Ebook: Handbook of Microbiome and Gut-Brain-Axis in Alzheimer’s Disease

Current State of Gut Microbiota: Where We Have Been, Where We Are Going

Giulio Maria Pasinetti, MD, PhD

Research in the gut microbiota field has been rapidly evolving over the past decade. Despite being confined to the gastrointestinal tract, the impact of the gut microbiota biology on human physiology is extremely broad. The gut microbiota itself forms a powerful endocrine organ with a unique metabolome that supplements the host’s biochemistry beyond what it is designed to provide for itself: a perfect symbiotic relationship! These metabolites, and the breadth of gut microbiota cells themselves, interact with, and/or transverse the protective gut epithelial barrier influencing several physiological systems including the immune system, metabolism, neurological signaling and perhaps the most unexpectedly, the brain, giving rise to the gut-brain-axis [1,2].

While microbiota is referred as all the microorganisms found in an environment, including bacteria or viruses, microbiome is here referred as the collection of genomes of the microorganisms found in a particular environment (i.e., gut or oral microbiota). In addition to the intrinsic heterogeneity in microbiota composition among each person, microbiome diversity also plays a major factor in microbiota heterogeneity. Indeed, microbiota and the microbiome in the gut can be radically different than oral, skin, eye, etc. Based on this, we believe this Handbook collection fully addresses the complex role of the microbiota and its microbiome heterogeneity and will bring to discussion novel approaches in Alzheimer’s disease (AD) leveraging, for example, the intervention of prebiotic, probiotic, and synbiotic supplementations. In this regard, we have chosen to discuss the influence of the gut and oral microbiota on the immune inflammatory signals including cytokines, neuroendocrine hormones, bacterial components, neuroactive molecules, or microbial metabolites among others. Given that the microbiome is a critical and often overlooked aspect of innate immunity, and which plays a role in cognition, the overarching goal of this Handbook is to review and summarize recent and current research of microbiota and microbiome and the far-reaching impacts on cognitive functioning and neurodegeneration, possibly through mechanisms involving immune inflammatory mechanisms. Interventions including probiotic supplementation, fecal microbiota transfer, and supplementation with microbial metabolites are also discussed. We want to point out that certain probiotics have been used not only to study the effects that the gut microbiota has on behavior and cognitive function, but also as potential therapeutics for AD.

Traditionally, the gut microbiota and its impact on biology were studied using surveillant and correlative techniques. The composition of the gut microbiota would be determined in the context of a disease state and related to a selection of biological markers such as cytokines, gene expression, or a behavioral output. Causality would be established by using germ-free mice or strong antibiotic treatment where the absence of a gut microbiota would create behavioral or biochemical changes [3,4]. While these seminal studies were absolutely essential to drive our current understanding of the breadth of the gut microbiota’s action through the host’s physiology, research moving forward must expand and become more sophisticated to address causal mechanisms and direct interactions such that the gut microbiota can be leveraged upon to develop useful therapeutic interventions.

This is especially true with studies of the gut-brain-axis. Current research seems to have reached a standstill with the climate focusing on behavioral correlations and general influences of the broad environmental changes of the gut microbiota. Studies using fecal transplants surmise that pathological neurological changes can be transferred into naive mice with a fecal transplant [5] and could even be used as a therapeutic intervention for Parkinson’s disease [6]. But the questions remain regarding how and why this works? One study by Bravo et al. eloquently showed that Lactobacillus rhamnosus can innervate the vagus nerve to influence emotional behavioral and GABA expression [7], which demonstrates that causal mechanisms exist—we just need to find them.

Translational research from mice to humans also forms a barrier to pushing the boundaries of gut microbiota research, which requires the creativity and innovation of the current generation of researchers. Studying artificial systems like heavy antibiotic treatment and germ-free animals does not have translatable potential to human studies as these are artificial environments. Studies understanding the causality of the gut microbiota need to use current tools but must also evolve to develop new tools to gain insight into the causal mechanisms linking the gut microbiota and its metabolome to human disease. Especially for studies of probiotic, prebiotic, or synbiotic interventions, translation to human utility requires pharmacokinetic understanding of metabolite production and the dissection of common molecular pathways.

Collectively, this Handbook contains four broad sections, each covering a pertinent research area pertaining to the overall literature on the gut-brain-axis and its relationship with cognitive functioning and AD. We hope that future research will be able to cohesively build upon the current foundation of rigorous studies by developing innovative and novel approaches that will progress our understanding of these complex, multi-variable biological mechanisms, particularly in the context of cognitive functioning and AD.

