口腔微生物；鼻腔微生物；阿尔兹海默

微生物与人体疾病、健康密切相关,如何理解微生物群落的组成及其发挥的功能是一大亟需研究的问题。近年来,宏蛋白质组学已经成为研究微生物组成与功能的重要技术手段。然而,由于微生物群落样本的复杂性与高度异质性,样品处理、质谱数据采集与数据分析成为宏蛋白质组目前面临的三大挑战。在宏蛋白质组分析中往往需要针对不同类型的样品进行前处理优化,采取不同的微生物分离富集、提取和裂解方案。与单一物种蛋白质组相类似,宏蛋白质组学中的质谱数据采集模式有数据依赖性采集(data-dependent acquisition, DDA)模式和数据非依赖性采集(data-independent acquisition, DIA)模式。DIA数据采集模式可以完整地采集样品的肽段信息,具有很强的发展潜力。但是由于宏蛋白质组样品的复杂性,其DIA数据解析已成为阻碍宏蛋白质组深度覆盖的一大难题。在数据解析方面,最重要的步骤在于蛋白质序列数据库的构建。数据库的大小和完整性不仅对鉴定数量有很大影响,还会影响物种和功能水平上的分析。目前宏蛋白质组数据库构建的金标准是基于宏基因组的蛋白质序列数据库。同时,基于迭代搜库的公共数据库过滤方法也已被证明具有很强的实用价值。从具体的数据解析策略角度,以肽段为中心的DIA数据解析方法占据了绝对的主流。随着深度学习和人工智能的发展,其会极大地推动宏蛋白质组数据解析的准确度、覆盖度与分析速度。在下游生物信息学分析方面,近年来开发了一系列注释工具,可以在蛋白水平、肽段水平、基因水平上进行物种注释来获得微生物群落组成。与其他组学方法相比,微生物群落的功能分析是宏蛋白质组学的一个独特特征。宏蛋白质组已经成为微生物群落多组学分析中的重要组成部分,并且仍在覆盖深度、检测灵敏度、数据解析完整度等方面具有很大的发展潜力。

Oral dysbiosis contributes to Alzheimer's disease (AD) by promoting neuroinflammation. Pathobionts such as Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum release virulence factors that induce amyloid beta aggregation and tau hyperphosphorylation, while the loss of commensals like Streptococcus salivarius and Neisseria spp. impairs anti‐inflammatory protection, worsening neuronal damage. P. gingivalis is strongly linked to an increased risk of AD, especially in individuals with systemic conditions like diabetes, hypertension, and chronic kidney disease. Its presence in brain tissue correlates with a higher likelihood of AD, while salivary Veillonella and periodontal pathogens in gingival crevicular fluid show potential as non‐invasive biomarkers for early AD detection. Therapeutic strategies targeting the oral microbiota, such as gingipain inhibitors, antimicrobials, probiotics, and prebiotics, show promise for mitigating AD risk. However, causal mechanisms and clinical efficacy remain to be fully established. Maintaining microbial balance through preventive and targeted modulation represents an innovative approach to reducing AD susceptibility.

The widespread use of mouthwashes, particularly those containing chlorhexidine (CHX), has raised concerns about their impact on the oral microbiome and potential systemic health effects. This perspective review examines the current evidence linking CHX mouthwash use to disruptions in the oral microbiome and explores the potential indirect implications for Alzheimer's disease (AD) risk. CHX mouthwash is effective in reducing dental plaque and gingival inflammation, but it also significantly alters the composition of the oral microbiome, decreasing the abundance of nitrate-reducing bacteria critical for nitric oxide (NO) production. This disruption can lead to increased blood pressure, a major risk factor for AD. Given the established connection between hypertension and AD, the long-term use of CHX mouthwash may indirectly contribute to the onset of AD. However, the relationship between CHX mouthwash use and AD remains largely indirect, necessitating further longitudinal and cohort studies to investigate whether a direct causal link exists. The review aims to highlight the importance of maintaining a balanced oral microbiome for both oral and systemic health and calls for more research into safer oral hygiene practices and their potential impacts on neurodegenerative disease risk.

The accumulation of amyloid-beta plaques in the brain is a central pathological feature of Alzheimer’s disease. It is believed that amyloid responses may be a result of the host immune response to pathogens in both the central nervous system and peripheral systems. Oral microbial dysbiosis is a chronic condition affecting more than 50% of older adults. Recent studies have linked oral microbial dysbiosis to a higher brain Aβ load and the development of Alzheimer’s disease in humans. Moreover, the presence of an oral-derived and predominant microbiome has been identified in the brains of patients with Alzheimer’s disease and other neurodegenerative diseases. Therefore, in this opinion article, we aim to provide a summary of studies on oral microbiomes that may contribute to the pathogenesis of the central nervous system in Alzheimer’s disease.

Advancing age is recognized as the primary risk factor for Alzheimer’s disease (AD); however approximately one third of dementia cases are attributable to modifiable risk factors such as hypertension, diabetes, smoking, and obesity. Recent research also implicates oral health and the oral microbiome in AD risk and pathophysiology. The oral microbiome contributes to the cerebrovascular and neurodegenerative pathology of AD via the inflammatory, vascular, neurotoxic, and oxidative stress pathways of known modifiable risk factors. This review proposes a conceptual framework that integrates the emerging evidence regarding the oral microbiome with established modifiable risk factors. There are numerous mechanisms by which the oral microbiome may interact with AD pathophysiology. Microbiota have immunomodulatory functions, including the activation of systemic pro-inflammatory cytokines. This inflammation can affect the integrity of the blood-brain barrier, which in turn modulates translocation of bacteria and their metabolites to brain parenchyma. Amyloid-β is an antimicrobial peptide, a feature which may in part explain its accumulation. There are microbial interactions with cardiovascular health, glucose tolerance, physical activity, and sleep, suggesting that these modifiable lifestyle risk factors of dementia may have microbial contributors. There is mounting evidence to suggest the relevance of oral health practices and the microbiome to AD. The conceptual framework presented here additionally demonstrates the potential for the oral microbiome to comprise a mechanistic intermediary between some lifestyle risk factors and AD pathophysiology. Future clinical studies may identify specific oral microbial targets and the optimum oral health practices to reduce dementia risk.

Recent studies have suggested that periodontal disease and alterations in the oral microbiome may be associated with cognitive decline and the development of Alzheimer’s disease (AD). Here, we report a pilot case‐control study of oral microbiota diversity in AD patients in comparison with healthy seniors from the Central Asian region.

No abstract available

This review aims to clarify the nature of the link between Alzheimer’s disease and the oral microbiome on an epidemiological and pathophysiological level, as well as to highlight new therapeutic perspectives that contribute to the management of this disease. We performed a systematic review, following the Preferred Reporting Items for Systematic Reviews checklist, from January 2000 to July 2021. The terms “plaque,” “saliva,” and “mouth” were associated with the search term “oral diseases” and used in combination with the Boolean operator “AND”/“OR”. We included experimental or clinical studies and excluded conferences, abstracts, reviews, and editorials. A total of 27 articles were selected. Evidence for the impact of the oral microbiome on the pathophysiological and immunoinflammatory mechanisms of Alzheimer’s disease is accumulating. The impact of the oral microbiome on the development of AD opens the door to complementary therapies such as phototherapy and/or the use of prebiotic compounds and probiotic strains for global or targeted modulation of the oral microbiome in order to have a favourable influence on the evolution of this pathology in the future.

The human oral microbiome can affect brain functions directly through the trigeminal nerve and olfactory system and indirectly via the oral–gut–brain axis. However, the potential link between the oral microbiome and mental health remains an area that requires further investigation. Taking into consideration that gut microbiota dysbiosis plays a role in the onset and progression of several mental disorders, as well as the potential influence of the oral microbiome on mental health via direct pathways, the present narrative review explores the role of the human oral microbiome in health and disease, along with the factors that affect its composition, with a particular focus on its potential impact on mental health, including its involvement in a range of mental disorders and brain-related conditions, such as Alzheimer's disease, Parkinson's disease, autism spectrum disorder, anxiety, depression, stress, bipolar disorder, Down's syndrome, cerebral palsy, epilepsy, and schizophrenia. Chronic oral diseases can impair the oral mucosal barrier, allowing microorganisms and endotoxins to enter the bloodstream, triggering systemic inflammation, and affecting the blood–brain barrier. This pathway can lead to neuroinflammation and cognitive dysfunction and contribute to adverse mental health effects. Additionally, translocation of oral bacteria to the gut can drive persistent inflammation and thereby affect brain health. Multiple studies suggest a potential relationship between the oral microbiome and several mental disorders, but further research is needed to strengthen the evidence surrounding these associations and to fully clarify the underlying mechanisms linking the oral microbiome to these conditions. Given the promising implications, future research should focus on elucidating the biological mechanisms through which alterations in the oral microbiome influence the development and progression of determinate neurodegenerative and neuropsychiatric disorders. Additionally, identifying reliable biomarkers linked to the oral microbiome could enhance early detection, diagnosis, and monitoring of these conditions.

