Periodontitis, by contrast, is a clinically defined inflammatory disease of the tooth-supporting tissues, driven in many cases by dysbiotic communities. While related, the two are not synonymous.

Despite the growing interest in the oral microbiome, several critical knowledge gaps remain. First, while the gut-brain axis has been extensively reviewed, the oral cavity, as a direct and proximal microbial niche to the brain, has received comparatively little attention in psychiatric research. Second, the mechanistic pathways by which oral dysbiosis may influence brain function are diverse and interconnected, yet they have rarely been synthesized within a unified framework. Third, the translational implications of these findings particularly whether oral microbial signatures can serve as clinically useful biomarkers or whether oral-targeted interventions can improve psychiatric outcomes, remain largely speculative. This minireview aims to address these gaps by systematically integrating the current evidence on oral dysbiosis, neuroinflammation, and psychiatric disorders, with a focus on mechanistic pathways and clinical translation.

Neuroinflammation is characterized by sustained activation of microglia and astrocytes, elevated pro-inflammatory cytokines has been consistently implicated in the pathophysiology of diverse psychiatric conditions, underpinning symptom domains such as anhedonia, cognitive impairment, and social withdrawal[6-8]. Crucially, oral microbial dysbiosis, as an imbalance marked by overgrowth of pathogens such as Porphyromonas gingivalis and depletion of commensals can trigger and perpetuate neuroinflammation via multiple interconnected routes: Hematogenous dissemination of bacterial lipopolysaccharide (LPS) and inflammatory mediators that compromise the blood-brain barrier[9,10], direct retrograde transport of oral pathogens along the trigeminal and olfactory nerves to limbic and brainstem regions[9], and the oral-gut-brain axis wherein swallowed oral microbes reshape gut microbiota and intestinal permeability[11], thereby amplifying peripheral signals that reach the central nervous system. Consequently, the oral microbiome represents a potentially modifiable, low-cost, and non-invasive potentially modifiable correlate of neuroinflammation-mediated psychiatric morbidity, opening new avenues for biomarker discovery and adjunctive therapeutic strategies.

This minireview is based on a comprehensive but non-systematic survey of the peer-reviewed literature published over the past two decades, with a focus on studies directly examining the associations among oral microbiome, neuroinflammation, and psychiatric disorders. Priority was given to high-quality systematic reviews, meta-analyses, and well-designed observational or mechanistic studies, while evidence from neurological conditions was included only for its mechanistic insights and explicitly distinguished from psychiatric evidence.

DYSBIOSIS OF ORAL MICROECOLOGY AND ITS ASSOCIATION WITH PSYCHIATRY DISORDERS

Alterations in the oral ecology of patients with psychiatric disorders

There is now growing evidence that the oral microbiome is markedly changed in people with psychiatric disorders. These changes include reduced salivary flow (xerostomia) primarily due to psychotropic medications, increased colonization of periodontopathic bacteria such as Porphyromonas gingivalis and Fusobacterium nucleatum, decreased abundance of commensal species like Streptococcus salivarius, and elevated inflammatory markers in gingival crevicular fluid. Furthermore, patients often present with higher plaque indices, greater probing pocket depths, and increased tooth loss compared to healthy controls[12,13].

Psychotropic medications pose a major confounder in oral microbiome studies. Antipsychotics, antidepressants, and mood stabilizers often cause dry mouth because of their anticholinergic and antiadrenergic effects. These effects lower saliva flow and change the pH in the mouth, which makes it easier for cavity-causing and gum-disease bacteria to grow, and this happens no matter what the psychiatric diagnosis is. So the changes in oral bacteria seen in patients on these drugs might come from the medication just as much as from the illness itself. But most crosssectional studies don’t really look at the specific drug, its dose, or how long the patient has been taking it, so it’s hard to tell whether the shifts are due to the disease or the treatment. To fix that, future studies should include patients who haven’t taken these drugs before and also collect thorough information about their treatment histories.

