Neurodegenerative disorders such as Alzheimer's disease (AD), the most common form of dementia, represent a growing global health crisis, yet current treatment strategies remain primarily palliative. Recent studies have shown that neurodegeneration through complex interactions within the gut-brain axis largely depends on the gut microbiota and its metabolites. This review explores the intricate molecular mechanisms linking gut microbiota dysbiosis to cognitive decline, emphasizing the impact of microbial metabolites, including short-chain fatty acids (SCFAs), bile acids, and tryptophan metabolites, on neuroinflammation, blood-brain barrier (BBB) integrity, and amyloid-β and tau pathology. The paper highlights major microbiome signatures associated with Alzheimer's disease, detailing their metabolic pathways and inflammatory crosstalk. Dietary interventions have shown promise in modulating gut microbiota composition, potentially mitigating neurodegenerative processes. This review critically examines the influence of dietary patterns, such as the Mediterranean and Western diets, on microbiota-mediated neuroprotection. Bioactive compounds like prebiotics, omega-3 fatty acids, and polyphenols exhibit neuroprotective effects by modulating gut microbiota and reducing neuroinflammation. Furthermore, it discusses emerging microbiome-based therapeutic strategies, including probiotics, prebiotics, postbiotics, and fecal microbiota transplantation (FMT), as potential interventions for slowing Alzheimer's progression. Despite these advances, several knowledge gaps remain, including interindividual variability in microbiome responses to dietary interventions and the need for large-scale, longitudinal studies. The study proposes an integrative, precision medicine approach, incorporating microbiome science into Alzheimer's treatment paradigms. Ultimately, cognizance of the gut-brain axis at a mechanistic level could unlock novel therapeutic avenues, offering a non-invasive, diet-based strategy for managing neurodegeneration and improving cognitive health.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and synaptic dysfunction. The accumulation of amyloid beta (Aβ) plaques and hyperphosphorylated tau protein leads to neuronal dysfunction, neuroinflammation, and glial cell activation. Emerging evidence suggests that peripheral insulin resistance and chronic inflammation, often associated with type 2 diabetes (T2D) and obesity, promote increased proinflammatory cytokines, oxidative stress, and immune cell infiltration. These conditions further damage the blood-brain barrier (BBB) integrity and promote neurotoxicity and chronic glial cell activation. This induces neuroinflammation and impaired neuronal insulin signaling, reducing glucose metabolism and exacerbating Aβ accumulation and tau hyperphosphorylation. Indeed, epidemiological studies have linked T2D and obesity with an increased risk of developing AD, reinforcing the connection between metabolic disorders and neurodegeneration. This review explores the relationships between peripheral insulin resistance, inflammation, and BBB dysfunction, highlighting their role in glial activation and the exacerbation of AD pathology.

The blood-brain barrier (BBB) is essential for maintaining brain homeostasis by regulating molecular exchange between the systemic circulation and the central nervous system. However, its dysfunction, often driven by peripheral inflammatory processes, has been increasingly linked to the development and progression of neurodegenerative diseases such as Alzheimer's and Parkinson's. Emerging evidence suggests that the gut-brain axis plays a key role in BBB integrity, with intestinal dysbiosis and chronic inflammation contributing to barrier disruption through immune and metabolic pathways. Furthermore, the selective vulnerability of specific brain regions to BBB dysfunction appears to be influenced by regional differences in vascularization, metabolic activity, and permeability, making certain areas more susceptible to neurodegenerative processes. This review explored the molecular mechanisms linking peripheral inflammation, gut microbiota, and BBB dysfunction, emphasizing their role in neurodegeneration. A comprehensive literature review was conducted using Web of Science, PubMed, Scopus, Wiley, ScienceDirect, and Medline, covering publications from 2015 to 2025. The findings highlight a complex interplay between gut microbiota-derived metabolites, immune signaling, and BBB permeability, underscoring the need for targeted interventions such as microbiome modulation, anti-inflammatory therapies, and advanced drug delivery systems. The heterogeneity of the BBB across different brain regions necessitates the development of region-specific therapeutic strategies. Despite advancements, critical knowledge gaps persist regarding the precise mechanisms underlying BBB dysfunction. Future research should leverage cutting-edge methodologies such as single-cell transcriptomics and organ-on-chip models to translate preclinical findings into effective clinical applications. Addressing these challenges will be crucial for developing personalized therapeutic approaches to mitigate the impact of BBB dysfunction in neurodegenerative diseases.