The link between oral health and Alzheimer’s disease (AD) has gained increasing attention in recent years. Emerging evidence suggests that this association is bidirectional, involving both biological mechanisms and behavioral consequences that reinforce one another over time. Literature Review: A narrative synthesis of systematic reviews, meta-analyses, and scoping reviews published between January 2010 and March 2024 was conducted. Searching was performed in four electronic databases (PubMed, Scopus, the Web of Science, and the Cochrane Library), using a combination of MeSH terms and free-text keywords related to dementia and oral health. Inclusion criteria targeted human studies published in English with full-text access and a clear focus on the interplay between oral status and Alzheimer’s disease. Results: The reviewed literature indicates that periodontal disease, tooth loss, and oral microbiome alterations may contribute to neuroinflammation and cognitive decline, potentially influencing the onset and progression of AD. Conversely, Alzheimer’s disease negatively affects oral health through impaired self-care, reduced motor coordination, salivary changes, and altered pain perception. Conclusions: By mapping out these interconnections, the findings support a shift in perspective; oral health should be considered a relevant factor in both the prevention and management of Alzheimer’s disease. Dentistry and neurology must move closer together in clinical practice, particularly in the care of older adults. Promoting oral health is not just about preserving teeth; it may be part of preserving cognitive function and quality of life.

AIM Periodontitis is caused by dysbiosis of oral microbes and is associated with increased cognitive decline in Alzheimer's disease (AD), and recently, a potential functional link was proposed between oral microbes and AD. We compared the oral microbiomes of patients with or without AD to evaluate the association between oral microbes and AD in periodontitis. MATERIALS AND METHODS Periodontitis patients with AD (n = 15) and cognitively unimpaired periodontitis patients (CU) (n = 14) were recruited for this study. Each patient underwent an oral examination and neuropsychological evaluation. Buccal, supragingival and subgingival plaque samples were collected, and microbiomes were analysed by next-generation sequencing. Alpha diversity, beta diversity, linear discriminant analysis effect size, analysis of variance-like differential expression analysis and network analysis were used to compare group oral microbiomes. RESULTS All 29 participants had moderate to severe periodontitis. Group buccal and supragingival samples were indistinguishable, but subgingival samples demonstrated significant alpha and beta diversity differences. Differential analysis showed subgingival samples of the AD group had higher prevalence of Atopobium rimae, Dialister pneumosintes, Olsenella sp. HMT 807, Saccharibacteria (TM7) sp. HMT 348 and several species of Prevotella than the CU group. Furthermore, subgingival microbiome network analysis revealed a distinct, closely connected network in the AD group comprised of various Prevotella spp. and several anaerobic bacteria. CONCLUSIONS A unique microbial composition was discovered in the subgingival region in the AD group. Specifically, potential periodontal pathogens were found to be more prevalent in the subgingival plaque samples of the AD group. These bacteria may possess a potential to worsen periodontitis and other systemic diseases. We recommend that AD patients receive regular, careful dental check-ups to ensure proper oral hygiene management.

Introduction Periodontitis-related oral microbial dysbiosis is thought to contribute to Alzheimer's disease (AD) neuroinflammation and brain amyloid production. Since probiotics can modulate periodontitis/oral dysbiosis, this study examined the effects of a probiotic/lantibiotic, nisin, in modulating brain pathology triggered by periodontitis. Methods A polymicrobial mouse model of periodontal disease was used to evaluate the effects of this disease on brain microbiome dysbiosis, neuroinflammation, Alzheimer’s-related changes, and nisin’s therapeutic potential in this context. Results 16S sequencing and real-time PCR data revealed that Nisin treatment mitigated the changes in the brain microbiome composition, diversity, and community structure, and reduced the levels of periodontal pathogen DNA in the brain induced by periodontal disease. Nisin treatment significantly decreased the mRNA expression of pro-inflammatory cytokines (Interleukin-1β/IL-1 β, Interleukin 6/IL-6, and Tumor Necrosis Factor α/TNF-α) in the brain that were elevated by periodontal infection. In addition, the concentrations of amyloid-β 42 (Aβ42), total Tau, and Tau (pS199) (445.69 ± 120.03, 1420.85 ± 331.40, 137.20 ± 36.01) were significantly higher in the infection group compared to the control group (193.01 ± 31.82, 384.27 ± 363.93, 6.09 ± 10.85), respectively. Nisin treatment markedly reduced the Aβ42 (261.80 ± 52.50), total Tau (865.37 ± 304.93), and phosphorylated Tau (82.53 ± 15.77) deposition in the brain of the infection group. Discussion Nisin abrogation of brain microbiome dysbiosis induces beneficial effects on AD-like pathogenic changes and neuroinflammation, and thereby may serve as a potential therapeutic for periodontal–dysbiosis-related AD.

The human oral microbiota is a community of microorganisms that reside in the oral cavity, including lingual, buccal, and saliva, each niche with a distinct microbial composition. Alterations in oral microbiota have been associated with an increased risk of Alzheimer’s disease (AD). This study used data from 143 older adults in the MIND trial to evaluate the association between oral microbiome and cognitive function. Oral niche-specific differences (saliva, buccal, and lingual), as well as the microbiome composition differences (α and β diversity), were associated with cognitive function. A lower abundance of Gemella and a higher abundance of anaerobic pro-inflammatory bacteria (e.g., Parvimonas, Treponema, Dialister) were linked to a lower Cognitive Z Score. Porphyromonas, previously linked to AD, was not associated with cognition. The outcomes suggest that oral microbiota may be a biomarker for cognitive function. Further research is required to assess whether oral microbiota-directed strategies can positively impact cognitive decline.

The involvement of the oral microbiome (OM) in the pathophysiology of Alzheimer's disease and vascular dementia has been recognized epidemiologically, but the molecular mechanisms remain elusive. In this study, we uncovered the presence of OM-derived proteins (OMdPs) in brain extracellular vesicles (bEVs) from post-mortem Alzheimer's disease and vascular dementia subjects using unbiased metaproteomics. OMdP circulation in blood EVs was also confirmed in an independent cohort. Our findings also reveal that specific OMdPs are present in bEVs, with their levels varying with disease progression. Peptidome-wide correlation analyses further explored their exchange dynamics and composition within bEVs. In addition, we validated the ability of OM-derived EVs to cross the blood–brain barrier using a blood–brain barrier–on-a-chip model, confirming a potential route for bacterial-derived molecules to reach the central nervous system. Bioinformatics-driven interaction analyses indicated that OMdPs engage with key neuropathological proteins, including amyloid-beta and tau, suggesting a novel mechanism linking dysbiotic OM to dementia. These results provide new insights into the role of the OM in neurodegeneration and highlight OMdPs as potential biomarkers and therapeutic targets.

Microbial communities in the intestinal tract have been suggested to impact the ethiopathogenesis of Alzheimer 's disease (AD). The human microbiome might modulate neuroinflammatory processes and thus contribute to neurodegeneration in AD. However, the microbial compositions in AD patients at different stages of the disease are still not fully characterized. We used 16S rRNA analyses to investigate the oral and fecal microbiota in patients with AD and mild cognitive impairment (MCI), a cohort of at-risk individuals (APOE4 carriers) and healthy controls, and investigated the relationship of microbial communities and disease specific markers. We found a slightly decreased diversity in the fecal microbiota of AD patients and identified differences in bacterial abundances including Bacteroidetes, Ruminococcus, Sutterella, Porphyromonadaceae. The diversity in the oral microbiota was increased in AD patients and at-risk individuals. Gram-negative pro-inflammatory bacteria including Haemophilus, Neisseria, Actinobacillus and Porphyromonas were dominant oral bacteria in AD and MCI patients and the abundance correlated with the cerebrospinal fluid (CSF) biomarker. Taken together, we observed a strong shift in the fecal and the oral communities of patients with AD already prominent in prodromal and, in case of the oral microbiota, in at-risk stages. This indicates stage-dependent alterations in oral and fecal microbiota in AD which may contribute to the pathogenesis via a facilitated intestinal and systemic inflammation leading to neuroinflammation and neurodegeneration.

We explored the effects of an oral health intervention on the oral microbiome and cognitive function of patients with mild Alzheimer's disease (AD) and determined the influence on disease progression. Sixty-six patients with mild AD were randomly assigned to intervention or control groups and received a 24-week oral health intervention and routine care, respectively. Data were collected at baseline and week 24. 16 S rRNA sequencing was used to analyze oral microbiota. After 24 weeks of oral health intervention, Kayser-Jones Brief Oral Health Status Examination (BOHSE), Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), Nursing Home Adjustment Scale (NHAS), and Alzheimer's Disease Cooperative Study-ADL (ADCS-ADL) scores were different between groups (p < 0.05). Subgingival plaque in patients with AD showed significant differences in the diversity and abundance of oral microbiomes, with a higher abundance of normal oral flora in the intervention group. We found oral health intervention strategies are effective in modifying subgingival microbiota differences and slowing cognitive decline in mild AD patients.

This case‐control study was designed to compare the composition of the predominant oral bacterial microbiome in Alzheimer's disease (AD) and control group.