Major depressive disorder

A number of cross-sectional studies have consistently found that people with major depressive disorder have a higher rates of periodontitis and dental caries than those without the disorder[14,15]. Longitudinal studies suggest that more severe depressive symptoms correlates with the degree of oral dysbiosis[12-16].

Schizophrenia

A meta-analysis of 13 case-control studies included in a systematic review of 33 relevant studies by Turner et al[17] demonstrated that individuals with serious mental illness exhibit worse oral hygiene habits than healthy controls, including lower odds of dental visits (odds ratio = 0.46, 95% confidence interval: 0.32-0.65, P < 0.001) and lower frequency of tooth brushing (odds ratio = 0.19, 95% confidence interval: 0.08-0.42, P < 0.001), which predispose them to dental plaque accumulation.

Bipolar disorder

For bipolar disorder, the evidence specifically focused remains limited. Available cross-sectional studies suggest a higher prevalence of periodontitis and dental caries in this population[14,15], but there has non-enough data to say anything specific about the microbial profiles that distinguish this condition from others.

Autism spectrum disorder

In autism spectrum disorder, some studies have reported distinct taxonomic changes in the oral microbiota. In fact, these changes have been used in exploratory analyses to build classification models that could discriminate cases from controls, though those findings still need external validation. These studies establish a fairly strong clinical association, which raises the question of what types of ecological disruptions occur in the mouth and how they are triggered.

It is important to emphasize that the observed associations between psychiatric disorders and oral ecological disturbances do not, by themselves, establish causality. Several factors complicate causal inference. First, the majority of human evidence is cross-sectional, precluding determination of temporal precedence. Second, psychiatric disorders may contribute to poor oral health through pathways unrelated to microbial dysbiosis per se, including reduced motivation for oral hygiene, higher rates of smoking and sugar consumption, and medication-induced xerostomia. Third, shared risk factors such as low socioeconomic status, chronic stress, and poor dietary habits may independently affect both oral and mental health, acting as confounders rather than causal intermediates. Therefore, while the bidirectional hypothesis is biologically plausible, it remains to be rigorously tested through prospective cohort designs and, ultimately, randomized controlled trials that evaluate whether improving oral health can modify psychiatric outcomes.

Types and mechanisms of oral ecological imbalance triggers

Oral dysbiosis represents a sophisticated transition from a symbiotic homeostatic state to a pathogenic profile, rather than a mere fluctuation in individual microbial abundance[18]. This ecological shift is characterized by a significant reduction in microbial alpha-diversity and a structural succession of the community; specifically, the healthy microenvironment, typically dominated by Gram-positive aerobes, is supplanted by pathogenic biofilms enriched with Gram-negative anaerobes, notably Porphyromonas gingivalis[3,18].

The mechanisms triggering this imbalance are multifaceted and host-dependent. Initially, impaired host immune surveillance or alterations in salivary physicochemical properties provide a competitive advantage for opportunistic pathogens within their ecological niches[19]. Notably, psychological distress can modulate the oral microenvironment via the hypothalamic-pituitary-adrenal axis, releasing glucocorticoids that facilitate the proliferation of specific pathogens, thereby establishing a “stress-microbiota” feedback loop[5,20].

At the molecular level, the core of this dysbiotic trigger involves the physical disintegration of the periodontal barrier. Virulence factors produced by pathogens, such as gingipains, degrade epithelial tight junction proteins, leading to increased gingival permeability which phenomenon is termed leaky mouth[16,19]. This breach activates pattern recognition receptors, precipitating a localized “cytokine storm” of pro-inflammatory mediators including interleukin (IL)-1β and tumor necrosis factor-α. Such localized immune hyperactivation not only compromises the integrity of oral tissues but also provides a pathological gateway for pathogens and their metabolic byproducts (e.g., LPS) to bypass mucosal barriers, enter systemic circulation, and ultimately exert neuroinflammatory effects on the central nervous system[21,22].

