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Alzheimer's disease (AD) is a complex neurodegenerative condition with growing evidence implicating the gut microbiota in its pathogenesis. This study aimed to investigate the effects of NMN synbiotics, a combination of β-nicotinamide mononucleotide (NMN), Lactobacillus plantarum, and lactulose, on the gut microbiota composition and metabolic profiles in APP/PS1 transgenic mice. Results demonstrated that NMN synbiotics led to a notable restructuring of the gut microbiota, with a decreased Firmicutes/Bacteroidetes ratio in the AD mice, suggesting a potential amelioration of gut dysbiosis. Alpha diversity indices indicated a reduction in microbial diversity following NMN synbiotics supplementation, while beta diversity analyses revealed a shift towards a more balanced microbial community structure. Functional predictions based on the 16S rRNA data highlighted alterations in metabolic pathways, particularly those related to amino acid and energy metabolism, which are crucial for neuronal health. The metabolomic analysis uncovered a significant impact of NMN synbiotics on the gut metabolome, with normalization of metabolic composition in AD mice. Differential metabolite functions were enriched in pathways associated with neurotransmitter synthesis and energy metabolism, pointing to the potential therapeutic effects of NMN synbiotics in modulating the gut-brain axis and synaptic function in AD. Immunohistochemical staining observed a significant reduction of amyloid plaques formed by Aβ deposition in the brain of AD mice after NMN synbiotics intervention. The findings underscore the potential of using synbiotics to ameliorate the neurodegenerative processes associated with Alzheimer's disease, opening new avenues for therapeutic interventions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Klebsiella pneumoniae is infamous for hospital-acquired infections and sepsis, which have also been linked to Alzheimer disease (AD)-related neuroinflammatory and neurodegenerative impairment. However, its causative and mechanistic role in AD pathology remains unstudied., Methods: A preclinical model of K. pneumoniae enteric infection and colonization is developed in an AD model (3xTg-AD mice) to investigate whether and how K. pneumoniae pathogenesis exacerbates neuropathogenesis via the gut-blood-brain axis., Results: K. pneumoniae, particularly under antibiotic-induced dysbiosis, was able to translocate from the gut to the bloodstream by penetrating the gut epithelial barrier. Subsequently, K. pneumoniae infiltrated the brain by breaching the blood-brain barrier. Significant neuroinflammatory phenotype was observed in mice with K. pneumoniae brain infection. K. pneumoniae-infected mice also exhibited impaired neurobehavioral function and elevated total tau levels in the brain. Metagenomic analyses revealed an inverse correlation of K. pneumoniae with gut biome diversity and commensal bacteria, highlighting how antibiotic-induced dysbiosis triggers an enteroseptic "pathobiome" signature implicated in gut-brain perturbations., Conclusions: The findings demonstrate how infectious agents following hospital-acquired infections and consequent antibiotic regimen may induce gut dysbiosis and pathobiome and increase the risk of sepsis, thereby increasing the predisposition to neuroinflammatory and neurobehavioral impairments via breaching the gut-blood-brain barrier., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Alzheimer's disease (AD) is a neurodegenerative disorder with limited therapeutic options. Accordingly, new approaches for prevention and treatment are needed. One focus is the human microbiome, the consortium of microorganisms that live in and on us, which contributes to human immune, metabolic, and cognitive development and that may have mechanistic roles in neurodegeneration. AD and Alzheimer's disease-related dementias (ADRD) are recognized as spectrum disorders with complex pathobiology. AD/ADRD onset begins before overt clinical signs, but initiation triggers remain undefined. We posit that disruption of the normal gut microbiome in early life leads to a pathological cascade within septohippocampal and cortical brain circuits. We propose investigation to understand how early-life microbiota changes may lead to hallmark AD pathology in established AD/ADRD models. Specifically, we hypothesize that antibiotic exposure in early life leads to exacerbated AD-like disease endophenotypes that may be amenable to specific microbiological interventions. We propose suitable models for testing these hypotheses., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Dysbiosis within microbiomes has been increasingly implicated in many systemic illnesses, such as cardiovascular disease, metabolic syndrome, respiratory infections, and Alzheimer disease (Ad). The correlation between Ad and microbial dysbiosis has been repeatedly shown, yet the etiologic cause of microbial dysbiosis remains elusive. From a neuropathology perspective, abnormal (often age-related) changes in the brain, associated structures, and bodily lumens tend toward an accumulation of oxygen-depleted pathologic structures, which are anaerobically selective niches. These anaerobic environments may promote progressive change in the microbial community proximal to the brain and thus deserve further investigation. In this review, we identify and explore what is known about the anaerobic niche near or associated with the brain and the anaerobes that it is harbors. We identify the anaerobe stakeholders within microbiome communities and the impacts on the neurodegenerative processes associated with Ad. Chronic oral dysbiosis in anaerobic dental pockets and the composition of the gut microbiota from fecal stool are the 2 largest anaerobic niche sources of bacterial transference to the brain. At the blood-brain barrier, cerebral atherosclerotic plaques are predominated by anaerobic species intimately associated with the brain vasculature. Focal cerebritis/brain abscess and corpora amylacea may also establish chronic anaerobic niches in direct proximity to brain parenchyma. In exploring the anaerobic niche proximal to the brain, we identify research opportunities to explore potential sources of microbial dysbiosis associated with Ad., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Sensory functions of organs of the head and neck allow humans to interact with the environment and establish social bonds. With aging, smell, taste, vision, and hearing decline. Evidence suggests that accelerated impairment in sensory abilities can reflect a shift from healthy to pathological aging, including the development of Alzheimer's disease (AD) and other neurological disorders. While the drivers of early sensory alteration in AD are not elucidated, insults such as trauma and infections can affect sensory function. Herein, we review the involvement of the major head and neck sensory systems in AD, with emphasis on microbes exploiting sensory pathways to enter the brain (the "gateway" hypothesis) and the potential feedback loop by which sensory function may be impacted by central nervous system infection. We emphasize detection of sensory changes as first-line surveillance in senior adults to identify and remove potential insults, like microbial infections, that could precipitate brain pathology., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Periodontitis is a chronic inflammatory disease driven by dysbiosis in subgingival microbial communities leading to increased abundance of a limited number of pathobionts, including Porphyromonas gingivalis and Treponema denticola. Oral health, particularly periodontitis, is a modifiable risk factor for Alzheimer disease (AD) pathogenesis, with components of both these bacteria identified in postmortem brains of persons with AD. Repeated oral inoculation of mice with P. gingivalis results in brain infiltration of bacterial products, increased inflammation, and induction of AD-like biomarkers. P. gingivalis displays synergistic virulence with T. denticola during periodontitis. The aim of the current study was to determine the ability of P. gingivalis and T. denticola, grown in physiologically relevant conditions, individually and in combination, to induce AD-like pathology following chronic oral inoculation of female mice over 12 weeks. P. gingivalis alone significantly increased all 7 brain pathologies examined: neuronal damage, activation of astrocytes and microglia, expression of inflammatory cytokines interleukin 1β (IL-1β) and interleukin 6 and production of amyloid-β plaques and hyperphosphorylated tau, in the hippocampus, cortex and midbrain, compared to control mice. T. denticola alone significantly increased neuronal damage, activation of astrocytes and microglia, and expression of IL-1β, in the hippocampus, cortex and midbrain, compared to control mice. Coinoculation of P. gingivalis with T. denticola significantly increased activation of astrocytes and microglia in the hippocampus, cortex and midbrain, and increased production of hyperphosphorylated tau and IL-1β in the hippocampus only. The host brain response elicited by oral coinoculation was less than that elicited by each bacterium, suggesting coinoculation was less pathogenic., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Periodontitis is a common chronic inflammatory disease, affecting approximately 19% of the global adult population. A relationship between periodontal disease and Alzheimer disease has long been recognized, and recent evidence has been uncovered to link these 2 diseases mechanistically. Periodontitis is caused by dysbiosis in the subgingival plaque microbiome, with a pronounced shift in the oral microbiota from one consisting primarily of Gram-positive aerobic bacteria to one predominated by Gram-negative anaerobes, such as Porphyromonas gingivalis. A common phenomenon shared by all bacteria is the release of membrane vesicles to facilitate biomolecule delivery across long distances. In particular, the vesicles released by P gingivalis and other oral pathogens have been found to transport bacterial components across the blood-brain barrier, initiating the physiologic changes involved in Alzheimer disease. In this review, we summarize recent data that support the relationship between vesicles secreted by periodontal pathogens to Alzheimer disease pathology., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Epidemiological studies have revealed an inverse relationship between the incidence of Alzheimer's disease (AD) and various cancers, including colorectal cancer (CRC). We aimed to determine whether the incidence of CRC is reduced in AD-like mice and whether gut microbiota confers resistance to tumorigenesis through inducing inflammatory tolerance using 16S ribosomal RNA gene sequencing and fecal microbiota transplantation (FMT). AD-like mice experienced a significantly decreased incidence of CRC tumorigenesis induced by azoxymethane-dextran sodium sulfate as evidenced by suppressed intestinal inflammation compared with control mice. However, FMT from age-matched control mice reversed the inhibitory effects on the tumorigenesis of CRC and inflammatory response in AD-like mice. The key bacterial genera in gut microbiota, including Prevotella , were increased in both the AD-like mice and in patients with amnestic mild cognitive impairment (aMCI) but were decreased in patients with CRC. Pretreatment with low-dose Prevotella -derived lipopolysaccharides (LPS) induced inflammatory tolerance both in vivo and in vitro and inhibited CRC tumorigenesis in mice. Imbalanced gut microbiota increased intestinal barrier permeability, which facilitated LPS absorption from the gut into the blood, causing cognitive decline in AD-like mice and patients with aMCI. These data reveal that intestinal Prevotella -derived LPS exerts a resistant effect to CRC tumorigenesis via inducing inflammatory tolerance in the presence of AD. These findings provide biological evidence demonstrating the inverse relationship between the incidence of AD and CRC., Competing Interests: Competing interests statement:The authors declare no competing interest.