OBJECTIVES To analyse the characteristics of the oral microbiomes and expected to find biomarkers about Alzheimer's disease (AD). SUBJECTS AND METHODS AD patients (n=26) and cognitive intact people (n=26) were examined for cognition, depression, oral health and collected saliva and gingival crevicular fluid (GCF) in the morning. Full-length 16S rRNA gene was amplified and sequencing was performed using the PacBio platform. RESULTS The predominant bacterium of salivary microbiome and periodontal microbiome from AD patients was Streptococcus oralis (S. oralis) and Porphyromonas gingivalis (P. gingivalis), respectively. With respect to β diversity analysis, there was a significance difference in periodontal microbiome between AD patients and cognitively intact subjects. The relative abundance of Veillonella parvula (V. parvula) significantly increased in oral microbiomes from AD patients. Interestingly, the dominant species were different between early-onset AD and late-onset AD patients. Moreover, the predominant species were changed as the clinical severity of AD. Furthermore, the correlation analysis revealed that V. parvula was associated with AD in both saliva and GCF and that P. gingivalis was associated with AD only in GCF. CONCLUSIONS In this study, the microbiome community of oral microbes were altered in AD patients and periodontal microbiome was sensitive to cognition changes. Moreover, V. parvula and P. gingivalis were associated with AD.

No abstract available

New studies have linked epidemiological and pathophysiological relationships between oral microbiota and Alzheimer’s disease (AD), a neurodegenerative disease more prevalent in the Puerto Rican population. Dysbiosis of the oral microbiome induces periodontal disease, which increases systemic chronic inflammation, an important component in the multifactorial pathogenesis of AD. This project aims to characterize the oral microbiota’s composition and diversity in AD patients compared to healthy controls, and explore the potential role of oral dysbiosis in dementia.

Inflammation and immune mechanisms are believed to play important roles in Alzheimer's disease pathogenesis. Research supports the link between poor oral health and Alzheimer's disease. Periodontal disease and dental caries represent the two most common infections of the oral cavity. This study focused on a precursor to Alzheimer's disease, mild cognitive impairment (MCI). Using 16S rRNA sequencing, we characterized and compared the oral microbiome of 68 older adults who met the criteria for MCI or were cognitively normal, then explored relationships between the oral microbiome, diagnostic markers of MCI, and blood markers of systemic inflammation. Two taxa, Pasteurellacae and Lautropia mirabilis were identified to be differentially abundant in this cohort. Although systemic inflammatory markers did not differentiate the two groups, differences in five cerebrospinal fluid inflammatory mediators were identified and had significant associations with MCI. Because inflammatory markers may reflect CNS changes, pursuing this line of research could provide opportunities for new diagnostic tools and illuminate mechanisms for prevention and mitigation of Alzheimer's disease.

A 78-year-old man with moderate Alzheimer disease (AD) dementia was treated with nasal-foralumab, a fully human anti-CD3 monoclonal antibody, as part of a Food and Drug Administration expanded-access-program, based on previously demonstrated efficacy of anti-CD3 antibody in animal models. 18F-PBR06-PET, utilizing a second-generation 18-kDa-translocator-protein ligand targeting microglia, showed diffuse reduction of radiotracer uptake throughout the brain, following 3 months of nasal-foralumab compared with baseline. In particular, precuneus, posterior cingulate and anterior cingulate gyri, regions that had high levels of amyloid deposition on a baseline 18F-Florbetapir-PET scan, showed reduction in microglial activation after nasal-foralumab treatment for 3 months.

No abstract available

BACKGROUND Emerging evidence suggests a compelling nexus between periodontitis, a chronic inflammatory disease associated with an oral infection, and the development of Alzheimer's disease. Porphyromonas gingivalis, a keystone periodontal pathogen, has been detected in Alzheimer's disease-affected brain tissue and implicated in triggering neuroinflammation and promoting hallmark pathologies, including amyloid-beta accumulation and tau hyperphosphorylation, through virulence factors such as gingipains. With Alzheimer's disease posing a mounting global health challenge and periodontitis affecting a significant portion of the population, recognizing this link is both timely and critical. METHODS This editorial explores the biological and epidemiological evidence linking periodontal health to cognitive decline, evaluating studies on pathogen presence, inflammatory mechanisms, and associations between oral infection and neurodegeneration. RESULTS Evidence indicates that oral infections, particularly periodontitis, may play a more central role in neurodegeneration than previously acknowledged. Detection of periodontal pathogens in brain tissue, along with mechanistic studies demonstrating promotion of hallmark Alzheimer's pathologies, highlights the potential impact of chronic oral inflammation on cognitive decline. CONCLUSION An integrated healthcare approach uniting dentistry, neurology, and public health is needed to prioritize oral health as a modifiable risk factor for dementia. Early diagnosis and treatment of periodontitis may represent a promising and underutilized strategy to reduce systemic inflammation and mitigate the risk of Alzheimer's disease.

Inflammation, especially neuroinflammation, which is caused by stress, leads to central nervous system (CNS) dysfunction. Because lipopolysaccharides (LPSs) cause neuroinflammation, we investigated the effect of LPSs to CNS. In PC-12 cells, LPSs derived from oral bacteria reduced the expression of KCC2, a Cl- transporter. LPS derived from P. gingivalis (P. g) administered to rat primary cultured cells also reduced the KCC2 expression. However, LPSs derived from E. coli did not reduce the KCC2 expression. LPS treatment activated TLR4, IL-1β, and REST gene expressions, which led to KCC2 inactivation in PC-12 cells. The mechanism of KCC2 has been shown to play an important role in brain maturation, function (such as the GABA switch), and behavioral problems, we investigated the GABA function. We found that the GABA function was changed from inhibitory to excitatory by the LPS derived from P. g treatment. We demonstrated that the GSK3β also involved in the KCC2 reduction by LPS treatment. We show that oxytocin rescued the reduction in KCC2 expression caused by LPSs by inhibiting GSK3β signaling but vasopressin could not. Considered together, our results indicate that the LPSs from oral bacteria but not the LPS from E. coli increase the risk for brain disorders and oxytocin might be a candidate to overcome the abnormal behavior caused by brain disorders such as psychiatric disorders.

Porphyromonas gingivalis is a gram-negative bacterium found in the human oral cavity and is responsible for the development of chronic periodontitis as well as neurological diseases, including Alzheimer’s disease (AD). Given the significance of the roles of P. gingivalis in AD pathogenesis, it is critical to understand the underlying mechanisms of P. gingivalis-driven neuroinflammation and their contribution to neurodegeneration. Herein, we hypothesize that P. gingivalis produces secondary metabolites that may cause neurodegeneration through direct or indirect pathways mediated by microglia. To test our hypothesis, we treated human neural cells with bacterial conditioned media on our brain platforms and assessed microgliosis, astrogliosis and neurodegeneration. We found that bacteria-mediated microgliosis induced the production of nitric oxide, which causes neurodegeneration assessed with high pTau level. Our study demonstrated the elevation of detrimental protein mediators, CD86 and iNOS and the production of several pro-inflammatory markers from stimulated microglia. Through inhibition of LPS and succinate dehydrogenase in a bacterial conditioned medium, we showed a decrease in neurodegenerative microgliosis. In addition, we demonstrated the bidirectional effect of microgliosis and astrogliosis on each other exacerbating neurodegeneration. Overall, our study suggests that the mouth-brain axis may contribute to the pathogenesis of AD.

Oral health represents a complex interplay between local microbial ecology, host immune responses, and systemic physiology. Far from being an isolated entity, the oral cavity is the entry point of the gastrointestinal and respiratory tracts and harbors up to one trillion microorganisms. While commensal species maintain ecological balance, pathogenic bacteria such as Porphyromonas gingivalis drive inflammatory conditions like gingivitis and periodontitis. Studies suggest that as chronic inflammation persists and is manifested through sustained breakdown of periodontal tissues, systemic dissemination of oral pathogens contributes to bacteremia, endothelial dysfunction, and neuroinflammation. As a result, increasing evidence has been found linking these oral pathogens and inflammatory mediators to systemic conditions including Alzheimer’s disease, cardiovascular disease, and arthritis. This narrative review synthesizes current evidence linking oral health to systemic disease while addressing practical strategies to strengthen preventive care. Evidence-based interventions are presented as accessible tools for reducing both oral and systemic inflammatory burden. Importantly, this article emphasizes the public health imperative of bridging mechanistic insights with actionable oral hygiene practices. By promoting evidence-based strategies such as scaling and root planing, dietary sugar reduction, and judicious use of antimicrobial agents, individuals may reduce their risk of chronic inflammatory and degenerative diseases. Future interdisciplinary research is needed to clarify causal mechanisms and optimize preventive frameworks integrating oral-systemic health.