Background/Objectives: Alzheimer's disease (AD) is the most common form of dementia, characterized by an irreversible decline in cognitive function. The pathogenesis of several neurodegenerative disorders has been linked to changes in the gut microbiota, transmitted through the gut-brain axis. Methods: We set out to establish by case-control study methodology whether there were any differences in the composition and/or function of the gut microbiota between older resident adults in care homes with or without an AD diagnosis via analysis of the microbial composition from fecal samples. Results: The microbial composition, determined by 16S rRNA gene profiling, indicated that AD sufferers had significantly increased proportions of Escherichia/Shigella and Clostridium_sensu_stricto_1, and significantly decreased proportions of Bacteroides, Faecalibacterium, Blautia, and Roseburia species. The increase in potentially pro-inflammatory bacteria was consistent with slightly higher concentrations of calprotectin, a biomarker of gut inflammation. Fecal concentrations of most microbial metabolites measured were similar across groups, although participants with AD had significantly increased proportions of the branched-chain fatty acid, iso-butyrate, and lower overall concentrations of total short chain fatty acids. Conclusions: Participants with Alzheimer's disease have several key differences within their gut microbiota profile, in contrast to care home residents without Alzheimer's disease. The altered microbiome included both compositional and functional changes linked to poorer health and gut inflammation.

The gut and brain interact through various metabolic and signaling pathways, each of which influences mental health. Gut dysbiosis caused by antibiotics is a well-known phenomenon that has serious implications for gut microbiota-brain interactions. Although antibiotics disrupt the gut microbiota's fundamental structure, the mechanisms that modulate the response and their impact on brain function are still unclear. It is imperative to comprehend and investigate crucial regulators and factors that play important roles. We aimed to study the effect of long-term antibiotic-induced disruption of gut microbiota, host metabolomes, and brain function and, particularly, to determine the basic interactions between them by treating the C57BL/6 mice with two different, most commonly used antibiotics, ciprofloxacin and amoxicillin. Anxiety-like behavior was confirmed by the elevated plus-maze test and open field test. Gut microbes and their metabolite profiles in fecal, serum, and brain samples were determined by 16S rRNA sequencing and untargeted metabolomics. In our study, long-term antibiotic treatment exerted anxiety-like effects. The fecal microbiota and metabolite status revealed that the top five genera found were Lactobacillus, Bacteroides, Akkermansia, Ruminococcus_gnavus_group, and unclassified norank_f_Muribaculaceae. The concentration of serotonin, L-Tyrosine, 5-Hydroxy-L-tryptophan, L-Glutamic acid, L-Glutamate, 5-Hydroxyindole acetic acid, and dopaminergic synapsis was comparatively low, while adenosine was high in antibiotic-treated mice. The KEGG enrichment analysis of serum and brain samples showed that amino acid metabolism pathways, such as tryptophan metabolism, threonine metabolism, serotonergic synapsis, methionine metabolism, and neuroactive ligand-receptor interaction, were significantly decreased in antibiotic-treated mice. Our study demonstrates that long-term antibiotic use induces gut dysbiosis and alters metabolic responses, leading to the dysregulation of brain signaling molecules and anxiety-like behavior. These findings highlight the complex interactions between gut microbiota and metabolic functions, providing new insights into the influence of microbial communities on gut-brain communication.

Microorganisms in the gut play a pivotal role in human health, influencing various pathophysiological processes. Certain microorganisms are particularly essential for maintaining intestinal homeostasis, reducing inflammation, supporting nervous system function, and regulating metabolic processes. Short-chain fatty acids (SCFAs) are a subset of fatty acids produced by the gut microbiota (GM) during the fermentation of indigestible polysaccharides. The interaction between GM and SCFAs is inherently bidirectional: the GM not only shapes SCFAs composition and metabolism but SCFAs also modulate microbiota's diversity, stability, growth, proliferation, and metabolism. Recent research has shown that GM and SCFAs communicate through various pathways, mainly involving mechanisms related to inflammation and immune responses, intestinal barrier function, the gut-brain axis, and metabolic regulation. An imbalance in GM and SCFA homeostasis can lead to the development of several chronic diseases, including inflammatory bowel disease, colorectal cancer, systemic lupus erythematosus, Alzheimer's disease, and type 2 diabetes mellitus. This review explores the synergistic interactions between GM and SCFAs, and how these interactions directly or indirectly influence the onset and progression of various diseases through the regulation of the mechanisms mentioned above.