There are complex interactions between the gut and the brain. With increasing research on the relationship between gut microbiota and brain function, accumulated clinical and preclinical evidence suggests that gut microbiota is intimately involved in the pathogenesis of neurodegenerative diseases (NDs). Increasingly studies are beginning to focus on the association between gut microbiota and central nervous system (CNS) degenerative pathologies to find potential therapies for these refractory diseases. In this review, we summarize the changes in the gut microbiota in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis and contribute to our understanding of the function of the gut microbiota in NDs and its possible involvement in the pathogenesis. We subsequently discuss therapeutic approaches targeting gut microbial abnormalities in these diseases, including antibiotics, diet, probiotics, and fecal microbiota transplantation (FMT). Furthermore, we summarize some completed and ongoing clinical trials of interventions with gut microbes for NDs, which may provide new ideas for studying NDs., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., Competing Interests: Declaration of Competing Interest We declare that we have no conflicts of interest. Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Microbiome studies have revealed gut microbiota's potential impact on complex diseases. However, many studies often focus on one disease per cohort. We developed a meta-analysis workflow for gut microbiome profiles and analyzed shotgun metagenomic data covering 11 diseases. Using interpretable machine learning and differential abundance analysis, our findings reinforce the generalization of binary classifiers for Crohn's disease (CD) and colorectal cancer (CRC) to hold-out cohorts and highlight the key microbes driving these classifications. We identified high microbial similarity in disease pairs like CD vs ulcerative colitis (UC), CD vs CRC, Parkinson's disease vs type 2 diabetes (T2D), and schizophrenia vs T2D. We also found strong inverse correlations in Alzheimer's disease vs CD and UC. These findings, detected by our pipeline, provide valuable insights into these diseases., Importance: Assessing disease similarity is an essential initial step preceding a disease-based approach for drug repositioning. Our study provides a modest first step in underscoring the potential of integrating microbiome insights into the disease similarity assessment. Recent microbiome research has predominantly focused on analyzing individual diseases to understand their unique characteristics, which by design excludes comorbidities in individuals. We analyzed shotgun metagenomic data from existing studies and identified previously unknown similarities between diseases. Our research represents a pioneering effort that utilizes both interpretable machine learning and differential abundance analysis to assess microbial similarity between diseases., Competing Interests: The authors declare no conflict of interest.

Alzheimer's disease (AD) is a neurodegenerative disease that is known to accumulate amyloid-β (Aβ) and tau protein. Clinical studies have not identified pathogenesis mechanisms or produced an effective cure for AD. The Aβ monoclonal antibody lecanemab reduces Aβ plaque formation for the treatment of AD, but more studies are required to increase the effectiveness of drugs to reduce cognitive decline. The lack of AD therapy targets and evidence of an association with an acute neuroinflammatory response caused by several bacteria and viruses in some individuals has led to the establishment of the infection hypothesis during the last 10 years. How pathogens cross the blood-brain barrier is highly topical and is seen to be pivotal in proving the hypothesis. This review summarizes the possible role of the gut microbiome in the pathogenesis of AD and feasible therapeutic approaches and current research limitations.

The gastrointestinal (GI) tract, home to the largest microbial population in the human body, plays a crucial role in overall health through various mechanisms. Recent advancements in research have revealed the potential implications of gut-brain and vice-versa communication mediated by gut-microbiota and their microbial products in various diseases including type-2 diabetes and Alzheimer's disease (AD). AD is the most common type of dementia where most of cases are sporadic with no clearly identified cause. However, multiple factors are implicated in the progression of sporadic AD which can be classified as non-modifiable (e.g., genetic) and modifiable (e.g. Type-2 diabetes, diet etc.). Present review focusses on key players particularly the modifiable factors such as Type-2 diabetes (T2D) and diet and their implications in microbiota-gut-brain (MGB) and brain-gut (BG) communication and cognitive functions of healthy brain and their dysfunction in Alzheimer's Disease. Special emphasis has been given on elucidation of the mechanistic aspects of the impact of diet on gut-microbiota and the implications of some of the gut-microbial products in T2D and AD pathology. For example, mechanistically, HFD induces gut dysbiosis with driven metabolites that in turn cause loss of integrity of intestinal barrier with concomitant colonic and systemic chronic low-grade inflammation, associated with obesity and T2D. HFD-induced obesity and T2D parallel neuroinflammation, deposition of Amyloid β (Aβ), and ultimately cognitive impairment. The review also provides a new perspective of the impact of diet on brain-gut and microbiota-gut-brain communication in terms of transcription factors as a commonly spoken language that may facilitates the interaction between gut and brain of obese diabetic patients who are at a higher risk of developing cognitive impairment and AD. Other commonality such as tyrosine kinase expression and functions maintaining intestinal integrity on one hand and the phagocytic clarence by migratory microglial functions in brain are also discussed. Lastly, the characterization of the key players future research that might shed lights on novel potential pharmacological target to impede AD progression are also discussed.