The oral microbiome has been increasingly implicated in the development and progression of neurological disorders. This narrative review synthesizes contemporary literature on alterations of oral microbial communities in Alzheimer’s disease, Parkinson’s disease, and migraine and evaluates their potential contribution to neuroinflammation and neurodegeneration. We first outline the core oral taxa that maintain microbial homeostasis and summarize evidence that patients with these neurological conditions exhibit dysbiosis characterized by reduced diversity and enrichment of periodontal pathogens. Proposed mechanisms include hematogenous or neural translocation of oral bacteria and their virulence factors, amplification of systemic inflammation, disruption of the blood-brain barrier, altered production of neuroactive metabolites, and bidirectional signaling along the ‘oral-gut-brain’ axis. On this mechanistic basis, microbiome-targeted strategies, particularly probiotics and fecal microbiota transplantation, have been explored as adjunctive approaches to restore microbial balance and potentially improve neurological outcomes, although available clinical data remain preliminary and heterogeneous. Current evidence is further limited by small samples, methodological variability in microbiome profiling, and a paucity of longitudinal and interventional studies, which hampers causal inference. Future research should adopt standardized sampling and multi-omic approaches and prioritize well-designed clinical trials to determine whether modulation of the oral microbiome can be translated into preventive or therapeutic strategies for neurological diseases.

Periodontitis, a chronic, inflammatory disease, induces systemic inflammation and contributes to the development of neurodegenerative diseases. The precise etiology of the most common neurodegenerative disorders, such as sporadic Alzheimer’s, Parkinson’s diseases and multiple sclerosis (AD, PD, and MS, respectively), remains to be revealed. Chronic neuroinflammation is a well-recognized component of these disorders, and evidence suggests that systemic inflammation is a possible stimulus for neuroinflammation development. Systemic inflammation can lead to deleterious consequences on the brain if the inflammation is sufficiently severe or if the brain shows vulnerabilities due to genetic predisposition, aging, or neurodegenerative diseases. It has been proposed that periodontal disease can initiate or contribute to the AD pathogenesis through multiple pathways, including key periodontal pathogens. Dysbiotic oral bacteria can release bacterial products into the bloodstream and eventually cross the brain-blood barrier; these bacteria can also cause alterations to gut microbiota that enhance inflammation and potentially affect brain function via the gut–brain axis. The trigeminal nerve has been suggested as another route for connecting oral bacterial products to the brain. PD and MS are often preceded by gastrointestinal symptoms or aberrant gut microbiome composition, and alterations in the enteric nervous system accompany the disease. Clinical evidence has suggested that patients with periodontitis are at a higher risk of developing PD and MS. This nexus among the brain, periodontal disease, and systemic inflammation heralds new ways in which microglial cells, the main innate immune cells, and astrocytes, the crucial regulators of innate and adaptive immune responses in the brain, contribute to brain pathology. Currently, the lack of understanding of the pathogenesis of neurodegeneration is hindering treatment development. However, we may prevent this pathogenesis by tackling one of its possible contributors (periodontitis) for systemic inflammation through simple preventive oral hygiene measures.

Chronic inflammatory conditions like periodontitis and inflammatory bowel disease (IBD) are reported to contribute to the pathogenesis of late‐onset Alzheimer's disease (AD). Gram‐negative bacteria are the main bacterial species causing oral and gut mucosal infections. Lipopolysaccharide (LPS) is a major inflammation‐inducing molecule in Gram‐negative bacteria. LPS derived from the oral bacterium Porphyromonas gingivalis exhibits heterogeneous tetra‐acylated and penta‐acylated lipid A, while LPS from Escherichia coli exhibits the classical hexa‐acylated lipid A. Whether P. gingivalis‐LPS and E. coli‐LPS play a similar role in the progression of late‐onset AD is unknown. Using adult, wild‐type C57BL/6J mice to mimic the adult population without genetically determined predisposition to AD, we showed that chronic inflammation induced by a 28‐day, subcutaneous infusion of P. gingivalis‐LPS or E. coli‐LPS can lead to neuroinflammation and AD‐like cognitive decline and pathology in male mice. At this relatively early stage (4 weeks) of chronic inflammation when the blood–brain barrier is intact, both P. gingivalis‐LPS and E. coli‐LPS cause neuroinflammation through Toll‐like receptor 4 (TLR4) and Toll‐like receptor 2 (TLR2) expressed at microglia in the brain. Notably, only E. coli‐LPS induces significant inflammatory responses systemically. In short, our results suggest that chronic P. gingivalis‐LPS release (occurring in chronic periodontitis) or E. coli‐LPS release (occurring in IBD) could harm the brain before the blood–brain barrier is disrupted; continuous local P. gingivalis‐LPS release might do harm to the brain before exhibiting adverse effects systemically.

Recent studies link infections with blood–brain barrier (BBB) dysfunctions, neuroinflammation and subsequent neurodegeneration. Here, we employed a zebrafish larval model to study the impact of systemic infection with an oral pathogen Porphyromonas gingivalis (Pg) and its major virulence factors – gingipains, on BBB integrity and cerebral vasculature. We demonstrated that systemic infection with wild-type Pg W83 significantly increased BBB permeability in zebrafish larvae, as evidenced by the extravasation of tracers into the brain parenchyma. This effect was absent in larvae infected with a gingipain-deficient mutant bacteria (ΔK/R-ab), indicating a pivotal role for gingipains in BBB disruption. Immunohistochemical analysis revealed a marked reduction in the expression of tight junction (TJ) proteins: Claudin-5 and Zo-1 on the cerebral vessels of Pg W83-infected larvae, while expression of genes encoding TJ proteins (cldn5a/b and tjp1a/b) was not changed, suggesting post-translational degradation as the primary mechanism. To verify the individual contributions of gingipains, larvae were injected with purified arginine- (RgpA and RgpB) or lysine- (Kgp) specific proteases. In larvae treated with RgpB and Kgp, but not those treated with RgpA, there was increased BBB permeability, loss of TJ proteins, and cerebrovascular changes. Among these, Kgp exerted the most pronounced effects, emphasizing its dominant role in Pg-mediated vascular destruction. Our findings for the first time provide in vivo evidence that Pg compromises BBB integrity via gingipain-dependent degradation of tight junction proteins on the cerebral vessels. Zebrafish larvae offer a robust model for studying Pg–BBB interactions and may support the development of therapeutic strategies targeting gingipains to preserve cerebrovascular integrity in neurodegenerative disease.

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Introduction Alzheimer’s (AD) and Parkinson’s disease (PD) are neurodegenerative conditions characterized by incremental deposition of β-amyloid (Aβ) and α-synuclein in AD and PD brain, respectively, in relatively conserved patterns. Both are associated with neuroinflammation, with a proposed microbial component for disease initiation and/or progression. Notably, Aβ and α-synuclein have been shown to possess antimicrobial properties. There is evidence for bacterial presence within the brain, including the oral pathobiont Porphyromonas gingivalis, with cognitive impairment and brain pathology being linked to periodontal (gum) disease and gut dysbiosis. Methods Here, we use high resolution 16S rRNA PCR-based Next Generation Sequencing (16SNGS) to characterize bacterial composition in brain areas associated with the early, intermediate and late-stage of the diseases. Results and discussion This study reveals the widespread presence of bacteria in areas of the brain associated with AD and PD pathology, with distinctly different bacterial profiles in blood and brain. Brain area profiles were overall somewhat similar, predominantly oral, with some bacteria subgingival and oronasal in origin, and relatively comparable profiles in AD and PD brain. However, brain areas associated with early disease development, such as the locus coeruleus, were substantially different in bacterial DNA content compared to areas affected later in disease etiology.

The human microbiome is increasingly recognized for its crucial role in the development and progression of neurodegenerative diseases. While the gut-brain axis has been extensively studied, the contribution of the oral microbiome and gut-oral tropism in neurodegeneration has been largely overlooked. Cognitive impairment (CI) is common in neurodegenerative diseases and develops on a spectrum. In Parkinson’s Disease (PD) patients, CI is one of the most common non-motor symptoms but its mechanistic development across the spectrum remains unclear, complicating early diagnosis of at-risk individuals. Here, we generated 228 shotgun metagenomics samples of the gut and oral microbiomes across PD patients with either mild cognitive impairment (PD-MCI) or dementia (PDD), and a healthy cohort, to study the role of the gut and oral microbiomes on CI in PD. In addition to revealing compositional and functional signatures, the role of pathobionts, and dysregulated metabolic pathways of the oral and gut microbiome in PD-MCI and PDD, we also revealed the importance of oral-gut translocation in increasing abundance of virulence factors in PD and CI. The oral-gut virulence was further integrated with saliva metaproteomics and demonstrated their potential role in dysfunction of host immunity and brain endothelial cells. Our findings highlight the significance of the oral-gut-brain axis and underscore its potential for discovering novel biomarkers for PD and CI.