REFERENCES

[1] Westfall S, Pasinetti GM (2019) The gut microbiota links dietary polyphenols with management of psychiatric mood disorders. Front Neurosci 13, 1196.

[2] Westfall S, Iqbal U, Sebastian M, Pasinetti GM (2019) Gut microbiota mediated allostasis prevents stress-induced neuroinflammatory risk factors of Alzheimer’s disease. Prog Mol Biol Transl Sci 168, 147-181.

[3] Neufeld KM, Kang N, Bienenstock J, Foster JA (2011) Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil 23, 255-264, e119.

[4] Luczynski P, McVey Neufeld KA, Oriach CS, Clarke G, Dinan TG, Cryan JF (2016) Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior. Int J Neuropsychopharmacol 19, pyw020.

[5] Li N, Wang Q, Wang Y, Sun A, Lin Y, Jin Y, Li X (2019) Fecal microbiota transplantation from chronic unpredictable mild stress mice donors affects anxiety-like and depression-like behavior in recipient mice via the gut microbiota-inflammation-brain axis. Stress 22, 592-602.

[6] Sun MF, Zhu YL, Zhou ZL, Jia XB, Xu YD, Yang Q, Cui C, Shen YQ (2018) Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson’s disease mice: Gut microbiota, glial reaction and TLR4/TNF-α signaling pathway. Brain Behav Immun 70, 48-60.

[7] Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, Bienenstock J, Cryan JF (2011) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A 108, 16050-16055.

Alzheimer’s disease (AD)-associated sequence (ADAS) of cultured fecal bacteria was discovered in human gut targeted screening. This study provides important information to expand our current understanding of the structure/activity relationship of ADAS and putative inhibitors/activators that are potentially involved in ADAS appearance/disappearance. The NCBI database analysis revealed that ADAS presents at a large proportion in American Indian Oklahoman (C&A) with a high prevalence of obesity/diabetes and in colorectal cancer (CRC) patients from the US and China. An Oklahoman non-native group (NNI) showed no ADAS. Comparison of two large US populations reveals that ADAS is more frequent in individuals aged ≥66 and in females. Prevalence and levels of fecal metabolites are altered in the C&A and CRC groups versus controls. Biogenic amines (histamine, tryptamine, tyramine, phenylethylamine, cadaverine, putrescine, agmatine, spermidine) that present in food and are produced by gut microbiota are significantly higher in C&A (e.g., histamine/histidine 95-fold) versus NNI (histamine/histidine 16-fold). The majority of these bio-amines are cytotoxic at concentrations found in food. Inositol phosphate signaling implicated in AD is altered in C&A and CRC. Tryptamine stimulated accumulation of inositol phosphate. The seizure-eliciting tryptamine induced cytoplasmic vacuolization and vesiculation with cell fragmentation. Present additions of ADAS-carriers at different ages including infants led to an ADAS-comprising human sample size of 2,830 from 27 studies from four continents (North America, Australia, Asia, Europe). Levels of food-derived monoamine oxidase inhibitors and anti-bacterial compounds, the potential modulators of ADAS-bacteria growth and biogenic amine production, were altered in C&A versus NNI. ADAS is attributable to potentially modifiable risk factors of AD associated diseases.

Background:

Dysbiotic microbiota in the gastrointestinal tract promotes and aggravates neurodegenerative disorders. Alzheimer’s disease (AD) has been shown to correlate to dysbiotic bacteria and the immune, metabolic, and endocrine abnormalities associated with abnormal gut-brain-axis signaling. Recent reports also indicate that brain dysbacteriosis may play a role in AD pathogenesis.

Objective:

To evaluate the presence and differences of brain-region dependent microbiomes in control and AD subjects and the contribution of study bias.

Methods:

Two independent cohorts of postmortem AD brain samples were collected from separate locations, processed with different extraction protocols and investigated for the presence of bacterial DNA indicative of a brain microbiome with V4 16S next generation sequencing.

Results:

In both cohorts, few differences between the control and AD groups were observed in terms of alpha and beta diversities, phyla and genera proportions. Independent of study in both AD and control subjects the most abundant phyla were Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. Variations in beta diversity between hippocampal and cerebellum samples were observed indicating an impact of brain region on the presence of microbial DNA. Importantly, differences in alpha and beta diversities between the two independent cohorts were found indicating a significant cohort- and processing-dependent effect on the microbiome. Finally, there were cohort-specific correlations between the gut microbiome and subject demographics indicate that postmortem interval may have a significant impact on brain microbiome determination.