Over the past decades, accumulating evidence suggests that the gut microbiome exerts a key role in Alzheimer's disease (AD). The Alzheimer's Association Workgroup is updating the diagnostic criteria for AD, which changed the profiles and categorization of biomarkers from "AT(N)" to "ATNIVS." Previously, most of studies focus on the correlation between the gut microbiome and amyloid beta deposition ("A"), the initial AD pathological feature triggering the "downstream" tauopathy and neurodegeneration. However, limited research investigated the interactions between the gut microbiome and other AD pathogenesis ("TNIVS"). In this review, we summarize current findings of the gut microbial characteristics in the whole spectrum of AD. Then, we describe the association of the gut microbiome with updated biomarker categories of AD pathogenesis. In addition, we outline the gut microbiome-related therapeutic strategies for AD. Finally, we discuss current key issues of the gut microbiome research in the AD field and future research directions. HIGHLIGHTS: The new revised criteria for Alzheimer's disease (AD) proposed by the Alzheimer's Association Workgroup have updated the profiles and categorization of biomarkers from "AT(N)" to "ATNIVS." The associations of the gut microbiome with updated biomarker categories of AD pathogenesis are described. Current findings of the gut microbial characteristics in the whole spectrum of AD are summarized. Therapeutic strategies for AD based on the gut microbiome are proposed., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Although the role of gut microbiota (GMB)-derived metabolites in mitochondrial and endolysosomal dysfunction in Alzheimer's disease (AD) under metabolic syndrome remains unclear, deciphering these host-metabolite interactions represents a major public health challenge. Dysfunction of mitochondria and endolysosomal networks (ELNs) plays a crucial role in metabolic syndrome and can exacerbate AD progression, highlighting the need to study their reciprocal regulation for a better understanding of how AD is linked to metabolic syndrome. Concurrently, metabolic disorders are associated with alterations in the composition of the GMB. Recent evidence suggests that changes in the composition of the GMB and its metabolites may be involved in AD pathology. This review highlights the mechanisms of metabolic syndrome-mediated AD development, focusing on the interconnected roles of mitochondrial dysfunction, ELN abnormalities, and changes in the GMB and its metabolites. We also discuss the pathophysiological role of GMB-derived metabolites, including amino acids, fatty acids, other metabolites, and extracellular vesicles, in mediating their effects on mitochondrial and ELN dysfunction. Finally, this review proposes therapeutic strategies for AD by directly modulating mitochondrial and ELN functions through targeting GMB metabolites under metabolic syndrome., (© 2024. The Author(s).)

Alzheimer's disease is the most common cause of dementia globally. The pathogenesis is multifactorial and includes deposition of amyloid-β in the central nervous system, presence of intraneuronal neurofibrillary tangles and a decreased amount of synapses. It remains uncertain what causes the progression of the disease. Nowadays, it is suggested that the brain is connected to the gastrointestinal tract, especially the enteric nervous system and gut microbiome. Studies have found a positive association between AD and gastrointestinal diseases such as periodontitis, Helicobacter pylori infection, inflammatory bowel disease and microbiome disorders. H. pylori and its metabolites can enter the CNS via the oropharyngeal olfactory pathway and may predispose to the onset and progression of AD. Periodontitis may cause systemic inflammation of low severity with high levels of pro-inflammatory cytokines and neutrophils. Moreover, lipopolysaccharide from oral bacteria accompanies beta-amyloid in plaques that form in the brain. Increased intestinal permeability in IBS leads to neuronal inflammation from transference. Chronic inflammation may lead to beta-amyloid plaque formation in the intestinal tract that spreads to the brain via the vagus nerve. The microbiome plays an important role in many bodily functions, such as nutrient absorption and vitamin production, but it is also an important factor in the development of many diseases, including Alzheimer's disease. Both the quantity and diversity of the microbiome change significantly in patients with AD and even in people in the preclinical stage of the disease, when symptoms are not yet present. The microbiome influences the functioning of the central nervous system through, among other things, the microbiota-gut-brain axis. Given the involvement of the microbiome in the pathogenesis of AD, antibiotic therapy, probiotics and prebiotics, and faecal transplantation are being considered as possible therapeutic options.

Aging is the most prominent risk factor for neurodegeneration occurrence. The most common neurodegenerative diseases (NDs), Alzheimer's (AD) and Parkinson's (PD) diseases, are characterized by the incidence of proteinopathy, abnormal activation of glial cells, oxidative stress, neuroinflammation, impaired autophagy and cellular senescence excessive for the patient's age. Moreover, mitochondrial disfunction, epigenetic alterations and neurogenesis inhibition, together with increased blood-brain barrier permeability and gut dysbiosis, have been linked to ND pathogenesis. Since NDs still lack curative treatment, recent research has sought therapeutic options in restoring gut microbiota and supplementing probiotic bacteria-derived metabolites with beneficial action to the host-so called postbiotics. The current review focuses on literature explaining cellular mechanisms involved in ND pathogenesis and research addressing the impact that postbiotics as a whole mixture and particular metabolites, such as short-chain fatty acids (SCFAs), lactate, polyamines, polyphenols, tryptophan metabolites, exopolysaccharides and bacterial extracellular vesicles, have on the ageing-associated processes underlying ND occurrence. The review also discusses the issue of implementing postbiotics into ND prophylaxis and therapy, depicting them as compounds addressing senescence-triggered dysfunctions that are worth translating from bench to pharmaceutical market in response to "silver consumers" demands.