Background: Parkinson’s disease (PD) is characterized by early-onset olfactory dysfunction preceding motor symptoms, yet its mechanisms remain elusive. Based on the studies on microbiota-gut-brain axis, the microbiota–nose–brain axis might be involved in the pathogenesis of PD. However relative studies are rare. Methods: By consecutive 14-days intranasally transplanting bacteria, we established mice models exhibiting nasal microbiota dysbiosis (NMD), including animal group received intranasal drops of fecal bacterial suspension from normal mice (NB group) and animal group received intranasal drops of fecal bacterial suspension from PD mice (PB group), with animals that only received anesthesia used as the control group. Then we analyzed the nasal microbiota composition via 16S rRNA sequencing, evaluated the olfactory and motor functions through behavioral experiments, including buried food test, open field test, pole descent test, and traction test. The neuropathology in olfactory-related and PD-related brain regions, including olfactory bulb, pyriform cortex, hippocampus, substantia nigra and striatum, was also detected by western blotting, immunofluorescence and immunohistochemical experiments using the antibodies of NeuN, TH and GFAP. Results: 16S rRNA sequencing revealed that PB mice were primarily characterized by an increase in bacteria associated with inflammation and PD. Behavioral assessments revealed that mice with NMD demonstrated impairments in the buried food test and pole descent test, indicative of olfactory and motor dysfunction. By detecting NeuN and GFAP expression, we identified neuronal loss and astrocytes activation in olfactory-related brain regions and adjacent structures, including the olfactory bulb, pyriform cortex, hippocampus, substantia nigra and striatum of both NMD groups, which may contribute to the observed functional disorders. Notably, animals exposed to PD-derived bacteria exhibited more pronounced changes in nasal bacteria, with more severe neuropathology. Conclusions: We present evidence supporting the microbiota–nose–brain axis, and the NMD-induced astrocyte activation and neurodegenerative pathology along the olfactory pathway may serve as a link between nose and brain.

In the recent years, the accelerating global demographic shift toward population aging has been accompanied by a marked increase in the prevalence of neurodegenerative disorders, notably Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. Among emerging approaches, dietary interventions targeting the gut–brain axis have garnered considerable attention, owing to their potential to modulate key pathogenic pathways underlying neurodegenerative processes. This review synthesizes current concepts in precision nutrition and elucidates neurohumoral, immune, and metabolic regulatory mechanisms mediated by the gut microbiota, including the roles of the vagus nerve, cytokines, short-chain fatty acids, vitamins, polyphenols, and microbial metabolites. Emerging evidence underscores that dysbiotic alterations contribute to compromised barrier integrity, the initiation and perpetuation of neuroinflammatory responses, pathological protein aggregations, and the progressive course of neurodegenerative diseases. Collectively, these insights highlight the gut microbiota as a pivotal target for the development of precision-based dietary strategies in the prevention and mitigation of neurodegenerative disorders. Particular attention is devoted to key bioactive components such as prebiotics, probiotics, psychobiotics, dietary fiber, omega-3 fatty acids, and polyphenols that critically participate in regulating the gut–brain axis. Contemporary evidence on the contribution of the gut microbiota to the pathogenesis of Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis is systematically summarized. The review further discusses the prospects of applying nutrigenomics, chrononutrition, and metagenomic analysis to the development of personalized dietary strategies. The presented findings underscore the potential of integrating precision nutrition with targeted modulation of the gut–brain axis as a multifaceted approach to reducing the risk of neurodegenerative diseases and preserving cognitive health.

BACKGROUND Growing evidence highlights the vital role by gut microbiota in brain health through the gut-brain axis, which involves neural, immune, endocrine, and metabolic signaling pathways. Disruption of this axis through microbial dysbiosis is increasingly linked to cognitive disorders, including dementia. However, the specific taxa and pathways involved remain poorly characterized. This study investigates taxonomic and functional shifts in the gut microbiome across healthy individuals, mild dementia, and dementia patients, aiming to identify microbial signatures and metabolic alterations associated with cognitive decline. METHODS A total of 184 participants (aged 60-98) were recruited and grouped into healthy, mild dementia, and dementia categories based on Clinical Dementia Rating scores. Demographic and clinical data were collected through structured interviews. Fecal samples were collected from participants and DNA was extracted and subjected to 16S rRNA gene sequencing. Sequencing data were processed using QIIME2 and classified using the SILVA database. Alpha (Shannon, Inverse Simpson) and beta diversity (Bray-Curtis PCoA) were analyzed between participant groups. Functional prediction was performed with PICRUSt2 to estimate KEGG orthologs from normalized ASVs. Statistical analyses were conducted in R using Kruskal-Wallis and PERMANOVA tests to assess group-level differences. RESULTS Dementia patients exhibited the highest proportion of unique ASVs (32.1%) but showed reduced alpha diversity compared to mild dementia and healthy controls. PCoA revealed distinct microbial clustering across groups, explaining 19.3% of total variance, with dementia samples forming a unique cluster. Taxonomically, dementia samples were enriched in Firmicutes and pro-inflammatory genera such as Peptoclostridium and Scardovia, while healthy controls harbored more SCFA-producing taxa like Lachnospiraceae_UCG-001. Co-occurrence networks in dementia were more complex, with increased inter-species connectivity and key drivers including Dorea and Clostridium innocuum. Functionally, dementia samples showed enrichment of vanillate degradation pathways and depletion of neuroprotective pathways like ergothioneine and vitamin E biosynthesis, correlating with specific microbial signatures. CONCLUSIONS Cognitive decline was associated with reduced microbial diversity and selective enrichment of pro-inflammatory taxa, reflecting gut ecological instability due to dementia. Microbial composition shifted progressively with dementia severity, indicating disease-specific gut microbial restructuring. Moreover, the loss of key functional microbial metabolites such as neuroprotective and anti-inflammatory metabolites supports targeting such metabolites and their producing gut microbiota as a therapeutic strategy for dementia. Future studies should ensure generalization by recruiting multi-center participants with strict guidelines for monitoring confounders.

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Alzheimer's Disease Analysis Model (ADAM) is a multi-agent reasoning large language model (LLM) framework designed to integrate and analyze multimodal data, including microbiome profiles, clinical datasets, and external knowledge bases, to enhance the understanding and classification of Alzheimer's disease (AD). By leveraging the agentic system with LLM, ADAM produces insights from diverse data sources and contextualizes the findings with literature-driven evidence. A comparative evaluation with XGBoost revealed a significantly improved mean F1 score and significantly reduced variance for ADAM, highlighting its robustness and consistency, particularly when utilizing human biological data. Although currently tailored for binary classification tasks with two data modalities, future iterations will aim to incorporate additional data types, such as neuroimaging and peripheral biomarkers, and expand them to predict disease progression, thereby broadening ADAM's scalability and applicability in AD research and diagnostic applications.

Alzheimer's disease is the most common form of dementia in the western world, however there is no cure available for this devastating neurodegenerative disorder. Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer's disease is not known. We generated a germ-free mouse model of Alzheimer's disease and discovered a drastic reduction of cerebral Ab amyloid pathology when compared to control Alzheimer's disease animals with intestinal microbiota. Sequencing bacterial 16S rRNA from fecal samples revealed a remarkable shift in the gut microbiota of conventionally-raised Alzheimer's disease mice as compared to healthy, wild-type mice. Colonization of germ-free Alzheimer mice with harvested microbiota from conventionally-raised Alzheimer mice dramatically increased cerebral Ab pathology. In contrast, colonization with microbiota from control wild-type mice was ineffective in increasing cerebral Ab levels. Our results indicate a microbial involvement in the development of Alzheimer's disease pathology, and suggest that microbiota may contribute to the development of neurodegenerative diseases.

Alzheimer's disease (AD) is a pervasive neurodegenerative disorder, and new approaches for its prevention and therapy are critically needed. Here, we elucidate a gut-microbiome-brain axis that offers actionable perspectives for achieving this objective. Using the 5xFAD mouse model, we identify increased Clostridium abundance and decreased Bacteroides abundance as key features associated with β-amyloid (Aβ) burden. Treatment with Bacteroides ovatus, or its associated metabolite lysophosphatidylcholine (LPC), significantly reduces Aβ load and ameliorates cognitive impairment. Mechanistically, LPC acts through the orphan receptor GPR119, inhibiting ACSL4 expression, thereby suppressing ferroptosis and ameliorating AD pathologies. Analysis of fecal and serum samples from individuals with AD also reveals diminished levels of Bacteroides and LPC. This study thus identifies a B.ovatus-triggered pathway regulating AD pathologies and indicates that the use of single gut microbiota, metabolite, or small molecule compound may complement current prevention and treatment approaches for AD.

Frailty is a critical intermediate status of the aging process with a multidimensional and multisystem nature and at higher risk for adverse health-related outcomes, including falls, disability, hospitalizations, institutionalization, mortality, dementia, and Alzheimer's disease. Among different frailty phenotypes, oral frailty has been recently suggested as a novel construct defined as a decrease in oral function with a coexisting decline in cognitive and physical functions. We briefly reviewed existing evidence on operational definitions of oral frailty, assessment and screening tools, and possible relationships among oral frailty, oral microbiota, and Alzheimer's disease neurodegeneration. Several underlying mechanism may explain the oral health-frailty links including undernutrition, sarcopenia linked to both poor nutrition and frailty, psychosocial factors, and the chronic inflammation typical of oral disease. Oral microbiota may influence Alzheimer's disease risk through circulatory or neural access to the brain and the interplay with periodontal disease, often causing tooth loss also linked to an increased Alzheimer's disease risk. On this bases, COR388, a bacterial protease inhibitor targeting Porphyromonas gingivalis implicated in periodontal disease, is now being tested in a double-blind, placebo-controlled Phase II/III study in mild-to-moderate Alzheimer's disease. Therefore, oral status may be an important contributor to general health, including Alzheimer's disease and late-life cognitive disorders, suggesting the central role of preventive strategies targeting the novel oral frailty phenotype and including maintenance and improvement of oral function and nutritional status to reduce the burden of both oral dysfunction and frailty.