Conclusion:

Regardless of the study bias, this study concludes that bacterial DNA can be isolated from the human brain suggesting that a brain microbiome may exist; however, more studies are required to understand the variation in AD.

Alzheimer’s disease (AD) is a neurodegenerative process characterized by loss of neurons in the hippocampus and cerebral cortex, leading to progressive cognitive decline. Pathologically, the hallmark of AD is accumulation of “senile” plaques composed of amyloid-β (Aβ) protein surrounding neurons in affected regions. Despite extensive research into AD pathogenesis and therapeutic targets, there remains no breakthroughs in its management. In recent years, there has been a spark of interest in the connection between the brain and gastrointestinal tract, referred to as the brain-gut axis, and its potential implications for both metabolic and neurologic disease. Moreover, the gastrointestinal flora, referred to as the microbiome, appears to exert significant influence over the brain-gut axis. With the need for expanded horizons in understanding and treating AD, many have turned to the brain-gut-microbiome axis for answers. Here we provide a review of the brain-gut-microbiome axis and discuss the evidence supporting alterations of the axis in the pathogenesis of AD. Specifically, we highlight the role for the microbiome in disruption of Aβ metabolism/clearance, increased permeability of the blood-brain barrier and modulation of the neuroinflammatory response, and inhibition of hippocampal neurogenesis. The majority of the above described findings are the result of excellent, albeit basic and pre-clinical studies. Therefore, we conclude with a brief description of documented clinical support for brain-gut-microbiome axis alteration in AD, including potential microbiome-based therapeutics for AD. Collectively, these findings suggest that the brain-gut-microbiome axis may be a “lost link” in understanding and treating AD and call for future work.

Alzheimer’s disease (AD) is one of the most common forms of dementia, which cannot be cured at the moment. Therefore, researchers also look for the alternative approaches to its treatment. It is suggested that changes in human gut microbiome mediated by exercise could influence the development and progression of AD and a new term “muscle-gut-brain axis” is introduced. There is much evidence to support this assumption. The gut microbiology is closely related to a wide range of diseases of the nervous system and therefore any negative qualitative and quantitative changes in the composition of the gut microbiota can potentially contribute to the pathophysiology of AD. Research shows that the treatment of intestinal dysbiosis with probiotics/synbiotics/eubiotics can prevent or alleviate the symptoms of these chronic neurological diseases. Studies also point to the positive effects of movement on the health of seniors. A positive correlation can be found between cognitive functions and physical stress, both in the elderly and in AD patients. Even short-term interventions with a relatively low frequency seem to produce positive results, while physical activities can be performed by using relatively simple and cost-effective means. In addition, physical activity can significantly modulate gut microbiome. Thus, it can be concluded that physical activity in humans seems to correlate with gut microbiome, which can prevent the incidence and development of AD.

Background:

Metagenomic data support an association between certain bacterial strains and Alzheimer’s disease (AD), but their functional dynamics remain elusive.

Objective:

To investigate the association between amyloid pathology, bacterial products such as lipopolysaccharide (LPS) and short chain fatty acids (SCFAs: acetate, valerate, butyrate), inflammatory mediators, and markers of endothelial dysfunction in AD.

Methods:

Eighty-nine older persons with cognitive performance from normal to dementia underwent florbetapir amyloid PET and blood collection. Brain amyloidosis was measured with standardized uptake value ratio versus cerebellum. Blood levels of LPS were measured by ELISA, SCFAs by mass spectrometry, cytokines by using real-time PCR, and biomarkers of endothelial dysfunction by flow cytometry. We investigated the association between the variables listed above with Spearman’s rank test.

Results:

Amyloid SUVR uptake was positively associated with blood LPS (rho ≥ 0.32, p ≤ 0.006), acetate and valerate (rho ≥ 0.45, p < 0.001), pro-inflammatory cytokines (rho ≥ 0.25, p ≤ 0.012), and biomarkers of endothelial dysfunction (rho ≥ 0.25, p ≤ 0.042). In contrast, it was negatively correlated with butyrate (rho ≤ –0.42, p ≤ 0.020) and the anti-inflammatory cytokine IL10 (rho ≤ −0.26, p ≤ 0.009). Endothelial dysfunction was positively associated with pro-inflammatory cytokines, acetate and valerate(rho ≥ 0.25, p ≤ 0.045)and negatively with butyrate and IL10 levels (rho ≤ −0.25, p ≤ 0.038).