Background: Caloric restriction (CR) might be effective for alleviating/preventing Alzheimer's disease (AD), but the biological mechanisms remain unclear. In the current study, we explored whether CR caused an alteration of gut microbiome and resulted in the attenuation of cognitive impairment of AD animal model., Methods: Thirty-week-old male APP/PS1 transgenic mice were used as AD models (AD mouse). CR was achieved by 30% reduction of daily free feeding (ad libitum, AL) amount. The mice were fed with CR protocol or AL protocol for six consecutive weeks., Results: We found that with CR treatment, AD mice showed improved ability of learning and spatial memory, and lower levels of Aβ40, Aβ42, IL-1β, TNF-α, and ROS in the brain. By sequencing 16S rDNA, we found that CR treatment resulted in significant diversity in composition and abundance of gut flora. At the phylum level, Deferribacteres (0.04%), Patescibacteria (0.14%), Tenericutes (0.03%), and Verrucomicrobia (0.5%) were significantly decreased in CR-treated AD mice; at the genus level, Dubosiella (10.04%), Faecalibaculum (0.04%), and Coriobacteriaceae UCG-002 (0.01%) were significantly increased in CR-treated AD mice by comparing with AL diet., Conclusions: Our results demonstrate that the attenuation of AD following CR treatment in APP/PS1 mice may result from alterations in the gut microbiome. Thus, gut flora could be a new target for AD prevention and therapy., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Sorghum is a promising treatment for Alzheimer's disease (AD), due to its rich antioxidant and anti-inflammatory qualities. Fermentation may also affect nutritional values. Therefore, the purpose of this study was to discover the phenolic and flavonoid chemicals found in both fermented and non-fermented red sorghum, as well as their potential therapeutic uses for AD. L. fermentum, and L. reuteri, and/or L. plantarum and L. casei were used to ferment samples of sorghum. The rats were grouped into five groups, healthy animals, and rats with Alzheimer's receiving 200 mg/kg of saline, non-fermented sorghum, and fermented sorghum fermented with L. fermentum and L. reuteri, as well as L. plantarum and L. casei. Various assessments were conducted, including evaluations of behavioral responses, antioxidant responses, inflammatory responses, acetylcholine levels and acetylcholine esterase, and bacterial populations in stool. P-hydroxybenzoic acid, eriodictyo naringenin, and apigenin were significantly higher in fermented samples, while glycerols were higher in non-fermented samples. The induction of Alzheimer's led to decrease step-through latency, time in target zone, FRAP, acetylcholine levels, Bifidobacterium population and lactobacillus population, while increased escape latency, platform location latency, MDA levels, IL-6, TNF-α, acetylcholine esterase, and coliform population (P = 0.001). The administration of both non-fermented sorghum and fermented sorghum demonstrated the potential to reverse the effects of AD, with a notably higher efficacy observed in the fermented samples compared to the non-fermented ones. In conclusion, fermentation exerted significant effects on the bioactive compounds the administration of fermented sorghum resulted in improved behavioral responses, characterized by a reduction in oxidation, inflammation and microbial population., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Emerging evidence links changes in the gut microbiome to late-onset Alzheimer's disease (LOAD), necessitating examination of AD mouse models with consideration of the microbiome., Methods: We used shotgun metagenomics and untargeted metabolomics to study the human amyloid beta knock-in (hAβ-KI) murine model for LOAD compared to both wild-type (WT) mice and a model for early-onset AD (3xTg-AD)., Results: Eighteen-month female (but not male) hAβ-KI microbiomes were distinct from WT microbiomes, with AD genotype accounting for 18% of the variance by permutational multivariate analysis of variance (PERMANOVA). Metabolomic diversity differences were observed in females, however no individual metabolites were differentially abundant. hAβ-KI mice microbiomes were distinguishable from 3xTg-AD animals (81% accuracy by random forest modeling), with separation primarily driven by Romboutsia ilealis and Turicibacter species. Microbiomes were highly cage specific, with cage assignment accounting for more than 40% of the PERMANOVA variance between the groups., Discussion: These findings highlight a sex-dependent variation in the microbiomes of hAβ-KI mice and underscore the importance of considering the microbiome when designing studies that use murine models for AD., Highlights: Microbial diversity and the abundance of several species differed in human amyloid beta knock-in (hAβ-KI) females but not males. Correlations to Alzheimer's disease (AD) genotype were stronger for the microbiome than the metabolome. Microbiomes from hAβ-KI mice were distinct from 3xTg-AD mice. Cage effects accounted for most of the variance in the microbiome and metabolome., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Sialic acid metabolism in oral bacteria is a complex process involving nutrient acquisition, immune evasion, cell surface modification, and the production of metabolites that contribute to bacterial persistence and virulence in the oral cavity. In addition to causing various periodontal diseases, certain oral pathogenic bacteria, such as Porphyromonas gingivalis, Tannerella forsythia, and Fusobacterium nucleatum, can induce inflammatory reactions and influence the immunity of host cells. These associations with host cells are linked to various diseases, particularly colorectal cancer and Alzheimer's disease. Sialic acid can be found in the host oral mucosa, saliva, or food residues in the oral cavity, and it may promote the colonization of oral bacteria and contribute to disease development. This review aims to summarize the role of sialic acid metabolism in oral bacteria and discuss its effect on the pathogenesis of colorectal cancer and Alzheimer's disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Polygala tenuifolia is a well-known traditional Chinese medicine. Polygala tenuifolia polysaccharide (PTP), as one of its main active ingredients, has excellent neuroprotective activity. PTP improved the disruption of the endogenous metabolites and gut microbiota caused by Alzheimer's disease (AD). Specifically, untargeted metabolomics results showed that 19 metabolites such as leukotriene B4, vanylglycol, and cer(d18:1/18:0) are significantly reduced, and 2 metabolites are elevated. It was significantly enriched in Sphingolipid metabolism, Glycerophospholipid metabolism, Tyrosine metabolism, and Arachidonic acid metabolism. Meanwhile, 16S rDNA analysis showed that PTP treatment significantly increased the relative abundance of bacteria such as Alistipes, Lachnospiraceae_NK4A136_group, and Lachnospiraceae_UCG-006. In addition, Spearman analysis showed that significant changes in gut microbiota were closely related to differential endogenous metabolites., Competing Interests: Declaration of Competing Interest The authors confirm that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Tauroursodeoxycholic acid (TUDCA) increases the influx of primary bile acids into the gut. Results obtained on animal models suggested that Firmicutes and Proteobacteria phyla are more resistant to bile acids in rats. As part of a pilot study investigating the role of probiotics supplementation in elderly people with home enteral nutrition (HEN), a case of a 92-year-old woman with HEN is reported in the present study. She lives in a nursing home and suffers from Alzheimer's disease (AD); the patient had been prescribed TUDCA for lithiasis cholangitis. The aim of this case report is therefore to investigate whether long-term TUDCA administration may play a role in altering the patient's gut microbiota (GM) and the impact of an antibiotic therapy on the diversity of microbial species. Using next generation sequencing (NGS) analysis of the bacterial 16S ribosomal RNA (rRNA) gene a dominant shift toward Firmicutes and a remodeling in Proteobacteria abundance was observed in the woman's gut microbiota. Considering the patient's age, health status and type of diet, we would have expected to find a GM with a prevalence of Bacteroidetes phylum. This represents the first study investigating the possible TUDCA's effect on human GM.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder and a leading cause of dementia. Aging is a significant risk factor for AD, emphasizing the importance of early detection since symptoms cannot be reversed once the advanced stage is reached. Currently, there is no established method for early AD diagnosis. However, emerging evidence suggests that the microbiome has an impact on cognitive function. The gut microbiome and the brain communicate bidirectionally through the gut-brain axis, with systemic inflammation identified as a key connection that may contribute to AD. Gut dysbiosis is more prevalent in individuals with AD compared to their cognitively healthy counterparts, leading to increased gut permeability and subsequent systemic inflammation, potentially causing neuroinflammation. Detecting brain activity traditionally involves invasive and expensive methods, but electroencephalography (EEG) poses as a non-invasive alternative. EEG measures brain activity and multiple studies indicate distinct patterns in individuals with AD. Furthermore, EEG patterns in individuals with mild cognitive impairment differ from those in the advanced stage of AD, suggesting its potential as a method for early indication of AD. This review aims to consolidate existing knowledge on the microbiome and EEG as potential biomarkers for early-stage AD, highlighting the current state of research and suggesting avenues for further investigation.

Introduction: Cognitive impairment is reported in a variety of clinical conditions including Alzheimer's disease, Parkinson's and 'long-COVID'. Interestingly, many of these clinical conditions are also associated with microbial dysbiosis. This comanifestation of cognitive and microbiome findings in seemingly unrelated maladies suggests that they could share a common mechanism and potentially presents a treatment target. Although a rapidly growing body of literature has documented this comorbid presentation within specific conditions, an overview highlighting potential parallels across healthy and clinical populations is lacking. The objective of this umbrella review, therefore, is to summarise and synthesise the findings of these systematic reviews., Methods and Analysis: On 2 April 2023, we searched MEDLINE (Pubmed), Embase (Ovid), the Web of Science (Core Collection), the Cochrane Library of Systematic Reviews and Epistemonikos as well as grey literature sources, for systematic reviews on clinical conditions and interventions where cognitive and microbiome outcomes were coreported. An updated search will be conducted before completion of the project if the search-to-publication date is >1 year old. Screening, data abstraction and quality assessment (AMSTAR 2, A MeaSurement Tool to Assess systematic Reviews) will be conducted independently and in duplicate, with disagreements resolved by consensus. Evidence certainty statements for each review's conclusions (eg, Grading of Recommendations Assessment, Development and Evaluation (GRADE)) will be extracted or constructed de novo. A narrative synthesis will be conducted and delineated by the review question. Primary study overlap will be visualised using a citation matrix as well as calculated using the corrected covered area method., Ethics and Dissemination: No participant-identifying information will be used in this review. No ethics approval was required due to our study methodology. Our findings will be presented at national and international conferences and disseminated via social media and press releases. We will recruit at least one person living with cognitive impairment to collaborate on writing the plain language summary for the review., Prospero Registration Number: CRD42023412903., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

GV1001, an anticancer vaccine, exhibits other biological functions, including anti-inflammatory and antioxidant activity. It also suppresses the development of ligature-induced periodontitis in mice. Porphyromonas gingivalis ( Pg ), a major human oral bacterium implicated in the development of periodontitis, is associated with various systemic disorders, such as atherosclerosis and Alzheimer's disease (AD). This study aimed to explore the protective effects of GV1001 against Pg -induced periodontal disease, atherosclerosis, and AD-like conditions in Apolipoprotein ( ApoE )-deficient mice. GV1001 effectively mitigated the development of Pg -induced periodontal disease, atherosclerosis, and AD-like conditions by counteracting Pg -induced local and systemic inflammation, partly by inhibiting the accumulation of Pg DNA aggregates, Pg lipopolysaccharides (LPS), and gingipains in the gingival tissue, arterial wall, and brain. GV1001 attenuated the development of atherosclerosis by inhibiting vascular inflammation, lipid deposition in the arterial wall, endothelial to mesenchymal cell transition (EndMT), the expression of Cluster of Differentiation 47 (CD47) from arterial smooth muscle cells, and the formation of foam cells in mice with Pg -induced periodontal disease. GV1001 also suppressed the accumulation of AD biomarkers in the brains of mice with periodontal disease. Overall, these findings suggest that GV1001 holds promise as a preventive agent in the development of atherosclerosis and AD-like conditions associated with periodontal disease.