Pre-clinical evidence implicates oral bacteria in the pathogenesis of Alzheimer's disease (AD), while clinical studies show diverse results. To comprehensively assess the association between oral bacteria and AD with clinical evidence. Studies investigating the association between oral bacteria and AD were identified through a systematic search of six databases PubMed, Embase, Cochrane Central Library, Scopus, ScienceDirect, and Web of Science. Methodological quality ratings of the included studies were performed. A best evidence synthesis was employed to integrate the results. When applicable, a meta-analysis was conducted using a random-effect model. Of the 16 studies included, ten investigated periodontal pathobionts and six were microbiome-wide association studies. Samples from the brain, serum, and oral cavity were tested. We found over a ten-fold and six-fold increased risk of AD when there were oral bacteria (OR = 10.68 95% CI: 4.48-25.43; p < 0.00001, I2 = 0%) and Porphyromonas gingivalis (OR = 6.84 95% CI: 2.70-17.31; p < 0.0001, I2 = 0%) respectively in the brain. While AD patients exhibited lower alpha diversity of oral microbiota than healthy controls, the findings of bacterial communities were inconsistent among studies. The best evidence synthesis suggested a moderate level of evidence for an overall association between oral bacteria and AD and for oral bacteria being a risk factor for AD. Current evidence moderately supports the association between oral bacteria and AD, while the association was strong when oral bacteria were detectable in the brain. Further evidence is needed to clarify the interrelationship between both individual species and bacterial communities and the development of AD.

The oral cavity (mouth) has various microbial habitats, including, teeth, gingival sulcus, gingiva, tongue, inner cheek, hard palate, and soft palate. The human oral cavity houses the second most diverse microbiome in the body harboring over 700 bacterial species. The fine-tuned equilibrium of the oral microbiome ecosystem maintains oral health. Oral dysbiosis caused by food habits and poor oral hygiene leads to various oral diseases such as periodontitis, caries, gingivitis, and oral cancer. Recent advances in technology have revealed the correlation between the oral microbiome and systemic diseases such as pulmonary diseases, cardiovascular diseases, rheumatoid arthritis, Alzheimer's disease, and other metabolic diseases. Since the oral cavity directly connects with the upper respiratory tract, the oral microbiome has easier access to the respiratory system compared to other organ systems. Direct aspiration of oral microflora in the respiratory system and oral dysbiosis-induced host immune reaction and inflammation are mainly responsible for various pulmonary complications. Numbers of literature have reported the correlation between oral diseases and pulmonary diseases, suggesting the possible role of the oral microbiome in respiratory diseases such as chronic obstructive pulmonary diseases, pneumonia, lung cancer, etc. This paper reviews the current evidence in establishing a link between the oral microbiome and pulmonary diseases. We also discuss future research directions focusing on the oral microbiome to unravel novel therapeutic approaches that could prevent or treat the various pulmonary complications.

The hypothesis of an infectious connection from the oro-pharyngeal sphere to the brain underlines the interest in analyzing the link between periodontal disease and Alzheimer's disease. The aim of this systematic review was to examine the link between Alzheimer's disease and periodontal disease in patients aged 65 and over. Databases (PubMed (MEDLINE), the Cochrane Library, and Embase) were analyzed for relevant references up to 21 June 2021. The authors independently selected the studies and extracted the data. The quality of included studies was checked using the National Institutes of Health's quality assessment tools. Five studies were included. The selected studies described in their results an increase in

Recent studies have suggested that periodontal disease and alterations in the oral microbiome may be associated with cognitive decline and Alzheimer's disease (AD) development. Here, we report a case-control study of oral microbiota diversity in AD patients compared to healthy seniors from Central Asia. We have characterized the bacterial taxonomic composition of the oral microbiome from AD patients (n = 64) compared to the healthy group (n = 71) using 16S ribosomal RNA sequencing. According to our results, the oral microbiome of AD has a higher microbial diversity, with an increase in

The oral cavity is the initial chamber of digestive tract; the saliva swallowed daily contains an estimated 1.5 × 10

The diversity of bacterial species in the oral cavity makes it a key site for research. The close proximity of the oral cavity to the brain and the blood brain barrier enhances the interest to study this site. Changes in the oral microbiome are linked to multiple systemic diseases. Alcohol is shown to cause a shift in the microbiome composition. This change, particularly in the oral cavity, may lead to neurological diseases. Alzheimer's disease (AD) is a common neurodegenerative disorder that may cause irreversible memory loss. This study uses the meta-analysis method to establish the link between binge drinking, the oral microbiome and AD. The QIAGEN Ingenuity Pathway Analysis (IPA) shows that high levels of ethanol in binge drinkers cause a shift in the microbiome that leads to the development of AD through the activation of eIF2, regulation of eIF4 and p70S6K signaling, and mTOR signaling pathways. The pathways associated with both binge drinkers and AD are also analyzed. This study provides a foundation that shows how binge drinking and the oral microbiome dysbiosis lead to permeability changes in the blood brain barrier (BBB), which may eventually result in the pathogenesis of AD.

To investigate the association between Alzheimer's disease (AD) and periodontitis in the aspects of periodontal status, serological markers, and oral microbiome. Twenty AD and 20 healthy subjects were enrolled in this age- and gender-matched case-control study. Clinical periodontal parameters and serum biomarkers, including amyloid β Alzheimer's disease patients with Clinical Dementia Rating (CDR) ≥1 exhibited significantly more clinical attachment loss (CAL) than those with lower CDR. The levels of serum Tau protein, hsCRP and anti-P. gingivalis LPS antibody were markedly elevated in the AD group compared with the control group. Serum pTau protein level was positively correlated with anti-P. gingivalis LPS antibody titer. Moreover, the increased abundances of Capnocytophaga sp ora clone DZ074, Eubacterium infirmum, Prevotella buccae, and Selenomonas artemidis were detected in the AD group. Interestingly, serum levels of Aβ Our study suggested the association of periodontal infection and oral microbiome with AD. Further large-scale studies with longitudinal follow-up are warranted.

An association between the gut microbiome and cognitive function has been demonstrated in prior studies. However, whether the oral microbiome, the second largest microbial habitant in humans, has a role in cognition remains unclear. Using weighted data from the 2011 to 2012 National Health and Nutrition Examination Survey, we examined the association between oral microbial composition and cognitive function in older adults. The oral microbiome was characterized by 16S ribosomal RNA gene sequencing. Cognitive status was assessed using the Consortium to Establish a Registry for Alzheimer's Disease immediate recall and delayed recall, Animal Fluency Test, and Digit Symbol Substitution Test (DSST). Subjective memory changes over 12 months were also assessed. Linear and logistic regression models were conducted to quantify the association of α-diversity with different cognitive measurements controlling for potential confounding variables. Differences in β-diversity were analyzed using permutational analysis of variance. A total of 605 participants aged 60-69 years were included in the analysis. Oral microbial α-diversity was significantly and positively correlated with DSST (β, 2.92; 95% CI, 1.01-4.84). Participants with higher oral microbial α-diversity were more likely to have better cognitive performance status based on DSST (adjusted odds ratio, 2.35; 95% CI, 1.28-4.30) and were less likely to experience subjective memory changes (adjusted odds ratio, 0.43; 95% CI, 0.25-0.74). In addition, β-diversity was statistically significant for the cognitive performance status based on DSST (P = 0.031) and subjective memory changes (P = 0.023). Oral microbial composition was associated with executive function and subjective memory changes among older adults among older U.S. adults in a nationally representative population sample. Oral dysbiosis is a potential biomarker or therapeutic target for cognitive decline. Further work is needed to elucidate the mechanisms underpinning the association between the oral microbiome and cognitive function.

Among millions of sufferers of chronic rhinosinusitis (CRS), the challenge is not only constantly coping with CRS-related symptoms, such as congested nose, sinus pain, and headaches, but also various complications, such as attention difficulties and possible depression. These complications suggest that neural activity in the central nervous system may be altered in those patients, leading to unexpected conditions, such as neurodegeneration in elderly patients. Recently, some studies linked the presence of CRS and cognitive impairments that could further develop into Alzheimer's disease (AD). AD is the leading cause of dementia in the elderly and is characterised by progressive memory loss, cognitive behavioural deficits, and significant personality changes. The microbiome, especially those in the gut, has been recognised as a human organ and plays an important role in the development of various conditions, including AD. However, less attention has been paid to the microbiome in the nasal cavity. Increased nasal inflammatory responses due to CRS may be an initial event that changes local microbiome homeostasis, which may further affect neuronal integrity in the central nervous system resulting in AD. Evidence suggests a potential of β-amyloid deposition starting in olfactory neurons, which is then expanded from the nasal cavity to the central nervous system. In this paper, we reviewed currently available evidence that suggests this potential mechanism to advise the need to investigate the link between these two conditions.