Alzheimer's disease (AD) is the most common form of dementia and is characterized by memory impairment that significantly interferes with daily life. Therapeutic options for AD that substantively modify disease progression remain a critical unmet need. In this regard, the gut microbiota is crucial in maintaining human health by regulating metabolism and immune responses, and increasing evidence suggests that probiotics, particularly beneficial bacteria, can enhance memory and cognitive functions. Recent studies have highlighted the positive effects of Bifidobacterium breve MCC1274 (B. breve MCC1274) on individuals with mild cognitive impairment (MCI) and schizophrenia. Additionally, oral supplementation with B. breve MCC1274 has been shown to effectively prevent memory decline in AppNL-G-F mice. In relation to Alzheimer's pathology, oral supplementation with B. breve MCC1274 has been found to reduce amyloid-β (Aβ) accumulation and tau phosphorylation in both AppNL-G-F and wild-type (WT) mice. It also decreases microglial activation and increases levels of synaptic proteins. In this review, we examine the beneficial effects of B. breve MCC1274 on AD, exploring potential mechanisms of action and how this probiotic strain may aid in preventing or treating the disease. Furthermore, we discuss the broader implications of B. breve MCC1274 for improving overall host health and provide insights into future research directions for this promising probiotic therapy.

Dr. Aloysius Alzheimer, a German neuropathologist and psychiatrist, recognized the primary instance of Alzheimer's disease (AD) for a millennium, and this ailment, along with its related dementias, remains a severe overall community issue related to health. Nearly fifty million individuals worldwide suffer from dementia, with Alzheimer's illness contributing to between 60 and 70% of the instances, estimated through the World Health Organization. In addition, 82 million individuals are anticipated to be affected by the global dementia epidemic by 2030 and 152 million by 2050. Furthermore, age, environmental circumstances, and inherited variables all increase the likelihood of acquiring neurodegenerative illnesses. Most recent pharmacological treatments are found in original hypotheses of disease, which include cholinergic (drugs that show affective cholinergic system availability) as well as amyloid-accumulation (a single drug is an antagonist receptor of Nmethyl D-aspartate). In 2020, the FDA provided approval on anti-amyloid drugs. According to mounting scientific data, this gut microbiota affects healthy physiological homeostasis and has a role in the etiology of conditions that range between obesity and neurodegenerative disorders like Alzheimer's. The microbiota-gut-brain axis might facilitate interconnection among gut microbes as well as the central nervous system (CNS). Interaction among the microbiota-gut system as well as the brain occurs through the "two-way" microbiota-gut-brain axis. Along this axis, the stomach as well as the brain develop physiologically and take on their final forms. This contact is constant and is mediated by numerous microbiota-derived products. The gut microbiota, for instance, can act as non-genetic markers to set a threshold for maintaining homeostasis or getting ill. The scientific community has conducted research and found that bowel dysbiosis and gastrointestinal tract dysregulation frequently occur in Alzheimer's disease (AD) patients. In this review, the effects of the microbiota- gut-brain axis on AD pathogenesis will be discussed.

