Evidence supportive of a bacterial component in the etiology for Alzheimer's disease and for a temporal-spatial development of a pathogenic microbiome in the brain.

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.

Toll-like receptor 4 and CD11b expressed on microglia coordinate eradication of Candida albicans cerebral mycosis.

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 ß (Aß)-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 Aß-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, Aß, candidalysin, and CD11b.

The role of microbiome-host interactions in the development of Alzheimer´s disease.

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.

Connectivity between Gut Microbiota and Terminal Awakenings in Alzheimer's Disease.

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.

Dietary neoagarotetraose extends lifespan and impedes brain aging in mice via regulation of microbiota-gut-brain axis.

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-ß (Aß) 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.

Bifidobacterium breve HNXY26M4 Attenuates Cognitive Deficits and Neuroinflammation by Regulating the Gut-Brain Axis in APP/PS1 Mice.

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.

Association Between Oral Bacteria and Alzheimer's Disease: A Systematic Review and Meta-Analysis.

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

Correlation between APOE4 gene and gut microbiota in Alzheimer's disease.

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_APOE4, Control_APOE4, AD_non-APOE4, and Control_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_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_APOE4 patients differed from those in control individuals, including decreases in unclassified_g__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_g_Clostridium_sensu_stricto_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_metagenome_g_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_g_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_APOE4 and AD_non-APOE4_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_APOE4_carrier and AD_non-APOE4_carrier individuals.

Longitudinal Analysis of the Microbiome and Metabolome in the 5xfAD Mouse Model of Alzheimer's Disease.

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.

Increased occurrence of Treponema spp. and double-species infections in patients with Alzheimer's disease.

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.

Intestinal Microflora Changes in Patients with Mild Alzheimer's Disease in a Chinese Cohort.

BACKGROUND: Understanding the relationship between Alzheimer's disease (AD) and intestinal flora is still a major scientific topic that continues to advance. OBJECTIVE: To determine characterized changes in the intestinal microbe community of patients with mild AD. METHODS: Comparison of the 16S ribosomal RNA (rRNA) high-throughput sequencing data was obtained from the Illumina MiSeq platform of fecal microorganisms of the patients and healthy controls (HC) which were selected from cohabiting caregivers of AD patients to exclude environmental and dietary factors. RESULTS: We found that the abundance of several bacteria taxa in AD patients was different from that in HC at the genus level, such as Anaerostipes, Mitsuokella, Prevotella, Bosea, Fusobacterium, Anaerotruncus, Clostridium, and Coprobacillus. Interestingly, the abundance of Akkermansia, an emerging probiotic, increased significantly in the AD group compared with that in the HC group. Meanwhile, the quantity of traditional probiotic Bifidobacteria of the AD group also rose. CONCLUSION: These alterations in fecal microbiome of the AD group indicate that patients with mild AD have unique gut microbial characteristics. These specific AD-associated intestinal microbes could serve as novel potential targets for early intervention of AD.

Association of perturbation of oral bacterial with incident of Alzheimer's disease: A pilot study.

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.

[Relationship between Oral Microbiota and Alzheimer's Disease].

Alzheimer's disease (AD) is a common neurodegenerative disease. In an aging society, the high prevalence of AD and the low quality of life of AD patients create serious problems for individuals, families and the society. However, the etiology and pathogenesis of AD are still not fully understood. Age, genetics, environment and other factors are all relevant to AD, and treatment has not achieved satisfactory results. Recent studies have found that oral dysbiosis is closely related to the pathogenesis of AD, and that oral bacterial infection may be one of the causes of AD. Oral cavity is the largest microbial ecosystem of human body, and its homeostasis is critical to health. Bacterial infections caused by oral dysbiosis can directly and indirectly induce the metabolic imbalance of amyloid ß-protein (Aß) in the brain and the hyperphosphorylation of Tau protein. Then, the precipitation forms senile plaques and neurofibrillary tangles (NFTs) that damage neurons. Based on the latest research findings, we herein discussed the correlation between oral microbiota and the pathogenesis of AD and the mechanisms involved, as well as the pathogenic mechanism of main oral bacteria. In addition, we explored the potential application prospects of oral microbiota-targeted therapy.