Conclusion:

We report a novel association between gut microbiota-related products and systemic inflammation with brain amyloidosis via endothelial dysfunction, suggesting that SCFAs and LPS represent candidate pathophysiologic links between the gut microbiota and AD pathology.

Progressive neurodegenerative diseases represent some of the largest growing treatment challenges for public health in modern society. These diseases mainly progress due to aging and are driven by microglial surveillance and activation in response to changes occurring in the aging brain. The lack of efficacious treatment options for Alzheimer’s disease (AD), as the focus of this review, and other neurodegenerative disorders has encouraged new approaches to address neuroinflammation for potential treatments. Here we will focus on the increasing evidence that dysbiosis of the gut microbiome is characterized by inflammation that may carry over to the central nervous system and into the brain. Neuroinflammation is the common thread associated with neurodegenerative diseases, but it is yet unknown at what point and how innate immune function turns pathogenic for an individual. This review will address extensive efforts to identify constituents of the gut microbiome and their neuroactive metabolites as a peripheral path to treatment. This approach is still in its infancy in substantive clinical trials and requires thorough human studies to elucidate the metabolic microbiome profile to design appropriate treatment strategies for early stages of neurodegenerative disease. We view that in order to address neurodegenerative mechanisms of the gut, microbiome and metabolite profiles must be determined to pre-screen AD subjects prior to the design of specific, chronic titrations of gut microbiota with low-dose antibiotics. This represents an exciting treatment strategy designed to balance inflammatory microglial involvement in disease progression with an individual’s manifestation of AD as influenced by a coercive inflammatory gut.

Accumulating evidence show that the gut microbiota is deeply involved not only in host nutrient metabolism but also in immune function, endocrine regulation, and chronic disease. In neurodegenerative conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis, the gut-brain axis, the bidirectional interaction between the brain and the gut, provides new route of pathological spread and potential therapeutic targets. Although studies of gut microbiota have been conducted mainly in mice, mammalian gut microbiota is highly diverse, complex, and sensitive to environmental changes. Drosophila melanogaster, a fruit fly, has many advantages as a laboratory animal: short life cycle, numerous and genetically homogenous offspring, less ethical concerns, availability of many genetic models, and low maintenance costs. Drosophila has a simpler gut microbiota than mammals and can be made to remain sterile or to have standardized gut microbiota by simple established methods. Research on the microbiota of Drosophila has revealed new molecules that regulate the brain-gut axis, and it has been shown that dysbiosis of the fly microbiota worsens lifespan, motor function, and neurodegeneration in AD and PD models. The results shown in fly studies represents a fundamental part of the immune and proteomic process involving gut-microbiota interactions that are highly conserved. Even though the fly’s gut microbiota are not simple mimics of humans, flies are a valuable system to learn the molecular mechanisms of how the gut microbiota affect host health and behavior.

Background:

Substantial evidence from recent research suggests an influential and underappreciated force in Alzheimer’s disease (AD) pathogenesis: the pathological signals originate from outside the brain. Pathogenic bacteria produce amyloid-like proteins “curli” that form biofilms and show functional similarities to human amyloid-β (Aβ). These proteins may contribute to neurological disease progression via signaling cascade from the gut to the brain.

Objective:

We propose that curli causes neuroendocrine activation from the gut to brain that promotes central Aβ pathology.

Methods:

PGP9.5 and TLR2 levels in response to curli in the lumen of Tg2576 AD mice were analyzed by immunohisto-chemical and qRT-PCR analysis. Western blot and human 3D in vitro enteroids culture systems were also used. 16S rRNA gene sequencing was used to investigate bacterial dysbiosis.

Results:

We found significant increase in bacterial-amyloid curli with elevated TLR2 at the mRNA level in the pre- and symptomatic Tg-AD gut compared to littermate WT controls. This data associates with increased gram-positive bacterial colonization in the ileum of the symptomatic AD mice. We found fundamental evidence for vagus nerve activation in response to bacterial curli. Neuroendocrine marker PGP9.5 was significantly elevated in the gut epithelium of symptomatic AD mice, and this was colocalized with increased TLR2 expression. Enteroids, 3D-human ileal mini-gut monolayer in vitro model system also revealed increase levels of TLR2 upon stimulation with purified bacterial curli fibrils.