Evidence suggests that exposure to organophosphate pesticides increases the risk of neurodegenerative diseases, but the mechanisms remain unclear. This study investigated the effects of malathion on Alzheimer's disease (AD)-like symptoms at environmentally relevant concentrations using wild-type (WT) and APP/PS1 transgenic mouse models. Results showed that malathion exposure induced AD-like cognitive impairment, amyloid-β (Aβ) accumulation, and neuroinflammation in WT mice, with worsened symptoms in APP/PS1 mice. Mechanistic studies revealed that malathion induced AD-like gut microbiota dysbiosis (reduced Lactobacillus and Akkermansia, and increased Dubosiella), causing gut barrier impairment and tryptophan metabolism disruptions. This resulted in a significant increase in indole derivatives and activation of the colonic aryl hydrocarbon receptor (AhR), promoting the kynurenine (KYN) pathway while inhibiting the serotonin (5-HT) pathway. Increased neurotoxic KYN metabolites (3-hydroxykynurenine and quinolinic acid) triggered gut and systemic inflammation, upregulating hippocampal IL-6 and IL-1β mRNA levels and thereby causing neuroinflammation. Gut tryptophan metabolism disruptions caused hippocampal neurotransmitter imbalances, reducing the levels of 5-HT and its derivatives. These effects promoted AD progression in both WT and APP/PS1 mice. This study highlights the crucial role of the microbiota-gut-brain axis in AD-like cognitive impairment induced by malathion exposure, providing insights into the neurodegenerative disease risks posed by organophosphate pesticides.

Numerous studies conducted over the last ten years have shown a strong correlation between the gut microbiota and the onset and progression of Alzheimer's disease (AD). However, the exact underlying mechanism is still unknown. An ongoing communication mechanism linking the gut and the brain is highlighted by the term "microbiota-gut-brain axis," which was originally coined the "gut-brain axis." Key metabolic, endocrine, neurological, and immunological mechanisms are involved in the microbiota‒gut‒brain axis and are essential for preserving brain homeostasis. Thus, the main emphasis of this review is how the gut microbiota contributes to the development of AD and how various natural products intervene in this disease. The first part of the review provides an outline of various pathways and relationships between the brain and gut microbiota, and the second part provides various mechanisms involved in the gut microbiota and AD. Finally, this review provides knowledge about natural products and their effectiveness in treating gut microbiota-induced AD. AD may be treated in the future by altering the gut microbiota with a customized diet, probiotics/prebiotics, plant products, and natural products. This entails altering the microbiological partners and products (such as amyloid protein) that these partners generate.

Growing evidence has proved that alterations in the gut microbiota have been linked to neurological disorders including stroke. Structural and functional disruption of the blood-brain barrier (BBB) is observed after stroke. In this context, there is pioneering evidence supporting that gut microbiota may be involved in the pathogenesis of stroke by regulating the BBB function. However, only a few experimental studies have been performed on stroke models to observe the BBB by altering the structure of gut microbiota, which warrant further exploration. Therefore, in order to provide a novel mechanism for stroke and highlight new insights into BBB modification as a stroke intervention, this review summarizes existing evidence of the relationship between gut microbiota and BBB integrity and discusses the mechanisms of gut microbiota on BBB dysfunction and its role in stroke.

Alzheimer's disease (AD) is characterized by cognitive decline stemming from the accumulation of beta-amyloid (Aβ) plaques and the propagation of tau pathology through synapses. Exosomes, crucial mediators in neuronal development, maintenance, and intercellular communication, have gained attention in AD research. Yet, the molecular mechanisms involving exosomal miRNAs in AD remain elusive. In this study, we treated APPswe/PSEN1dE9 transgenic (APP/PS1) mice, a model for AD, with either vehicle (ADNS) or fasudil (ADF), while C57BL/6 (control) mice received vehicle (WT). Cognitive function was evaluated using the Y-maze test, and AD pathology was confirmed through immunostaining and western blot analysis of Aβ plaques and phosphorylated tau. Exosomal RNAs were extracted, sequenced, and analyzed from each mouse group. Our findings revealed that fasudil treatment improved cognitive function in AD mice, as evidenced by increased spontaneous alternation in the Y-maze test and reduced Aβ plaque load and phosphorylated tau protein expression in the hippocampus. Analysis of exosomal miRNAs identified three miRNAs (mmu-let-7i-5p, mmu-miR-19a-3p, mmu-miR-451a) common to both ADNS vs ADF and WT vs ADNS groups. Utilizing miRTarBase software, we predicted and analyzed target genes associated with these miRNAs. Gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of miRNA target genes indicated that mmu-miR-19a-3p and mmu-miR-451a are implicated in signal transduction, immune response, cellular communication, and nervous system pathways. Specifically, mmu-miR-19a-3p targeted genes involved in the sphingolipid signaling pathway, such as Pten and Tnf, while mmu-miR-451a targeted Nsmaf, Gnai3, and Akt3. Moreover, mmu-miR-451a targeted Myc in signaling pathways regulating the pluripotency of stem cells. In conclusion, fasudil treatment enhanced cognitive function by modulating exosomal MicroRNAs, particularly mmu-miR-451a and mmu-miR-19a-3p. These miRNAs hold promise as potential biomarkers and therapeutic targets for novel AD treatments.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β outside neurons and Tau protein inside neurons. Various pathological mechanisms are implicated in AD, including brain insulin resistance, neuroinflammation, and endocrinal dysregulation of adrenal corticosteroids. These factors collectively contribute to neuronal damage and destruction. Recently, bile acids (BAs), which are metabolites of cholesterol, have shown neuroprotective potential against AD by targeting the above pathological changes. BAs can enter the systematic circulation and cross the blood-brain barrier, subsequently exerting neuroprotective effects by targeting several endogenous receptors. Additionally, BAs interact with the microbiota-gut-brain (MGB) axis to improve immune and neuroendocrine function during AD episodes. Gut microbes impact BA signaling in the brain through their involvement in BA biotransformation. In this review, we summarize the role and molecular mechanisms of BAs in AD while considering the MGB axis and propose novel strategies for preventing the onset and progression of AD.

Cerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the elderly. Although at first it was considered innocuous, small vessel disease is nowadays regarded as one of the major vascular causes of dementia. Radiological signs of small vessel disease include small subcortical infarcts, white matter magnetic resonance imaging hyperintensities, lacunes, enlarged perivascular spaces, cerebral microbleeds, and brain atrophy; however, great heterogeneity in clinical symptoms is observed in small vessel disease patients. The pathophysiology of these lesions has been linked to multiple processes, such as hypoperfusion, defective cerebrovascular reactivity, and blood-brain barrier dysfunction. Notably, studies on small vessel disease suggest that blood-brain barrier dysfunction is among the earliest mechanisms in small vessel disease and might contribute to the development of the hallmarks of small vessel disease. Therefore, the purpose of this review is to provide a new foundation in the study of small vessel disease pathology. First, we discuss the main structural domains and functions of the blood-brain barrier. Secondly, we review the most recent evidence on blood-brain barrier dysfunction linked to small vessel disease. Finally, we conclude with a discussion on future perspectives and propose potential treatment targets and interventions.

This review article focuses on the upstream pertinent pathophysiology leading to neurodegenerative disease. Specifically, the nexus appears to be blood-brain barrier (BBB) leakiness resulting in a two-prong inflammatory disease spectrum damaging the microvasculature and corrupting protein synthesis and degradation with accumulating misfolded toxic proteins. The suboptimal results of removing misfolded proteins mean a new approach to disease in the preclinical state is required aimed at other targets. Validated noninvasive imaging and serologic biomarkers of early preclinical disease implemented in the high-risk patient cohort along with periodic surveillance once effective treatments are developed will be required. This review discusses the physiology and pathophysiology of the BBB, new MRI imaging techniques identifying the leak, and altered fluid dynamic effects in the preclinical state. The risk factors for disease development, preventative measures, and potential treatment targets are also discussed.

The intestinal ecological environment plays a crucial role in nutrient absorption and overall well-being. In recent years, research has focused on the effects of extracellular vesicles (EVs) in both physiological and pathological conditions of the intestine. The intestine does not only consume EVs from exogenous foods, but also those from other endogenous tissues and cells, and even from the gut microbiota. The alteration of conditions in the intestine and the intestinal microbiota subsequently gives rise to changes in other organs and systems, including the central nervous system (CNS), namely the microbiome-gut-brain axis, which also exhibits a significant involvement of EVs. This review first gives an overview of the generation and isolation techniques of EVs, and then mainly focuses on elucidating the functions of EVs derived from various origins on the intestine and the intestinal microenvironment, as well as the impacts of an altered intestinal microenvironment on other physiological systems. Lastly, we discuss the role of microbial and cellular EVs in the microbiome-gut-brain axis. This review enhances the understanding of the specific roles of EVs in the gut microenvironment and the central nervous system, thereby promoting more effective treatment strategies for certain associated diseases.