Alzheimer's disease (AD) comprises a group of neurodegenerative disorders with some changes in the brain, which could lead to the deposition of certain proteins and result in the degeneration and death of brain cells. Patients with AD manifest primarily as cognitive decline, psychiatric symptoms, and behavioural disorders. Short-chain fatty acids (SCFAs) are a class of saturated fatty acids (SFAs) produced by gut microorganisms through the fermentation of dietary fibre ingested. SCFAs, as a significant mediator of signalling, can have diverse physiological and pathological roles in the brain through the gut-brain axis, and play a positive effect on AD via multiple pathways. Firstly, differences in SCFAs and microbial changes have been stated in AD cases of humans and mice in this paper. And then, mechanisms of three main SCFAs in treating with AD have been summarized, as well as differences of gut bacteria. Finally, functions of SCFAs played in regulating intestinal flora homeostasis, modulating the immune system, and the metabolic system, which were considered to be beneficial for the treatment of AD, have been elucidated, and the key roles of gut bacteria and SCFAs were pointed out. All in all, this paper provides an overview of SCFAs and gut bacteria in AD, and can help people to understand the importance of gut-brain axis in AD., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Shifts in the magnitude and nature of gut microbial metabolites have been implicated in Alzheimer's disease (AD), but the host receptors that sense and respond to these metabolites are largely unknown. Here, we develop a systems biology framework that integrates machine learning and multi-omics to identify molecular relationships of gut microbial metabolites with non-olfactory G-protein-coupled receptors (termed the "GPCRome"). We evaluate 1.09 million metabolite-protein pairs connecting 408 human GPCRs and 335 gut microbial metabolites. Using genetics-derived Mendelian randomization and integrative analyses of human brain transcriptomic and proteomic profiles, we identify orphan GPCRs (i.e., GPR84) as potential drug targets in AD and that triacanthine experimentally activates GPR84. We demonstrate that phenethylamine and agmatine significantly reduce tau hyperphosphorylation (p-tau181 and p-tau205) in AD patient induced pluripotent stem cell-derived neurons. This study demonstrates a systems biology framework to uncover the GPCR targets of human gut microbiota in AD and other complex diseases if broadly applied., Competing Interests: Declaration of interests J.B.L. has received consulting fees from Vaxxinity and grant support from GE Healthcare and serves on a data safety monitoring board for Eisai., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The intestinal microbiota exhibits a strong correlation with the function of the central nervous system, exerting influence on the host brain through neural pathways, immune pathways, and microbial metabolites along the gut-brain axis. Disorders in the composition of the intestinal microbial are closely associated with the onset and progression of neurological disorders, such as depression, Alzheimer's disease, and Parkinson's disease. It has been proven that fecal microbiota transplantation can improve symptoms in animal models of neurological diseases and clinical patients. This paper provides a comprehensive review of the composition and function of the human intestinal microbiota, as well as the intricate the relationship between the human intestinal microbiota and nervous system diseases through the gut-brain axis. Additionally, it delves into the research advancements and underlying mechanism of fecal microbiota transplantation in the treatment of nervous system diseases. These findings offer novel insights and potential avenues for clinical interventions targeting nervous system diseases.

The gut microbiota and microglia play critical roles in Alzheimer's disease (AD), and elevated Bacteroides is correlated with cerebrospinal fluid amyloid-β (Aβ) and tau levels in AD. We hypothesize that Bacteroides contributes to AD by modulating microglia. Here we show that administering Bacteroides fragilis to APP/PS1-21 mice increases Aβ plaques in females, modulates cortical amyloid processing gene expression, and down regulates phagocytosis and protein degradation microglial gene expression. We further show that administering Bacteroides fragilis to aged wild-type male and female mice suppresses microglial uptake of Aβ1-42 injected into the hippocampus. Depleting murine Bacteroidota with metronidazole decreases amyloid load in aged 5xFAD mice, and activates microglial pathways related to phagocytosis, cytokine signaling, and lysosomal degradation. Taken together, our study demonstrates that members of the Bacteroidota phylum contribute to AD pathogenesis by suppressing microglia phagocytic function, which leads to impaired Aβ clearance and accumulation of amyloid plaques., (© 2024. The Author(s).)

An essential regulator of neurodegenerative conditions like Alzheimer's disease (AD) is the gut microbiota. Alterations in intestinal permeability brought on by gut microbiota dysregulation encourage neuroinflammation, central immune dysregulation, and peripheral immunological dysregulation in AD, as well as hasten aberrant protein aggregation and neuronal death in the brain. However, it is unclear how the gut microbiota transmits information to the brain and how it influences brain cognition and function. In this review, we summarized the multiple pathways involved in the gut microbiome in AD and provided detailed treatment strategies based on the gut microbiome. Based on these observations, this review also discusses the problems, challenges, and strategies to address current therapeutic strategies.

Alterations in the gut-microbiome-brain axis are increasingly being recognized to be involved in Alzheimer's disease (AD) pathogenesis. However, the functional consequences of enteric dysbiosis linking gut microbiota and brain pathology in AD progression remain largely undetermined. The present work investigated the causal role of age-associated temporal decline in butyrate-producing bacteria and butyrate in the etiopathogenesis of AD. Longitudinal metagenomics, neuropathological, and memory analyses were performed in the 3×Tg-AD mouse model. Metataxonomic analyses showed a significant temporal decline in the alpha diversity marked by a decrease in butyrate-producing bacterial communities and a concurrent reduction in cecal butyrate production. Inferred metagenomics analysis identified the bacterial acetyl-CoA pathway as the main butyrate synthesis pathway impacted. Concomitantly, there was an age-associated decline in the transcriptionally permissive acetylation of histone 3 at lysines 9 and 14 (H3K9/K14-Ac) in hippocampal neurons. Importantly, these microbiome-gut-brain changes preceded AD-related neuropathology, including oxidative stress, tau hyperphosphorylation, memory deficits, and neuromuscular dysfunction, which manifest by 17-18 months. Initiation of oral administration of tributyrin, a butyrate prodrug, at 6 months of age mitigated the age-related decline in butyrate-producing bacteria, protected the H3K9/K14-Ac status, and attenuated the development of neuropathological and cognitive changes associated with AD pathogenesis. These data causally implicate age-associated decline in butyrate-producing bacteria as a key pathogenic feature of the microbiome-gut-brain axis affecting the onset and progression of AD. Importantly, the regulation of butyrate-producing bacteria and consequent butyrate synthesis could be a significant therapeutic strategy in the prevention and treatment of AD.

Background: Previous research has suggested that pathogen infections may serve as potential contributors to dementia., Objective: Consequently, the study aimed to evaluate whether pathogen exposure heightens the risk of dementia., Methods: Between 2006 and 2010, a total of 8,144 individuals from the UK Biobank had data on pathogen antibodies and were included in the baseline assessment. Cox proportional hazard models were employed for the analysis., Results: Out of the 8,144 participants, 107 eventually developed dementia, while 55 participants were diagnosed with Alzheimer's disease (AD). Multivariate Cox regression analysis revealed that the levels of pathogen antibody titers of EBV and C. trachomatis were associated with an increased risk of dementia/AD. The highest quartile of EBV EBNA-1 and EBV VCA p18, and the second quartile of H. pylori VacA significantly increased the risk of dementia compared lower quartile (EBV EBNA-1: HR = 1.938, p = 0.018; EBV VCA p18: HR = 1.824, p = 0.040; H. pylori VacA: HR = 1.890, p = 0.033). Besides, the highest quartile of EBV VCA p18 had a higher risk of AD compared lower quartile (HR = 2.755, p = 0.029)., Conclusions: The study demonstrated that exposure to EBV, H. pylori, and C. trachomatis substantially elevated the risk of dementia/AD. Despite the relatively widespread occurrence of EBV infection in the population, elevated pathogen antibody titers were still found to increase the risk of dementia/AD. Besides, since C. trachomatis and C. pneumoniae are quite homologous, this study found that trachomatis (C. trachomatis/C. pneumoniae) may be significantly associated with the risk of AD/dementia.