THE MEDIATING ROLE OF NEUROINFLAMMATION: PATHWAYS LINKING ORAL MICROBIOTA TO PSYCHIATRIC DISORDERS

Before exploring each pathway, we should first clarify that neuroinflammation is not a single, uniform process. In the central nervous system, neuroimmune responses vary widely by region and change over time. Depending on when, where, and how intensely they occur, these responses can either harm or help, for instance, they may drive chronic microglial activation and cytokine release, but they can also clear pathogens and support tissue repair. In psychiatric disorders, the relevant evidence mostly points to persistent low-grade neuroinflammation as a correlate, or perhaps a contributing factor, to symptom expression, rather than an acute inflammatory assault. With that in mind, this minireview centers on the detrimental aspects of neuroinflammation most consistently tied to psychiatric outcomes, while keeping in mind that the full picture is more complex.

The hematogenous pathway

The hematogenous route is a primary conduit for oral to brain communication. During chronic periodontitis, the integrity of the gingival crevicular epithelium is compromised, allowing to translocate into the systemic circulation[23-25]. The inflammatory destruction of the periodontal attachment apparatus creates a direct gateway for oral pathogens to enter the systemic venous drainage. Systemic dissemination of LPS and gingipains from Porphyromonas gingivalis triggers a low-grade chronic inflammatory state, characterized by elevated levels of circulating cytokines such as IL-6 and C-reactive protein[20,26]. This systemic inflammatory state subsequently increases the permeability of the blood-brain barrier, thereby facilitating the paracellular infiltration of neurotoxic agents into the brain parenchyma and which may contribute to neuroinflammatory processes that have been associated with psychiatric symptomatology.

The trigeminal and olfactory pathways

Distinct from the hematogenous route, the trigeminal and olfactory nerves provide a short circuit that allows microbial components to bypass the restrictive filtration of the blood-brain barrier[27,28]. Pathogens living in the gingival sulcus can invade nerve endings of the trigeminal nerve’s upper and lower branches, and then travel backwards along these fibers to reach the pons and medulla[29]. The olfactory epithelium provides another route microbes from the mouth and nose can move along this pathway directly to the olfactory bulb and then on to the hippocampus, a region closely tied to emotional regulation[30,31]. These direct neural pathways offer a mechanistic basis for understanding how an imbalance in the oral microbiome could quickly and specifically effect brain areas that control mood, anxiety and thinking. That means oral problems might contribute to psychiatric conditions or make them worse, even without involving inflammation throughout the body. Notably, once microbial components such as LPS gain access to the brain parenchyma via trigeminal neural conduits, they can directly trigger local neuroinflammation and depressive onset, as demonstrated by Zhao et al[32] who showed that midbrain formaldehyde derived from LPS activates microglia and elicits cytokine storms (IL-1β, IL-6, tumor necrosis factor-α) not only in the midbrain dorsal raphe nucleus but also in limbic regions, resulting in blood-brain barrier disruption and depression-like behaviors in both acute and chronic mouse models.

The oral-gut-brain axis (indirect pathway)

Beyond hematogenous and neuronal routes, the oral-gut-brain axis provides an indirect pathway by which oral dysbiosis affects the central nervous system. Swallowed oral microorganisms, estimated at 10¹¹-10¹² per day, continuously seed the gut[20]. Under healthy conditions, most are eliminated by gastric acid. However, chronic oral dysbiosis, particularly overgrowth of periodontopathic bacteria such as Porphyromonas gingivalis and Fusobacterium nucleatum, enables these pathogens to survive gastric transit and colonize the distal gut[19,33]. Once established, they disrupt gut microbial composition, deplete short-chain fatty acid-producing commensals and increase intestinal permeability. This allows bacterial LPS and pro-inflammatory metabolites to enter the portal circulation, amplifying systemic inflammation that ultimately reaches the brain via TLR4-mediated microglial activation[34]. Additionally, oral-derived pathobionts can activate gut-associated lymphoid tissue, promoting pro-inflammatory Th17 cells that migrate to the central nervous system and sustain neuroinflammation[35].