Conclusion:

These findings reveal the importance of pathological changes within the gut-vagus-brain signaling in response to luminal bacterial amyloid that might play a vital role in central Aβ pathogenesis seen in the AD brain.

Given the complex bidirectional communication system that exists between the gut microbiome and the brain, there is growing interest in the gut microbiome as a novel and potentially modifiable risk factor for Alzheimer’s disease (AD). Gut dysbiosis has been implicated in the pathogenesis and progression of AD by initiating and prolonging neuroinflammatory processes. The metabolites of gut microbiota appear to be critical in the mechanism of the gut-brain axis. Gut microbiota metabolites, such as trimethylamine-n-oxide, lipopolysaccharide, and short chain fatty acids, are suggested to mediate systemic inflammation and intracerebral amyloidosis via endothelial dysfunction. Emerging data suggest that the fungal microbiota (mycobiome) may also influence AD pathology. Importantly, 60% of variation in the gut microbiome is attributable to diet, therefore modulating the gut microbiome through dietary means could be an effective approach to reduce AD risk. Given that people do not eat isolated nutrients and instead consume a diverse range of foods and combinations of nutrients that are likely to be interactive, studying the effects of whole diets provides the opportunity to account for the interactions between different nutrients. Thus, dietary patterns may be more predictive of a real-life effect on gut microbiome and AD risk than foods or nutrients in isolation. Accumulating evidence from experimental and animal studies also show potential effects of gut microbiome on AD pathogenesis. However, data from human dietary interventions are lacking. Well-designed intervention studies are needed in diverse populations to determine the influence of diet on gut microbiome and inform the development of effective dietary strategies for prevention of AD.

The gut microbiota comprises a complex community of microorganism species that resides in our gastrointestinal ecosystem and whose alterations influence not only various gut disorders but also central nervous system disorders such as Alzheimer’s disease (AD). AD, the most common form of dementia, is a neurodegenerative disorder associated with impaired cognition and cerebral accumulation of amyloid-β peptides (Aβ). Most notably, the microbiota-gut-brain axis is a bidirectional communication system that is not fully understood, but includes neural, immune, endocrine, and metabolic pathways. Studies in germ-free animals and in animals exposed to pathogenic microbial infections, antibiotics, probiotics, or fecal microbiota transplantation suggest a role for the gut microbiota in host cognition or AD-related pathogenesis. The increased permeability of the gut and blood-brain barrier induced by microbiota dysbiosis may mediate or affect AD pathogenesis and other neurodegenerative disorders, especially those associated with aging. In addition, bacteria populating the gut microbiota can secrete large amounts of amyloids and lipopolysaccharides, which might contribute to the modulation of signaling pathways and the production of proinflammatory cytokines associated with the pathogenesis of AD. Moreover, imbalances in the gut microbiota can induce inflammation that is associated with the pathogenesis of obesity, type 2 diabetes mellitus, and AD. The purpose of this review is to summarize and discuss the current findings that may elucidate the role of the gut microbiota in the development of AD. Understanding the underlying mechanisms may provide new insights into novel therapeutic strategies for AD.

A growing body of experimental data suggests that microbes in the gut influence behavior and can alter brain physiology and neurochemistry. Although promising, researchers are only starting to understand the potential of the gut microbiota for use in neurological disease. Recent evidence demonstrated that gastrointestinal activities are linked to mood disorders such as anxiety, depression, and most recently, cognitive functions in age-related neurodegenerative disorders. Studies from our group and others are uncovering new evidence suggesting that the gut microbiota plays a crucial role in the metabolism and bioavailability of certain dietary compounds and synthetic drugs. Based on this evidence, this review article will discuss the implications of the gut microbiota in mechanisms of bioavailability and biotransformation with an emphasis on dietary polyphenol compounds. This will be followed by a survey of ongoing innovative research identifying the ability of individual gut bacteria to enhance the bioavailability of gut-derived, brain-penetrating, bioactive polyphenol metabolites that ultimately influence mechanisms associated with the promotion of resilience against psychological and cognitive impairment in response to stress. Lastly, current research initiatives aimed at promoting the generation of brain bioactive polyphenol metabolites by specialized gut microbes will be discussed, specifically the use of gnotobiotic mice to develop bioengineered second generation probiotics. We propose that leveraging the gut microbial ecosystem to generate brain targeted bioactive metabolites from dietary polyphenols can attenuate lifestyle risk factors and promote resilience against age-related cognitive decline.