The gut microbial ecosystem communicates bidirectionally with the brain in what is known as the gut-microbiome-brain axis. Bidirectional signaling occurs through several pathways including signaling via the vagus nerve, circulation of microbial metabolites, and immune activation. Alterations in the gut microbiota are implicated in Alzheimer's disease (AD), a progressive neurodegenerative disease. Perturbations in gut microbial communities may affect pathways within the gut-microbiome-brain axis through altered production of microbial metabolites including ɣ-aminobutyric acid (GABA), the primary inhibitory mammalian neurotransmitter. GABA has been shown to act on gut integrity through modulation of gut mucins and tight junction proteins and may be involved in vagus nerve signal inhibition. The GABAergic signaling pathway has been shown to be dysregulated in AD, and may be responsive to interventions. Gut microbial production of GABA is of recent interest in neurological disorders, including AD. Bacteroides and Lactic Acid Bacteria (LAB), including Lactobacillus , are predominant producers of GABA. This review highlights how temporal alterations in gut microbial communities associated with AD may affect the GABAergic signaling pathway, intestinal barrier integrity, and AD-associated inflammation.

Background: Multiple studies have demonstrated that the gut microbiome is closely related to the onset of Alzheimer's disease, but the causal relationship between the gut microbiome and AD, as well as potential mediating factors, have not been fully explored., Objective: Our aim is to validate the causal relationship between the gut microbiome and the onset of AD and determine the key mechanism by which the gut microbiome mediates AD through blood metabolites using Mendelian randomization (MR) analysis methods., Methods: We first conducted bidirectional and mediating MR analyses using gut microbiota, blood amino acid metabolites, and AD-related single nucleotide polymorphisms as research data. In the analysis process, the inverse variance-weighted average method was mainly used as the primary method, with other methods serving as supplementary evidence., Results: Ultimately, we found that six types of gut bacteria and two blood amino acid metabolites have a causal effect on AD. Subsequent mediation analysis proved that decreased glutamine concentration mediates the negative causal effect of Holdemanella bacteria on AD (mediation ratio of 14.5%), and increased serum alanine concentration mediates the positive causal effect of Parabacteroide bacteria on AD (mediation ratio of 9.4%)., Conclusions: Our study demonstrates the causality of Holdemanella and Parabacteroides bacteria in the onset of AD and suggests that the reduced glutamine and increased alanine serums concentration may be key nodes in mediating this effect.

Background: Alzheimer's Disease (AD) is the most prevalent type of dementia. The early change of gut microbiota is a potential biomarker for preclinical AD patients., Objective: The study aimed to explore changes in gut microbiota characteristics in preclinical AD patients, including those with Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI), and detect the correlation between gut microbiota characteristics and cognitive performances., Methods: This study included 117 participants [33 MCI, 54 SCD, and 30 Healthy Controls (HC)]. We collected fresh fecal samples and blood samples from all participants and evaluated their cognitive performance. We analyzed the diversity and structure of gut microbiota in all participants through qPCR, screened characteristic microbial species through machine learning models, and explored the correlations between these species and cognitive performances and serum indicators., Results: Compared to the healthy controls, the structure of gut microbiota in MCI and SCD patients was significantly different. The three characteristic microorganisms, including Bacteroides ovatus, Bifidobacterium adolescentis , and Roseburia inulinivorans , were screened based on the best classification model (HC and MCI) having intergroup differences. Bifidobacterium adolescentis is associated with better performance in multiple cognitive scores and several serum indicators. Roseburia inulinivorans showed negative correlations with the scores of the Functional Activities Questionnaire (FAQ)., Conclusion: The gut microbiota in patients with preclinical AD has significantly changed in terms of composition and richness. Correlations have been discovered between changes in characteristic species and cognitive performances. Gut microbiota alterations have shown promise in affecting AD pathology and cognitive deficit., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Gut bacteria regulate brain pathology of Alzheimer's disease (AD) patients and animal models; however, the underlying mechanism remains unclear. In this study, 3-month-old APP-transgenic female mice with and without knock-out of Il-17a gene were treated with antibiotics-supplemented or normal drinking water for 2 months. The antibiotic treatment eradicated almost all intestinal bacteria, which led to a reduction in Il-17a-expressing CD4-positive T lymphocytes in the spleen and gut, and to a decrease in bacterial DNA in brain tissue. Depletion of gut bacteria inhibited inflammatory activation in both brain tissue and microglia, lowered cerebral Aβ levels, and promoted transcription of Arc gene in the brain of APP-transgenic mice, all of which effects were abolished by deficiency of Il-17a. As possible mechanisms regulating Aβ pathology, depletion of gut bacteria inhibited β-secretase activity and increased the expression of Abcb1 and Lrp1 in the brain or at the blood-brain barrier, which were also reversed by the absence of Il-17a. Interestingly, a crossbreeding experiment between APP-transgenic mice and Il-17a knockout mice further showed that deficiency of Il-17a had already increased Abcb1 and Lrp1 expression at the blood-brain barrier. Thus, depletion of gut bacteria attenuates inflammatory activation and amyloid pathology in APP-transgenic mice via Il-17a-involved signaling pathways. Our study contributes to a better understanding of the gut-brain axis in AD pathophysiology and highlights the therapeutic potential of Il-17a inhibition or specific depletion of gut bacteria that stimulate the development of Il-17a-expressing T cells.

The fungal pathogen Candida albicans is linked to chronic brain diseases such as Alzheimer's disease (AD), but the molecular basis of brain anti-Candida immunity remains unknown. We show that C. albicans enters the mouse brain from the blood and induces two neuroimmune sensing mechanisms involving secreted aspartic proteinases (Saps) and candidalysin. Saps disrupt tight junction proteins of the blood-brain barrier (BBB) to permit fungal brain invasion. Saps also hydrolyze amyloid precursor protein (APP) into amyloid β (Aβ)-like peptides that bind to Toll-like receptor 4 (TLR4) and promote fungal killing in vitro while candidalysin engages the integrin CD11b (Mac-1) on microglia. Recognition of Aβ-like peptides and candidalysin promotes fungal clearance from the brain, and disruption of candidalysin recognition through CD11b markedly prolongs C. albicans cerebral mycosis. Thus, C. albicans is cleared from the brain through innate immune mechanisms involving Saps, Aβ, candidalysin, and CD11b., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Dietary oligosaccharides can impact the gut microbiota and confer tremendous health benefits., Objectives: The aim of this study was to determine the impact of a novel functional oligosaccharide, neoagarotetraose (NAT), on aging in mice., Methods: 8-month-old C57BL/6J mice as the natural aging mice model were orally administered with NAT for 12 months. The preventive effect of NAT in Alzheimer's disease (AD) mice was further evaluated. Aging related indicators, neuropathology, gut microbiota and short-chain fatty acids (SCFAs) in cecal contents were analyzed., Results: NAT treatment extended the lifespan of these mice by up to 33.3 %. Furthermore, these mice showed the improved aging characteristics and decreased injuries in cerebral neurons. Dietary NAT significantly delayed DNA damage in the brain, and inhibited reduction of tight junction protein in the colon. A significant increase at gut bacterial genus level (such as Lactobacillus, Butyricimonas, and Akkermansia) accompanied by increasing concentrations of SCFAs in cecal contents was observed after NAT treatment. Functional profiling of gut microbiota composition indicated that NAT treatment regulated the glucolipid and bile acid-related metabolic pathways. Interestingly, NAT treatment ameliorated cognitive impairment, attenuated amyloid-β (Aβ) and Tau pathology, and regulated the gut microbiota composition and SCFAs receptor-related pathway of Alzheimer's disease (AD) mice., Conclusion: NAT mitigated age-associated cerebral injury in mice through gut-brain axis. The findings provide novel evidence for the effect of NAT on anti-aging, and highlight the potential application of NAT as an effective intervention against age-related diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Production and hosting by Elsevier B.V.)