Cognitive impairment (CI) is a multifaceted neurological condition that can trigger negative emotions and a range of concurrent symptoms, imposing significant public health and economic burdens on society. Therefore, it is imperative to discover a remedy for CI. Nevertheless, the mechanisms behind the onset of this disease are multifactorial, which makes the search for effective amelioration difficult and complex, hindering the search for effective measures. Intriguingly, preclinical research indicates that gut microbiota by influencing brain function, plays an important role in the progression of CI. Furthermore, numerous preclinical studies have highlighted the potential of probiotics, prebiotics, fecal microbiota transplantation (FMT), and diet in modulating the gut microbiota, thereby ameliorating CI symptoms. This review provides a comprehensive evaluation of CI pathogenesis, emphasizing the contribution of gut microbiota disorders to CI development. It also summarizes and discusses current strategies and mechanisms centered on the synergistic role of gut microbiota modulation in the microbiota-gut-brain axis in CI development. Finally, problems with existing approaches are contemplated and the development of microbial modulation strategies as therapeutic approaches to promote and restore brain cognition is discussed. Further research considerations and directions are highlighted to provide ideas for future CI prevention and treatment strategies.

Crohn's disease (CD), one of the main phenotypes of inflammatory bowel disease (IBD), can affect any part of the gastrointestinal tract. It can impact the function of gastrointestinal secretions, as well as increasing the intestinal permeability leading to an aberrant immunological response and subsequent intestinal inflammation. Studies have reported anatomical and functional brain changes in Crohn's Disease patients (CDs), possibly due to increased inflammatory markers and microglial cells that play key roles in communicating between the brain, gut, and systemic immune system. To date, no studies have demonstrated similarities between morphological brain changes seen in IBD and brain morphometry observed in older healthy controls..

For the present study, twelve young CDs in remission (M = 26.08 years, SD = 4.9 years, 7 male) were recruited from an IBD Clinic. Data from 12 young age-matched healthy controls (HCs) (24.5 years, SD = 3.6 years, 8 male) and 12 older HCs (59 years, SD = 8 years, 8 male), previously collected for a different study under a similar MR protocol, were analyzed as controls. T1 weighted images and structural image processing techniques were used to extract surface-based brain measures, to test our hypothesis that young CDs have different brain surface morphometry than their age-matched young HCs and furthermore, appear more similar to older HCs. The phonemic verbal fluency (VF) task (the Controlled Oral Word Association Test, COWAT) (Benton, 1976) was administered to test verbal cognitive ability and executive control.

On the whole, CDs had more brain regions with differences in brain morphometry measures when compared to the young HCs as compared to the old HCs, suggesting that CD has an effect on the brain that makes it appear more similar to old HCs. Additionally, our study demonstrates this atypical brain morphometry is associated with function on a cognitive task. These results suggest that even younger CDs may be showing some evidence of structural brain changes that demonstrate increased resemblance to older HC brains rather than their similarly aged healthy counterparts.

The composition of the human gut microbiome has been observed to change over the course of an individual's life. From birth, it is shaped by mode of delivery, diet, environmental exposures, geographic location, exposures to medications, and by aging itself. Here, we present a narrative review of the gut microbiome across the lifespan with a focus on its impacts on aging and age-related diseases in humans. We will describe how it is shaped, and features of the gut microbiome that have been associated with diseases at different phases of life and how this can adversely affect healthy aging. Across the lifespan, and especially in old age, a diverse microbiome that includes organisms suspected to produce anti-inflammatory metabolites such as short-chain fatty acids, has been reported to be associated with healthy aging. These findings have been remarkably consistent across geographic regions of the world suggesting that they could be universal features of healthy aging across all cultures and genetic backgrounds. Exactly how these features of the microbiome affect biologic processes associated with aging thus promoting healthy aging will be crucial to targeting the gut microbiome for interventions that will support health and longevity.