The Oral and Fecal Microbiota in a Canadian Cohort of Alzheimer's Disease.

BACKGROUND: Despite decades of research, our understanding of Alzheimer's disease (AD) etiology remains incomplete. In recent years, appreciation has grown for potential roles for the microbiota in shaping neurological health. OBJECTIVE: This study aimed to examine associations between the microbiota and AD in a human cross-sectional cohort. METHODS: Forty-five AD patients and 54 matched controls were recruited in Vancouver, Canada. Fecal and oral samples underwent 16S microbiota sequencing. A wide array of demographic and clinical data were collected. Differences between participant groups were assessed, and associations between microbes and clinical variables were examined within the AD population. RESULTS: The gut microbiota of AD patients displayed lower diversity relative to controls, although taxonomic differences were sparse. In contrast, the AD oral microbiota displayed higher diversity, with several taxonomic differences relative to controls, including a lower abundance of the families Streptococcaceae and Actinomycetaceae, and a higher abundance of Weeksellaceae, among others. The periodontitis-associated oral microbe Porphyromonas gingivalis was 5 times more prevalent among patients. No significant associations between gut or oral microbes and cognition were detected, but several correlations existed between microbes and mood disorders and BMI among patients, including a strong positive correlation between Alphaproteobacteria and depression score. CONCLUSION: The gut microbiota of AD patients was not overtly different from controls, although it displayed lower diversity, an overall marker of microbiota health. The oral microbiota did display marked differences. Cognition was not associated with a microbial signature, but other relevant AD factors including mood and BMI did demonstrate an association.

Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves and contributes to Alzheimer's disease risk.

Chlamydia pneumoniae is a respiratory tract pathogen but can also infect the central nervous system (CNS). Recently, the link between C. pneumoniae CNS infection and late-onset dementia has become increasingly evident. In mice, CNS infection has been shown to occur weeks to months after intranasal inoculation. By isolating live C. pneumoniae from tissues and using immunohistochemistry, we show that C. pneumoniae can infect the olfactory and trigeminal nerves, olfactory bulb and brain within 72 h in mice. C. pneumoniae infection also resulted in dysregulation of key pathways involved in Alzheimer's disease pathogenesis at 7 and 28 days after inoculation. Interestingly, amyloid beta accumulations were also detected adjacent to the C. pneumoniae inclusions in the olfactory system. Furthermore, injury to the nasal epithelium resulted in increased peripheral nerve and olfactory bulb infection, but did not alter general CNS infection. In vitro, C. pneumoniae was able to infect peripheral nerve and CNS glia. In summary, the nerves extending between the nasal cavity and the brain constitute invasion paths by which C. pneumoniae can rapidly invade the CNS likely by surviving in glia and leading to Aß deposition.

Treponema denticola Induces Alzheimer-Like Tau Hyperphosphorylation by Activating Hippocampal Neuroinflammation in Mice.

Alzheimer's disease (AD) is the most common type of dementia. Tau hyperphosphorylation and amyloid ß (Aß) 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 GSK3ß 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.

Gut microbiota in patients with Alzheimer's disease spectrum: a systematic review and meta-analysis.