Background: Over the last few decades, a growing body of evidence has suggested a role for various infectious agents in Alzheimer's disease (AD) pathogenesis. Despite diverse pathogens (virus, bacteria, fungi) being detected in AD subjects' brains, research has focused on individual pathogens and only a few studies investigated the hypothesis of a bacterial brain microbiome. We profiled the bacterial communities present in non-demented controls and AD subjects' brains., Results: We obtained postmortem samples from the brains of 32 individual subjects, comprising 16 AD and 16 control age-matched subjects with a total of 130 samples from the frontal and temporal lobes and the entorhinal cortex. We used full-length 16S rRNA gene amplification with Pacific Biosciences sequencing technology to identify bacteria. We detected bacteria in the brains of both cohorts with the principal bacteria comprising Cutibacterium acnes (formerly Propionibacterium acnes ) and two species each of Acinetobacter and Comamonas genera. We used a hierarchical Bayesian method to detect differences in relative abundance among AD and control groups. Because of large abundance variances, we also employed a new analysis approach based on the Latent Dirichlet Allocation algorithm, used in computational linguistics. This allowed us to identify five sample classes, each revealing a different microbiota. Assuming that samples represented infections that began at different times, we ordered these classes in time, finding that the last class exclusively explained the existence or non-existence of AD., Conclusions: The AD-related pathogenicity of the brain microbiome seems to be based on a complex polymicrobial dynamic. The time ordering revealed a rise and fall of the abundance of C. acnes with pathogenicity occurring for an off-peak abundance level in association with at least one other bacterium from a set of genera that included Methylobacterium , Bacillus , Caulobacter , Delftia , and Variovorax . C. acnes may also be involved with outcompeting the Comamonas species, which were strongly associated with non-demented brain microbiota, whose early destruction could be the first stage of disease. Our results are also consistent with a leaky blood-brain barrier or lymphatic network that allows bacteria, viruses, fungi, or other pathogens to enter the brain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Moné, Earl, Król, Ahmed, Sen, Ehrlich and Lapides.)

Gut microbiota (GM) dysbiosis has been increasingly associated with Alzheimer's disease (AD). However, the association between APOE4, the most common genetic risk factor for sporadic AD, and GM in AD remains unclear. In this study, we conducted a comparative analysis of the GM of participants from China and the USA, with and without APOE4 genes and with or without AD (67 AD cases, 67 control cases). Our results revealed that the GM alpha diversity was not different between groups (AD&#95;APOE4, Control&#95;APOE4, AD&#95;non-APOE4, and Control&#95;non-APOE4) (419.031 ± 143.631 vs 391.091 ± 126.081, 351.086 ± 169.174 and 386.089 ± 177.200, respectively. P > 0.05). Interestingly, individuals in the AD&#95;APOE4 group had different bacterial compositions and bacterial biomarkers. The Kruskal-Wallis rank sum test indicated that the abundances of many bacterial species in the AD&#95;APOE4 patients differed from those in control individuals, including decreases in unclassified&#95;g&#95;&#95;Escherichia-Shigella (1.763 ± 6.73, 4.429 ± 11.13, 8.245 ± 16.55, and 5.69 ± 13.91 in four groups, respectively; P < 0.05), and unclassified&#95;g&#95;Clostridium&#95;sensu&#95;stricto&#95;1 (0.1519 ± 0.348, 2.502 ± 5.913, 0.5146 ± 0.9487, 1.063 ± 3.428 in four groups, respectively; P < 0.05), and increases in gut&#95;metagenome&#95;g&#95;Faecalibacterium (2.885 ± 4.47, 2.174 ± 3.957, 0.5765 ± 1.784, 1.582 ± 2.92 in four groups, respectively. P < 0.01) and unclassified&#95;g&#95;Bacteroides (3.875 ± 3.738, 2.47 ± 2.748, 2.046 ± 3.674, 3.206 ± 3.446 in four groups, respectively; P < 0.05). In the KEGG pathway level 2 analysis, we identified three significant differences in relative abundances of predicted functions between AD&#95;APOE4 and AD&#95;non-APOE4&#95;carrier groups: neurodegenerative diseases (0.0007 ± 0.0005 vs 0.0009 ± 0.0004; P < 0.01), metabolism (0.0240 ± 0.0003 vs 0.0250 ± 0.0003; P < 0.05), and biosynthesis of other secondary metabolites (0.0094 ± 0.0002 vs 0.0090 ± 0.0002; P < 0.05). Receiver operating characteristic curves further demonstrated an area under the curve (AUC) of 0.74 for the discrimination of AD&#95;APOE4&#95;carrier and AD&#95;non-APOE4&#95;carrier individuals.

Alzheimer`s disease (AD) is the most prevalent cause of dementia. It is often assumed that AD is caused by an aggregation of extracellular beta-amyloid and intracellular tau-protein, supported by a recent study showing reduced brain amyloid levels and reduced cognitive decline under treatment with a beta-amyloid-binding antibody. Confirmation of the importance of amyloid as a therapeutic target notwithstanding, the underlying causes of beta-amyloid aggregation in the human brain, however, remain to be elucidated. Multiple lines of evidence point towards an important role of infectious agents and/or inflammatory conditions in the etiology of AD. Various microorganisms have been detected in the cerebrospinal fluid and brains of AD-patients and have thus been hypothesized to be linked to the development of AD, including Porphyromonas gingivalis (PG) and Spirochaetes . Intriguingly, these microorganisms are also found in the oral cavity under normal physiological conditions, which is often affected by multiple pathologies like caries or tooth loss in AD patients. Oral cavity pathologies are mostly accompanied by a compositional shift in the community of oral microbiota, mainly affecting commensal microorganisms and referred to as 'dysbiosis'. Oral dysbiosis seems to be at least partly mediated by key pathogens such as PG, and it is associated with a pro-inflammatory state that promotes the destruction of connective tissue in the mouth, possibly enabling the translocation of pathogenic microbiota from the oral cavity to the nervous system. It has therefore been hypothesized that dysbiosis of the oral microbiome may contribute to the development of AD. In this review, we discuss the infectious hypothesis of AD in the light of the oral microbiome and microbiome-host interactions, which may contribute to or even cause the development of AD. We discuss technical challenges relating to the detection of microorganisms in relevant body fluids and approaches for avoiding false-positives, and introduce the antibacterial protein lactoferrin as a potential link between the dysbiotic microbiome and the host inflammatory reaction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Weber, Dilthey and Finzer.)

Alzheimer's disease (AD) is a neurodegenerative disease, pathological markers of which are amyloid plaques and neurofibrillary tangles. As a key node of gut-brain axis, gut microbiota is increasingly associated with changes in cognitive behaviors and brain function. Psychobiotics are known to benefit patients with neurodegenerative diseases by the production and deliberation of neuroactive substances. However, psychobiotics are strain-specific probiotics, and their neuroprotective effects on the brain and modulation effects on the gut microbiome are not generalizable. In this study, we investigated the effects of Bifidobacterium breve HNXY26M4 in APP/PS1 mice. By assessing the alterations associated with brain function, we found that B. breve HNXY26M4 attenuated cognitive deficits and suppressed neuroinflammation and synaptic dysfunction in APP/PS1 mice. Moreover, by determining the modulation effects of B. breve HNXY26M4 on gut homeostasis, we identified that B. breve HNXY26M4 supplementation restored the composition of gut microbiota and short-chain fatty acids, as well as enhanced the function of the intestinal barrier. These findings indicate that microbiome-derived acetate and butyrate modulated by B. breve HNXY26M4 administration may be transported to the brain through the blood-brain barrier, and thus confer neuroprotective effects against AD-associated brain deficits and inflammation via the gut-brain axis.