Although there is a consensus that the dominant species that make up the adult microbiota remains unchanged in elderly people, it has been reported that there are significant alterations in the proportion and composition of the different taxa, leading to reduced microbiota diversity, as well as an increase of enteropathogens that may lead to chronic inflammation. The ageing of mucosal immune and motor systems also contributes to these changes. As the individual ages, there is a loss in the number of Peyer's patches, an altered local capacity of T and B cell functions as well as chronic macrophage activation. Also, environment, diet, place of residence and biogeography are regulatory factors of the microbiota. Communication in the gut-brain-axis is regulated by many intermediaries including diverse metabolites of the microbiota. Microbial changes have been observed in several geriatric diseases, like Parkinson's and Alzheimer's. In addition, evidence has shown that individuals with high frailty scores had a significant reduction on lactobacilli species when compared to non-frail individuals. Oral microbiota may be also especially important because of the opportunities for access to the brain through the olfactory nerve at the roof of the nose or through the abundant innervations of the oral cavity by the trigeminal and other cranial nerves. Also, there are an increasing number of reports that have suggested potential mechanisms by which the microbiota promote human health span and aging. The study of the microbiota represents an important advance in the understanding of the aging process.

The human body harbors a diverse ecosystem of microorganisms, including bacteria, viruses, and fungi, collectively known as the microbiota. Current research is increasingly focusing on the potential association between the microbiota and various neuropsychiatric disorders. The microbiota resides in various parts of the body, such as the oral cavity, nasal passages, lungs, gut, skin, bladder, and vagina. The gut microbiota in the gastrointestinal tract has received particular attention due to its high abundance and its potential role in psychiatric and neurodegenerative disorders. However, the microbiota presents in other body tissues, though less abundant, also plays crucial role in immune system and human homeostasis, thus influencing the development and progression of neuropsychiatric disorders. For example, oral microbiota imbalance and associated periodontitis might increase the risk for neuropsychiatric disorders. Additionally, studies using the postmortem brain samples have detected the widespread presence of oral bacteria in the brains of patients with Alzheimer's disease. This article provides an overview of the emerging role of the host microbiota in neuropsychiatric disorders and discusses future directions, such as underlying biological mechanisms, reliable biomarkers associated with the host microbiota, and microbiota-targeted interventions, for research in this field.

In recent times, the nasal region has emerged as a distinctive and dynamic environment where a myriad of microbial communities establish residence from infancy, persisting as both commensal and opportunistic pathogens throughout the lifespan. Understanding the coexistence of microorganisms in respiratory mucosal layers, their potential for infections, and the underlying molecular mechanisms shaping these interactions is crucial for developing efficient diagnostic and therapeutic interventions against respiratory and neurodegenerative diseases. Despite significant strides in understanding the olfactory system's nexus with nasal microbiota, comprehensive correlations with neurological diseases still need to be discovered. The nasal microbiome, a sentinel in immune defense, orchestrates a delicate equilibrium that, when disrupted, can precipitate severe respiratory infections, including Chronic Rhinosinusitis, Chronic obstructive pulmonary disorder (COPD), and Asthma, and instigate a cascade effect on central nervous system diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Multiple sclerosis (MS). This review aims to redress this imbalance by meticulously exploring the anatomical and microbiological nuances of the nasal mucosal surface in health and disease. By delineating the molecular intricacies of these interactions, this review unravels the molecular mechanisms that govern the intricate nexus between nasal microbiota dysbiosis, olfactory dysfunction, and the progression of respiratory and neurological diseases.

Inflammation and neurodegeneration are key features of many chronic neurological diseases, yet the causative mechanisms underlying these processes are poorly understood. There has been mounting interest in the role of the human microbiome in modulating the inflammatory milieu of the central nervous system (CNS) in health and disease. To date, most research has focussed on a gut-brain axis, with other mucosal surfaces being relatively neglected. We herein take the novel approach of comprehensively reviewing the roles of the microbiome across several key mucosal interfaces - the nose, mouth, lung and gut - in health and in Parkinson's disease (PD), Alzheimer's disease (AD) and multiple sclerosis (MS). This review systematically appraises the anatomical and microbiological landscape of each mucosal surface in health and disease before considering relevant mechanisms that may influence the initiation and progression of PD, AD and MS. The cumulative effects of dysbiosis from the nose to the gut may contribute significantly to neurological disease through a wide variety of mechanisms, including direct translocation of bacteria and their products, and modulation of systemic or CNS-specific immunity. This remains an understudied and exciting area for future research and may lead to the development of therapeutic targets for chronic neurological disease.

Dysbiosis or imbalance of gut microbiota in Alzheimer's disease (AD) affects the production of short-chain fatty acids (SCFAs), whereas exogenous SCFAs supplementation exacerbates brain Aβ burden in APP/PS1 mice. Bifidobacterium is the main producer of SCFAs in the gut flora, but oral administration of Bifidobacterium is ineffective due to strong acids and bile salts in the gastrointestinal tract. Therefore, regulating the levels of SCFAs in the gut is of great significance for AD treatment. We investigated the feasibility of intranasal delivery of MSNs-Bifidobacterium (MSNs-Bi) to the gut and their effect on behavior and brain pathology in APP/PS1 mice. Mesoporous silica nanospheres (MSNs) were efficiently immobilized on the surface of Bifidobacterium. After intranasal administration, fluorescence imaging of MSNs-Bi in the abdominal cavity and gastrointestinal tract revealed that intranasally delivered MSNs-Bi could be transported through the brain to the peripheral intestine. Intranasal administration of MSNs-Bi not only inhibited intestinal inflammation and reduced brain Aβ burden but also improved olfactory sensitivity in APP/PS1 mice. These findings suggested that restoring the balance of the gut microbiome contributes to ameliorating cognitive impairment in AD, and that intranasal administration of MSNs-Bi may be an effective therapeutic strategy for the prevention of AD and intestinal disease.

Traumatic brain injury and chronic traumatic encephalopathy are both major health problems, well-publicized for the severe delayed effects attributed to them, including cognitive decline, psychiatric disorders, seizures, impaired motor function, and personality changes. For convenience, the two afflictions are considered together under the rubric traumatic brain injury. Despite the need for neuroprotective agents, no substances have shown efficacy in clinical studies. Thus, a deeper understanding of the neuropathological mechanism of such injury is still needed. Proposed here is a theory that microorganisms from within the brain and elsewhere in the body contribute to the long-term neurological deterioration characteristic of traumatic brain injury. The label, "The Beehive Theory", is drawn from the well-known fact that disturbing a tranquil beehive with a blow can cause a swarm of angry bees to exit their dwelling place and attack nearby humans. Similarly, an impact to the head can initiate dislocations and disruptions in the microbiota present in the brain and body. First, since the normal human brain is not sterile, but is host to a variety of microorganisms, blows to the skull may dislodge them from their accustomed local environments, in which they have been living in quiet equilibrium with neighboring brain cells. Deleterious substances may be released by the displaced microbes, including metabolic products and antigens. Second, upon impact commensal microbes already resident on surfaces of the nose, mouth, and eyes, and potentially harmful organisms from the environment, may gain access to the brain through the distal ends of the olfactory and optic nerves or even a disrupted blood-brain barrier. Third, microbes dwelling in more distant parts of the body may be propelled through the walls of local blood vessels into the bloodstream, and then leak out into damaged areas of the brain that have increased blood-brain barrier permeability. Fourth, the impact may cause dysbiosis in the gastrointestinal microbiome, thereby disrupting signaling via the gut-brain axis. Possible preventatives or therapeutics that would address the adverse contributions of microbes to the late sequelae of traumatic brain injury include anti-inflammatories, antibacterials, antivirals, and probiotics.

Recent studies underscore the role of gut and oral microbiota in influencing neuroinflammation through the microbiota-gut-brain axis, including in Alzheimer's disease (AD). This review aims to provide a comprehensive synthesis of recent findings on the involvement of gut and oral microbiota in the neuroinflammatory processes associated with AD, emphasizing novel insights and therapeutic implications. This review reveals that dysbiosis in AD patients' gut and oral microbiota is linked to heightened peripheral and central inflammatory responses. Specific bacterial taxa, such as Bacteroides and Firmicutes in the gut, as well as Porphyromonas gingivalis in the oral cavity, are notably altered in AD, leading to significant changes in microglial activation and cytokine production. Gut microbiota alterations are associated with increased intestinal permeability, facilitating the translocation of endotoxins like lipopolysaccharides (LPS) into the bloodstream and exacerbating neuroinflammation by activating the brain's toll-like receptor 4 (TLR4) pathways. Furthermore, microbiota-derived metabolites, including short-chain fatty acids (SCFAs) and amyloid peptides, can cross the blood-brain barrier and modulate neuroinflammatory responses. While microbial amyloids may contribute to amyloid-beta aggregation in the brain, certain SCFAs like butyrate exhibit anti-inflammatory properties, suggesting a potential therapeutic avenue to mitigate neuroinflammation. This review not only highlights the critical role of microbiota in AD pathology but also offers a ray of hope by suggesting that modulating gut and oral microbiota could represent a novel therapeutic strategy for reducing neuroinflammation and slowing disease progression.