The blood-brain barrier (BBB) impairment plays a crucial role in the pathological processes of aging-accompanied neurological diseases (AAND). Meanwhile, circadian rhythms disruption and gut microbiota dysbiosis are associated with increased morbidity of neurological diseases in the accelerated aging population. Importantly, circadian rhythms disruption and gut microbiota dysbiosis are also known to induce the generation of toxic metabolites and pro-inflammatory cytokines, resulting in disruption of BBB integrity. Collectively, this provides a new perspective for exploring the relationship among circadian rhythms, gut microbes, and the BBB in aging-accompanied neurological diseases. In this review, we focus on recent advances in the interplay between circadian rhythm disturbances and gut microbiota dysbiosis, and their potential roles in the BBB disruption that occurs in AAND. Based on existing literature, we discuss and propose potential mechanisms underlying BBB damage induced by dysregulated circadian rhythms and gut microbiota, which would serve as the basis for developing potential interventions to protect the BBB in the aging population through targeting the BBB by exploiting its links with gut microbiota and circadian rhythms for treating AAND.

Studies on the association between proton pump inhibitor (PPI) use and dementia report mixed results and do not examine the impact of cumulative PPI use. We evaluated the associations between current and cumulative PPI use and risk of incident dementia in the Atherosclerosis Risk in Communities (ARIC) Study.

These analyses used participants from a community-based cohort (ARIC) from the time of enrollment (1987-1989) through 2017. PPI use was assessed through visual medication inventory at clinic visits 1 (1987-1989) to 5 (2011-2013) and reported annually in study phone calls (2006-2011). This study uses ARIC visit 5 as baseline because this was the first visit in which PPI use was common. PPI use was examined 2 ways: current use at visit 5 and duration of use before visit 5 (from visit 1 to 2011, exposure categories: 0 day, 1 day-2.8 years, 2.8-4.4 years, >4.4 years). The outcome was incident dementia after visit 5. Cox proportional hazard models were used, adjusted for demographics, comorbid conditions, and other medication use.

A total of 5,712 dementia-free participants at visit 5 (mean age 75.4 ± 5.1 years; 22% Black race; 58% female) were included in our analysis. The median follow-up was 5.5 years. The minimum cumulative PPI use was 112 days, and the maximum use was 20.3 years. There were 585 cases of incident dementia identified during follow-up. Participants using PPIs at visit 5 were not at a significantly higher risk of developing dementia during subsequent follow-up than those not using PPIs (hazard ratio (HR): 1.1 [95% confidence interval (CI) 0.9-1.3]). Those who used PPIs for >4.4 cumulative years before visit 5 were at 33% higher risk of developing dementia during follow-up (HR: 1.3 [95% CI 1.0-1.8]) than those reporting no use. Associations were not significant for lesser durations of PPI use.

Future studies are needed to understand possible pathways between cumulative PPI use and the development of dementia.

This study provides Class III evidence that the use of prescribed PPIs for >4.4 years by individuals aged 45 years and older is associated with a higher incidence of newly diagnosed dementia.

Diabetic cognitive dysfunction (DCD) is one of the most insidious complications of type 2 diabetes mellitus, which can seriously affect the ability to self-monitoring of blood glucose and the quality of life in the elderly. Previous pathological studies of cognitive dysfunction have focused on neuronal dysfunction, characterized by extracellular beta-amyloid deposition and intracellular tau hyperphosphorylation. In recent years, astrocytes have been recognized as a potential therapeutic target for cognitive dysfunction and important participants in the central control of metabolism. The disorder of gut microbiota and their metabolites have been linked to a series of metabolic diseases such as diabetes mellitus. The imbalance of intestinal flora has the effect of promoting the occurrence and deterioration of several diabetes-related complications. Gut microbes and their metabolites can drive astrocyte activation.

We reviewed the pathological progress of DCD related to the "gut microbiota-astrocyte" axis in terms of peripheral and central inflammation, intestinal and blood-brain barrier (BBB) dysfunction, systemic and brain energy metabolism disorders to deepen the pathological research progress of DCD and explore the potential therapeutic targets.

"Gut microbiota-astrocyte" axis, unique bidirectional crosstalk in the brain-gut axis, mediates the intermediate pathological process of neurocognitive dysfunction secondary to metabolic disorders in diabetes mellitus.