CONTEXT: Gut dysbiosis has been proposed as one of pathologies in patients with Alzheimer's disease (AD) spectrum. Despite such enthusiasm, the relevant results remain substantially controversial. OBJECTIVE: A systematic review and meta-analysis were performed to investigate the differences of gut microbiota (GM) between patients with AD spectrum (including mild cognitive impairment [MCI] and AD) and healthy controls (HC). DATA SOURCES: PubMed, MEDLINE, Scopus, and Cochrane Library from January 2000 to August 2021. Eligibility criteria for study selection: Observational trials and pre-intervention data of intervention trials that investigated the abundance of GM in patients with AD spectrum and HC. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently identified articles, extracted data, and evaluated the risk of bias. The effect sizes were performed by a random-effect, inverse-variance weighted model. The effects of different countries and of clinical stages on GM abundance were also examined. RESULTS: 11 studies consisting of 378 HC and 427 patients with AD spectrum were included in the meta-analysis. Patients with AD, but not MCI, showed significantly reduced GM diversity as compared to HC. We also found more abundance of Proteobacteria, Bifidobacterium and Phascolarctobacterium, but less abundance of Firmicutes, Clostridiaceae, Lachnospiraceae and Rikenellaceae in patients with AD spectrum as compared with HC. The profiles of abundance of Alistipes and Bacteroides in HC and AD spectrum were differentially affected by countries. Finally, when considering clinical stage as a moderator, the comparisons of abundance in Clostridiaceae and Phascolarctobacterium showed large effect sizes, with gradient changes from MCI to AD stage. LIMITATIONS: The inclusion of studies originating only from China and the U.S. was a possible limitation. CONCLUSIONS: Patients with AD spectrum demonstrated altered GM abundance, which was differentially mediated by countries and clinical stages.

Gut Microbiome and Serum Metabolome Profiles of Capsaicin with Cognitive Benefits in APP/PS1 Mice.

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_f_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.

Composition of intestinal flora affects the risk relationship between Alzheimer's disease/Parkinson's disease and cancer.

An increasing number of epidemiological studies have shown that there is a significant inverse relationship between the onset of Alzheimer's disease/Parkinson's disease (AD/PD) and cancer, but the mechanism is still unclear. Considering that intestinal flora can connect them, we tried to explain this phenomenon from the intestinal flora. This review briefly introduced the relationship among AD/PD, cancer, and intestinal flora, studied metabolites or components of the intestinal flora and the role of intestinal barriers and intestinal hormones in AD/PD and cancer. After screening, a part of the flora capable of participating in the occurrence processes of the three diseases at the same time was obtained, the abundance changes of the special flora in AD/PD and various types of cancers were summarized, and they were classified according to the flora function and abundance, which in turn innovatively and reasonably explained the fact that AD/PD and cancer showed certain antagonism in epidemiological statistics from the perspective of intestinal flora. This review also proposed that viewing the risk relationship between diseases from the perspective of intestinal flora may provide new research ideas for the treatment of fecal microbiota transplantation (FMT) and related diseases.

Borrelia burgdorferi Co-Localizing with Amyloid Markers in Alzheimer's Disease Brain Tissues.

BACKGROUND: Infections by bacterial or viral agents have been hypothesized to influence the etiology of neurodegenerative diseases. OBJECTIVE: This study examined the potential presence of Borrelia burgdorferi spirochete, the causative agent of Lyme disease, in brain autopsy tissue of patients diagnosed with either Alzheimer's (AD) or Parkinson's diseases. METHODS: Brain tissue sections from patients with age-matched controls were evaluated for antigen and DNA presence of B. burgdorferi using various methods. Positive Borrelia structures were evaluated for co-localization with biofilm and AD markers such as amyloid and phospho-tau (p-Tau) using immunohistochemical methods. RESULTS: The results showed the presence of B. burgdorferi antigen and DNA in patients with AD pathology and among those, one of them was previously diagnosed with Lyme disease. Interestingly, a significant number of Borrelia-positive aggregates with a known biofilm marker, alginate, were found along with the spirochetal structures. Our immunohistochemical data also showed that Borrelia-positive aggregates co-localized with amyloid and phospho-tau markers. To further prove the potential relationship of B. burgdorferi and amyloids, we infected two mammalian cell lines with B. burgdorferi which resulted in a significant increase in the expression of amyloid-ß and p-Tau proteins in both cells lines post-infection. CONCLUSION: These results indicate that B. burgdorferi can be found in AD brain tissues, not just in spirochete but a known antibiotics resistant biofilm form, and its co-localized amyloid markers. In summary, this study provides evidence for a likely association between B. burgdorferi infections and biofilm formation, AD pathology, and chronic neurodegenerative diseases.