The outer membrane vesicles of Pg OMVs impaired memory and learning ability of mice and decreased tight junction-related gene expression ZO-1, occludin, claudin-5, and occludin protein expression in the hippocampus. Pg OMVs could be detected in the hippocampus and cortex three days after oral gavage. Furthermore, Pg OMVs activated both astrocytes and microglia and elevated IL-1β, tau phosphorylation on the Thr231 site, and NLRP3 inflammasome-related protein expression in the hippocampus. In These results indicate that Pg OMVs prompt memory dysfunction, neuroinflammation, and tau phosphorylation and trigger NLRP3 inflammasome in the brain of middle-aged mice. We propose that Pg OMVs play an important role in activating neuroinflammation in the AD-like pathology triggered by

Periodontitis is a risk factor linked to Alzheimer's disease (AD), and characterized by amyloid-beta (Aβ) pathology. Mounting evidence suggests a contributory role of periodontitis in the onset and progression of AD. Type I interferons are upregulated in Porphyromonas gingivalis (Pg)-induced periodontitis in murine models. Colonization of Pg has been identified in the brains of patients with AD. Recently, interferon-induced transmembrane protein 3 (IFITM3), an inflammation-induced innate immunity protein, was identified as a novel γ-secretase modulatory protein for Aβ production in AD. However, whether periodontitis triggers an increase in type I interferons in the brain, subsequently inducing AD-like pathology by eliciting the innate immune response of glial cells and activating the IFITM3-Aβ axis, remains unclear. Additionally, the question of whether colonization of Pg in brain induces innate immune in astrocytes and microglia remains unanswered. We assessed the impact of Pg-induced periodontitis on cognitive impairment in C57BL/6J and APP/PS1 mice using behavioral tests. The effects of Periodontitis/Pg on microglia and astrocytes were measured using quantitative reverse transcriptase PCR (qRT-PCR), western blotting, and histological staining. Pg-induced periodontitis led to cognitive impairment in C57BL/6J mice and exacerbated a cognitive decline in APP/PS1 mice. Furthermore, Pg-induced periodontitis elevated the levels of interferon (IFN)-β, IFITM3, and Aβ deposition in the brains of both C57BL/6J and APP/PS1 mice. We also identified Pg DNA, glial activation, and the expression of inflammatory mediators in the brain of a Pg-induced periodontitis model. Additionally, our findings confirmed astrocytes as the primary responders to Pg-induced innate immunity and inflammation both in vitro and in vivo. Periodontitis also induces an increase in IFITM3 expression in periodontal tissue, salivary glands. We define a previously unidentified link between periodontitis and cognitive decline, and provide new evidence linking oral pathogenic bacteria-induced innate immunity and neuroinflammation to AD pathogenesis and cognitive decline, partly through increased blood-brain barrier (BBB) permeability, triggered neuroinflammation, and elevated IFITM3 in glial cells for Aβ deposition. Moreover, periodontitis exacerbates innate immunity and cognitive impairment in AD mice, underscoring the importance of preventive and therapeutic strategies for periodontal disease in AD patients.

Oral health is increasingly recognized as an important factor in the regulation of systemic immune responses and neurological health. Disruption of immune homeostasis in oral tissues, particularly in chronic conditions such as periodontitis, has been linked to the development and progression of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). This chapter explores how chronic inflammatory conditions in the oral cavity, oral dysbiosis, and the presence of specific periodontopathogens contribute to systemic immune activation, microglial priming, and blood-brain barrier dysfunction. The discussion addresses multiple mechanistic pathways underlying these relationships, such as hematogenous spread of microbial components with subsequent systemic immune stimulation, neural signaling via trigeminal and vagal pathways, and alterations in gut-brain communication through the integrated oral-gut-brain axis. The chapter also reviews findings from clinical and experimental studies demonstrating correlations between oral inflammation and cognitive impairment, structural brain alterations, and elevated inflammatory and neurodegenerative biomarkers. Oral health disturbances are considered not only as secondary outcomes of neurological disease but also as a potential contributing factor in their pathogenesis. The emphasis is on the importance of incorporating oral health assessment and maintenance into preventive and therapeutic strategies for neurodegenerative conditions, while highlighting the necessity for well-designed mechanistic investigations to further explain these complex relationships.

Alcohol use is associated with cognitive impairment and dysregulated inflammation. Oral nitrate may benefit cognitive impairment in aging through altering the oral microbiota. Similarly, the beneficial effects of nitrate on alcohol-induced cognitive decline and the roles of the oral microbiota merit investigation. Here we found that nitrate supplementation effectively mitigated cognitive impairment induced by chronic alcohol exposure in mice, reducing both systemic and neuroinflammation. Furthermore, nitrate restored the dysbiosis of the oral microbiota caused by alcohol consumption. Notably, removing the oral microbiota led to a subsequent loss of the beneficial effects of nitrate. Oral microbiota from donor alcohol use disordered humans who had been taking the nitrate intervention were transplanted into germ-free mice which then showed increased cognitive function and reduced neuroinflammation. Finally, we examined 63 alcohol drinkers with varying levels of cognitive impairment and found that lower concentrations of nitrate metabolism-related bacteria were associated with higher cognitive impairment and lower nitrate levels in plasma. These findings highlight the protective role of nitrate against alcohol-induced cognition impairment and neuroinflammation and suggest that the oral microbiota associated with nitrate metabolism and brain function may form part of a "microbiota-mouth-brain axis".

The oral microbiota dysbiosis, as well as lifestyle, geographical location, drug consumption, and dietary habits, are involved in the incidence and progression of dementia, Mild Cognitive Impairment (MCI), and some diseases such as obesity, diabetes, cardiovascular disease, preterm birth, rheumatoid arthritis, cancer, inflammatory bowel disease, and neurodegenerative disease e.g., Parkinson's Disease (PD) and Alzheimer's Disease (AD). AD is the most common cause of neurodegenerative disorder in the elderly. Also, neuroinflammation is the most common cause of AD pathogenesis. This study investigated the possible relationship between Porphyromonas gingivalis (P. gingivalis) and Alzheimer's Disease. This review is based on research studies indexed in Scopus, Science Direct, PubMed, and Google Scholar databases.  The oral microbiota comprised various microorganisms, such as fungi, archaea, and bacteria. Porphyromonas gingivalis (P. gingivalis) is one of the microorganisms, it stimulates host immune cells and releases cytokines, lysosomal enzymes, nitric oxide, and reactive oxygen species that lead to cell damage, apoptosis, and inflammation. Therefore, periodontal disease (PerioD) through systemic inflammation leads to some problems like the progression of MCI, production and aggregation of beta-amyloid (Aβ) and tau protein in the brain of the elderly population. In addition, some treatment methods could modulate the adverse effects of P. gingivalis like probiotic dietary supplements, maintaining personal hygiene, as well as gingipain inhibitors which modulate cytokines through blocked Aβ production, ApoE proteolysis, and reduced neuroinflammation. In addition, therapeutic compounds like COR388 and COR286, as gingipain inhibitors, prevent P. gingivalis colonization in the brain and have a beneficial action in some conditions like aspiration pneumonia, low birth rate, rheumatoid arthritis, PerioD and AD.

Alzheimer's disease (AD) is the most common chronic neurodegenerative disorder, with neuroinflammation playing an important role in its progression to become a major research focus. The role of Porphyromonas gingivalis (Pg) and its outer membrane vesicles (Pg OMVs) in AD development is uncertain, particularly regarding their effects on neuroinflammation. The cognition of mice injected with Pg, Pg OMVs, or PBS via the tail vein was assessed by the Morris water maze test. Pathological changes in the mouse brain were analyzed via immunohistochemistry, immunofluorescence and hematoxylin‒eosin (H&E) staining, and the ultrastructure of the hippocampus was observed via transmission electron microscopy (TEM). Plasma levels of inflammatory factors were assessed by enzyme-linked immunosorbent assay (ELISA). Protein levels of brain inflammatory factor, occludin, and NLRP3 inflammasome-related proteins were assessed by western blotting. Memory impairment; notable neuroinflammation, including astrocyte and microglial activation; and elevated protein levels of IL-1β, TNF-α, and IL-6 in the hippocampus were detected in the Pg and Pg OMV groups. However, Pg induced weight loss and systemic inflammation, such as splenomegaly and increased IL-1β and TNF-α levels in plasma, whereas Pg OMVs had minimal impact. In addition, Pg induced more pronounced activation of the NLRP3 inflammasome compared to Pg OMVs. In contrast, only the Pg OMV group exhibited blood-brain barrier (BBB) disruption characterized by reduced integrity of tight junctions and lower levels of occludin protein. Pg is associated with a significant immune response and systemic inflammation, which in turn exacerbates neuroinflammation via activating NLRP3 inflammasome. However, Pg OMVs might elude the systemic immune response and disrupt tight junctions, thereby entering the brain and directly triggering neuroinflammation.