Alzheimer's disease (AD) is the most common neurodegenerative disease and the leading cause of dementia worldwide. Different pathologic changes have been introduced to be involved in its progression. Although amyloid-β (Aβ) deposition and tau hyperphosphorylation and aggregation are mainly considered the main characterizations of AD, several other processes are involved. In recent years, several other changes, including alterations in gut microbiota proportion and circadian rhythms, have been noticed due to their role in AD progression. However, the exact mechanism indicating the association between circadian rhythms and gut microbiota abundance has not been investigated yet. This paper aims to review the role of gut microbiota and circadian rhythm in AD pathophysiology and introduces a hypothesis to explain their association.

This narrative review seeks to examine the relationships between bacterial microbiomes and infectious disease. This is achieved by detailing how different human host microbiomes develop and function, from the earliest infant acquisitions of maternal and environmental species through to the full development of microbiomes by adulthood. Communication between bacterial species or communities of species within and outside of the microbiome is a factor in both maintenance of homeostasis and management of threats from the external environment. Dysbiosis of this homeostasis is key to understanding the development of disease states. Several microbiomes and the microbiota within are used as prime examples of how changes in species composition, particularly at the phylum level, leads to such diverse conditions as inflammatory bowel disease (IBD), type 2 diabetes, psoriasis, Parkinson's disease, reflux oesophagitis and others. The review examines spatial relationships between microbiomes to understand how dysbiosis in the gut microbiome in particular can influence diseases in distant host sites via routes such as the gut-lung, gut-skin and gut-brain axes. Microbiome interaction with host processes such as adaptive immunity is increasingly identified as critical to developing the capacity of the immune system to react to pathogens. Dysbiosis of essential bacteria involved in modification of host substrates such as bile acid components can result in development of Crohn's disease, small intestine bacterial overgrowth, hepatic cancer and obesity. Interactions between microbiomes in distantly located sites are being increasingly being identified, resulting in a 'whole of body' effect by the combined host microbiome.

Recently, research on the microbiota-gut-brain axis (MGBA) has received increasing attention, and the number of studies related to Alzheimer's disease (AD) has increased rapidly, but there is currently a lack of summary of MGBA in AD.

To capture research hotspots, grasp the context of disciplinary research, and explore future research development directions.

In the core dataset of Web of Science, documents are searched according to specific subject words. CiteSpace software is used to perform statistical analysis on measurement indicators such as the number of published papers, publishing countries, institutions, subject areas, authors, cocited journals, and keywords, and to visualize of a network of relevant content elements.

The research of MGBA in AD has shown an upward trend year by year, and the cooperation between countries is relatively close, and mainly involves the intersection of neuroscience, pharmacy, and microbiology. This research focuses on the relationship between MGBA and AD symptoms. Keyword hotspots are closely related to new technologies. Alzheimer's disease, anterior cingulate cortex, inflammatory degeneration, dysbiosis, and other research are the focus of this field.

The study revealed that the research and development of MGBA in AD rapidly progressed, but no breakthrough has been made in the past decade, it still needs to be closely combined with multidisciplinary technology to grasp the frontier hotspots. Countries should further strengthen cooperation, improve the disciplinary system, and increase the proportion of empirical research in all research.

Structural and functional alterations to the gut microbiome, referred to as gut dysbiosis, have emerged as potential key mediators of neurodegeneration and Alzheimer disease (AD) pathogenesis through the "gut -brain" axis. Emerging data from animal and clinical studies support an important role for gut dysbiosis in mediating neuroinflammation, central and peripheral immune dysregulation, abnormal brain protein aggregation, and impaired intestinal and brain barrier permeability, leading to neuronal loss and cognitive impairment. Gut dysbiosis has also been shown to directly influence various mechanisms involved in neuronal growth and repair, synaptic plasticity, and memory and learning functions. Aging and lifestyle factors including diet, exercise, sleep, and stress influence AD risk through gut dysbiosis. Furthermore, AD is associated with characteristic gut microbial signatures which offer value as potential markers of disease severity and progression. Together, these findings suggest the presence of a complex bidirectional relationship between AD and the gut microbiome and highlight the utility of gut modulation strategies as potential preventative or therapeutic strategies in AD. We here review the current literature regarding the role of the gut-brain axis in AD pathogenesis and its potential role as a future therapeutic target in AD treatment and/or prevention.