Psychological stress is common in psychiatric disorders, which further dysregulates the hypothalamic-pituitary-adrenal axis, elevates glucocorticoids, and alters saliva composition, promoting oral pathogen overgrowth and exacerbating gut dysbiosis, thus creating a self-perpetuating cycle. Clinical evidence supports this axis (Table 1). Chang et al[1] showed that oral Lactobacillus supplementation ameliorated hypoxia-induced anxiety- and depression-like behaviors in mice. Li et al[36] reviewed how periodontitis influences depression via this axis. Paudel et al[20] highlighted stress-driven oral-gut dysbiosis as a three-way interaction. Toader et al[37] noted probiotics targeting the gut may alleviate psychiatric symptoms. Cho et al[38] identified oral and gut dysbiosis in migraine, with oral signatures as potential biomarkers. These findings don’t directly apply to primary psychiatric disorders, but they do support the idea that oral microbes might be linked to brain conditions. Thus, the oral-gut-brain axis represents a functionally integrated network where oral dysbiosis indirectly contributes to neuroinflammation and psychiatric morbidity. Targeting this axis via periodontal therapy or probiotics offers a promising adjunctive strategy for psychiatric disorders, particularly in treatmentresistant cases with concurrent oral health issues.

Table 1 Studies on the oral-brain axis in psychiatric conditions.

Evidence type	Research type	Key findings	Relevance to psychiatry	Evidence level/limitations	Ref.
Animal study	Mouse model	Administration of Lactobacillus in mouse models improves hypoxia-induced anxiety/depressive-like behaviors	Providing exploratory evidence for the gut-brain axis	Animal model; behavioral endpoints do not equate to clinical diagnosis	Chang et al[1], 2025
Meta analysis	Systematic review and meta-analysis of 33 studies	Patients with severe mental illness show poorer oral hygiene habits (odds ratio for tooth brushing = 0.19)	Confirms a clinical association, but findings are largely driven by behavioral factors	Cross-sectional in nature; multiple potential confounders	Turner et al[17], 2022
Mechanistic study (animal)	Mouse depression model	LPS activates microgram, triggering neuroinflammation and depressive-like behaviors	Highlights neuroinflammation as a possible mediating pathway	Animal model; LPS injection does not fully recapitulate oral microbial translocation	Zhao et al[32], 2024
Mechanistic study (animal)	Mouse model	Periodontitis promotes bacterial extracellular vesicles that induce neuroinflammation in the brain and trigeminal ganglion	Suggests a potential mechanism via the trigeminal nerve pathway	Animal model; findings require validation in psychiatric populations	Ha et al[30], 2023
Clinical association	Systematic review and meta-analysis	Oral microbiome composition is significantly altered in patients with psychiatric disorders	Confirm a stable association between oral microbiota and psychiatric conditions	Predominantly cross-sectional studies; high heterogeneity across studies	Cao et al[14], 2025
Clinical association	Review	Mental health status is associated with periodontal and peri-implant disease	Supports clinical relevance of the oral-systemic link	Review article; no original data presented	Ball and Darby[13], 2022
Mechanistic	Review	Periodontitis may affect the brain through neuroinflammatory mechanisms	Indirectly supports the oral-neuroinflammation connection	Review article; lacks primary experimental evidence	Li et al[10], 2022
Clinical observation	Prospective commentary	Mental disorders are associated with oral diseases, with a proposed bidirectional relationship	Introduces the hypothesis of bidirectionality	Opinion piece; not based on original empirical	Joury et al[12], 2023

LPS: Lipopolysaccharide.

CLINICAL TRANSLATION AND FUTURE PERSPECTIVE

The accessibility of oral biofluids renders the oral microbiome theoretically attractive reservoir for non-invasive biomarkers, though clinical applications in psychiatric screening, risk stratification, or treatment monitoring remain investigational and require further validation. Shifting the focus from systemic treatment to localized oral intervention offers a novel therapeutic dimension for neuroinflammation management. Moreover, adjusting the side-effect profiles of antipsychotic medications by specifically addressing drug-induced xerostomia may further enhance treatment outcomes. It is warranted to explore the efficacy of orally administered probiotics (which in the studies cited were delivered via the oral route but are intended to act primarily through the gastrointestinal tract) periodontal therapy in alleviating depressive symptoms[39-41], but their clinical utility for psychiatric indications has not yet been established.