Memory is empirically described as a brain function that connects the past to the present. This reductionist approach has focused on memory function within neurons and synapses, leading to an understanding that memory loss in dementia is caused by irreversible neuronal damage. However, recent palliative case reports and the Human Connectome Project have challenged the "irreversible" paradigm by indicating that some demented patients are able to retrieve supposed 'lost' memories and cognitive functions near death. The serotonin-centric hypothesis and the lifelong oligodendrocyte differentiation capacity may explain terminal awakening symptoms in these patients. Furthermore, an increased rate of serotonin-secreting and oligodendrocyte precursor cell-triggering gut bacteria near death temporally correlates with lucid improvements in demented patients. These findings may shift the context of terminal memory retrieval from a purely neuronal to a systemic idea that bridges terminal lucidity and gut microbiota. In this review, we take the systemic approach further and point out a temporal correlation between the gut microbiome and terminal lucid episodes in Alzheimer's patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Capsaicin, a natural bioactive component, has been reported to improve cognition and ameliorate the pathology of Alzheimer's disease (AD). Studies have linked AD to alterations in gut microbiota composition and serum metabolites. In the present study, we examined the alterations in serum metabolome and gut microbiome in APPswe/PS1dE9 (APP/PS1) mice treated with capsaicin. Capsaicin treatments resulted in a significant increase in the abundance of Akkermansia , Faecalibaculum , Unclassified&#95;f&#95;Atopobiaceae , and Gordonibacter and a significant decrease in the abundance of Adlercreutzia , Peptococcaceae , Alistipes , Oscillibacter and Erysipelatoclostridium . Furthermore, the species Akkermansia muciniphila ( A. muciniphila ) was significantly enriched in capsaicin-treated APP/PS1 mice ( p = 0.0002). Serum metabolomic analysis showed that capsaicin-treated APP/PS1 mice had a significant higher level of tryptophan (Trp) metabolism and a significantly lower level of lipid metabolism compared with vehicle-treated mice. Capsaicin altered serum metabolites, including Kynurenine (Kyn), 5-Hydroxy-L-tryptophan (5-HIT), 5-Hydroxyindoleacetic acid (5-HIAA), indoxylsulfuric acid, lysophosphatidyl cholines (LysoPCs), and lysophosphatidyl ethanolamine (LysoPE). Significant correlations were observed between the gut bacteria and serum metabolite. With regard to the increased abundance of A. muciniphila and the ensuing rise in tryptophan metabolites, our data show that capsaicin alters both the gut microbiota and blood metabolites. By altering the gut microbiome and serum metabolome, a diet high in capsaicin may reduce the incidence and development of AD.

Recent reports implicate gut microbiome dysbiosis in the onset and progression of Alzheimer's disease (AD), yet studies involving model animals overwhelmingly omit the microbial perspective. Here, we evaluate longitudinal microbiomes and metabolomes from a popular transgenic mouse model for familial AD (5xfAD). Cecal and fecal samples from 5xfAD and wild-type B6J (WT) mice from 4 to 18 months of age were subjected to shotgun Illumina sequencing. Metabolomics was performed on plasma and feces from a subset of the same animals. Significant genotype, sex, age, and cage-specific differences were observed in the microbiome, with the variance explained by genotype at 4 and 18 months of age rising from 0.9 to 9% and 0.3 to 8% for the cecal and fecal samples, respectively. Bacteria at significantly higher abundances in AD mice include multiple Alistipes spp., two Ligilactobacillus spp., and Lactobacillus sp. P38, while multiple species of Turicibacter , Lactobacillus johnsonii, and Romboutsia ilealis were less abundant. Turicibacter is similarly depleted in people with AD, and members of this genus both consume and induce the production of gut-derived serotonin. Contradicting previous findings in humans, serotonin is significantly more concentrated in the blood of older 5xfAD animals compared to their WT littermates. 5xfAD animals exhibited significantly lower plasma concentrations of carnosine and the lysophospholipid lysoPC a C18:1. Correlations between the microbiome and metabolome were also explored. Taken together, these findings strengthen the link between Turicibacter abundance and AD, provide a basis for further microbiome studies of murine models for AD, and suggest that greater control over animal model microbiomes is needed in AD research. IMPORTANCE Microorganisms residing within the gastrointestinal tract are implicated in the onset and progression of Alzheimer's disease (AD) through the mediation of inflammation, exchange of small-molecules across the blood-brain barrier, and stimulation of the vagus nerve. Unfortunately, most animal models for AD are housed under conditions that do not reflect real-world human microbial exposure and do not sufficiently account for (or meaningfully consider) variations in the microbiome. An improved understanding of AD model animal microbiomes will increase model efficacy and the translatability of research findings into humans. Here, we present the characterization of the microbiome and metabolome of the 5xfAD mouse model, which is one of the most common animal models for familial AD. The manuscript highlights the importance of considering the microbiome in study design and aims to lay the groundwork for future studies involving mouse models for AD.

Although the link between microbial infections and Alzheimer's disease (AD) has been demonstrated in multiple studies, the involvement of pathogens in the development of AD remains unclear. Here, we investigated the frequency of the 10 most commonly cited viral (HSV-1, EBV, HHV-6, HHV-7, and CMV) and bacterial (Chlamydia pneumoniae, Helicobacter pylori, Borrelia burgdorferi, Porphyromonas gingivalis, and Treponema spp.) pathogens in serum, cerebrospinal fluid (CSF) and brain tissues of AD patients. We have used an in-house multiplex PCR kit for simultaneous detection of five bacterial and five viral pathogens in serum and CSF samples from 50 AD patients and 53 healthy controls (CTRL). We observed a significantly higher frequency rate of AD patients who tested positive for Treponema spp. compared to controls (AD: 62.2 %; CTRL: 30.3 %; p-value = 0.007). Furthermore, we confirmed a significantly higher occurrence of cases with two or more simultaneous infections in AD patients compared to controls (AD: 24 %; CTRL 7.5 %; p-value = 0.029). The studied pathogens were detected with comparable frequency in serum and CSF. In contrast, Borrelia burgdorferi, human herpesvirus 7, and human cytomegalovirus were not detected in any of the studied samples. This study provides further evidence of the association between microbial infections and AD and shows that paralleled analysis of multiple sample specimens provides complementary information and is advisable for future studies., Competing Interests: Declaration of competing interest TB, MB and MH works in the company BioVendor. All other authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: This case-control study was designed to compare the composition of the predominant oral bacterial microbiome in Alzheimer's disease (AD) and control group., Subject: A total of 30 adult participants (15 AD and 15 healthy individuals) were entered in this study. The composition of oral bacterial microbiome was examined by quantitative real-time polymerase chain reaction (qPCR) using bacterial 16S rDNA gene. The levels of systemic inflammatory cytokines in both groups were assessed using enzyme-linked immunosorbent assays (ELISA)., Results: The loads of Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia were significantly more abundant in the AD compared to the control group (p < 0.05). Although Aggregatibacter actinomycetemcomitans and Streptococcus mutans were relatively frequent in the AD group, no significance difference was observed in their copy number between two groups. Although the concentrations of IL-1, IL-6, and TNF-α were higher in the AD group, there was a significant difference in their levels between the two groups (p < 0.05). Finally, there was a significant relationship between increased number of pathogenic bacteria in oral microbiome and higher concentration of cytokines in patient's blood., Conclusion: Our knowledge of oral microbiome and its exact association with AD is rather limited; our study showed a significant association between changes in oral microbiome bacteria, increased inflammatory cytokines, and AD., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Alzheimer's disease (AD) is the most common type of dementia. Tau hyperphosphorylation and amyloid β (Aβ) deposition are the key pathological hallmarks of AD. Recent studies have shown that periodontitis is a significant risk factor for AD. The periodontal pathogen Porphyromonas gingivalis and its virulence factors have been shown to initiate and promote the hallmark pathologies and behavioral symptoms of AD. A possible link between Treponema denticola , another main periodontal pathogen, and AD has been reported. However, the role of T. denticola in AD pathogenesis is still unclear, and whether T. denticola and P. gingivalis exert a synergistic effect to promote AD development needs to be further studied. In this study, we investigated whether oral infection with T. denticola caused tau hyperphosphorylation in the hippocampi of mice and explored the underlying mechanisms. Orally administered T. denticola induced alveolar bone resorption, colonized brain tissues, and increased the activity of the phosphokinase GSK3β by activating neuroinflammation in the hippocampus, thus promoting the hyperphosphorylation of the tau protein at Ser396, Thr181, and Thr231 in mice. An in vitro study with BV2 and N2a cell models of T. denticola invasion also verified the role of this pathogen in tau phosphorylation. T. denticola and P. gingivalis were not found to exert a synergistic effect on tau phosphorylation. In summary, these findings provide new insight into the important role of T. denticola in AD pathogenesis, providing biological connections between periodontal diseases and AD.