Emerging evidence linking oral dysbiosis to psychiatric disorders via neuroinflammation offers several potential translational avenues, though most remain at an exploratory stage. First, oral microbial signatures may serve as non-invasive diagnostic biomarkers. Cho et al[38] reported oral and gut dysbiosis in migraine, a condition often comorbid with anxiety and depression. While these findings cannot be directly extrapolated to primary psychiatric disorders, they suggest that oral microbial profiles might aid in identifying central nervous system pathology and warrant investigation in psychiatric populations.

Second, interventions targeting the oral-gut-brain axis are emerging. Chang et al[1] demonstrated that oral Lactobacillus supplementation ameliorated hypoxia-induced anxiety- and depression-like behaviors in mice. Periodontal non-surgical treatment has been associated with reduced inflammation and improved mood scores, but randomized controlled trials with psychiatric outcomes are lacking. Several challenges remain. Causality is unclear, as most studies are cross-sectional. Longitudinal cohorts tracking oral microbiota before psychiatric onset are needed. Standardization of sampling (saliva, plaque, gingival fluid) and sequencing protocols is essential. Well-powered randomized clinical trials must test whether periodontal therapy or oral probiotics produce clinically meaningful improvements.

Future priorities include: Prospective cohorts to assess the oral microbiome as a predictor of incident psychiatric disorders; animal models testing causal pathways via neuroinflammation; multi-omics integrative analysis; and interdisciplinary collaboration among psychiatrists, dentists, and microbiologists. Given its modifiable, low-cost, and non-invasive nature, the oral microbiome represents a promising target for precision psychiatry.

Several limitations of this minireview should be noted. For one, most human evidence comes from cross-sectional studies, which means we cannot infer causality or even the direction of the association. Animal models are useful for generating mechanistic hypotheses, but they cannot fully reflect the complexity of human psychiatric disorders and the behavioral readouts in rodents are only crude approximations of clinical symptoms. Psychotropic medications are another major confounder. They can substantially alter the oral environment and may explain much of the microbial variation observed in medicated patients. There is also considerable heterogeneity across studies in sample type, sequencing platforms and analysis methods, which makes direct comparisons challenging. Lastly, we still lack rigorous interventions trials examining whether oral health improvement translates to better psychiatric outcomes, so any clinical implications remain speculative. Future work will need to rely on prospective cohort designs, standardized protocols, and well-designed intervention studies to overcome these issues.

CONCLUSION

This minireview synthesizes accumulating evidence that oral microbiome dysbiosis is robustly associated with psychiatric disorders, with neuroinflammation serving as the principal mechanistic link (Figure 1). Three distinct pathways help explain how a local microbial imbalance might reach and affect the central nervous system. Beyond mechanistic insights, this body of work carries a broader implication for psychiatry: It reframes oral health not merely as a comorbidity or consequence of mental illness, but as a potentially modifiable domain that intersects with neuroimmune function. This perspective encourages a shift from a brain-centric view of psychiatric pathophysiology toward a more integrated, multi-system model.

Figure 1 Proposed mechanisms of oral microbiota-driven neuroinflammation in psychiatric disorders. IL: Interleukin; TNF-α: Tumor necrosis factor-α; CRP: C-reactive protein; LPS: Lipopolysaccharide; BBB: Blood-brain barrier.

That said, we’re still a long way from using the oral microbiome in the clinic, either as a diagnostic tool or as a treatment target. To get there, we need well-designed longitudinal studies that actually tease apart cause and effect, plus randomized trials that ask whether changing oral health can improve psychiatric symptoms. Until we have that kind of data, the oral-brain axis is better seen as an important research direction than something clinicians can act on right now. All in all, the oral microbiome gives us a fresh way to think about psychiatric illness. It’s easy to sample and relatively easy to modify, which makes it tempting for future personalised approaches. But that potential will only be realized if researchers put in the hard work to move beyond correlations and test real interventions.