Gut microbiota plays a crucial role in human health and disease. The alterations in the composition of gut microbiota may cause the onset of certain human pathologies. One of these is Alzheimer’s disease (AD). High-fat diets, administration of antibiotics, lack of probiotics and/or prebiotics in diet increase the risk of AD. On the other hand, modulation of the composition of gut microbiota may decrease the risk of AD and be able to slow down the progression of AD.

Alzheimer’s disease (AD) is a neurodegenerative condition affecting millions of people worldwide. It is associated with cerebral amyloid-β (Aβ) plaque deposition in the brain, synaptic disconnection, and subsequent progressive neuronal death. Although considerable progress has been made to elucidate the pathogenesis of AD, the specific causes of the disease remain highly unknown. Recent research has suggested a potential association between certain infectious diseases and dementia, either directly due to bacterial brain invasion and toxin production, or indirectly by modulating the immune response. Therefore, in the present review we focus on the emerging issues of bacterial infection and AD, including the existence of antimicrobial peptides having pore-forming properties that act in a similar way to pores formed by Aβ in a variety of cell membranes. Special focus is placed on oral bacteria and biofilms, and on the potential mechanisms associating bacterial infection and toxin production in AD. The role of bacterial outer membrane vesicles on the transport and delivery of toxins as well as porins to the brain is also discussed. Aβ has shown to possess antimicrobial activity against several bacteria, and therefore could be upregulated as a response to bacteria and bacterial toxins in the brain. Although further research is needed, we believe that the control of biofilm-mediated diseases could be an important potential prevention mechanism for AD development.

Emerging evidence suggests that gut microbiota dysbiosis plays a role in neurodegenerative disorders. However, whether the composition and diversity of the gut microbiota are altered in tauopathies remains largely unknown. This study was aimed to examine the diversity and composition of the gut microbiota in tauopathies, as well as the correlation with pathological changes in the brain. We collected fecal samples from 32 P301L tau transgenic mice and 32 age- and gender-matched littermate mice at different ages. The 16S ribosomal RNA sequencing technique was used to analyze the microbiota composition in feces. Brain tau pathology levels were measured by immunohistochemistry. The diversity and composition of the gut microbiota significantly changed with aging. At the phylum level, the relative abundance of Bacteroidetes was increased, while Firmicutes were decreased in P301L mice compared with that in Wt mice after 3 months of age. In addition, Actinobacteria was decreased in P301L mice at 3 and 6 months of age, meanwhile Tenericutes was decreased in P301L mice at 10 months of age. Moreover, several specific macrobiota were highly associated with the levels of AT8-tau or pT231-tau protein in the brain. Our findings suggest that gut microbiota changed with aging, as well as in the tauopathy mice model. Modulation of the gut microbiota may be a potential strategy for treatment of tauopathy.

Recent investigations have demonstrated an important role of gut microbiota (GM) in the pathogenesis of Alzheimer’s disease (AD). GM modulates a host’s health and disease by production of several substances, including lipopolysaccharides (LPS) and short-chain fatty acids (SCFAs), among others. Diet can modify the composition and diversity of GM, and ingestion of a healthy diet has been suggested to lower the risk to develop AD. We have previously shown that bioactive food (BF) ingestion can abate neuroinflammation and oxidative stress and improve cognition in obese rats, effects associated with GM composition. Therefore, BF can impact the gut-brain axis and improved behavior. In this study, we aim to explore if inclusion of BF in the diet may impact central pathological markers of AD by modulation of the GM. Triple transgenic 3xTg-AD (TG) female mice were fed a combination of dried nopal, soy, chia oil, and turmeric for 7 months. We found that BF ingestion improved cognition and reduced Aβ aggregates and tau hyperphosphorylation. In addition, BF decreased MDA levels, astrocyte and microglial activation, PSD-95, synaptophysin, GluR1 and ARC protein levels in TG mice. Furthermore, TG mice fed BF showed increased levels of pGSK-3β. GM analysis revealed that pro-inflammatory bacteria were more abundant in TG mice compared to wild-type, while BF ingestion was able to restore the GM’s composition, LPS, and propionate levels to control values. Therefore, the neuroprotective effects of BF may be mediated, in part, by modulation of GM and the release of neurotoxic substances that alter brain function.

Earlier we reported induction of neurotoxicity and neurodegeneration by tryptophan metabolites that link the metabolic alterations to Alzheimer’s disease (AD). Tryptophan is a product of the Shikimate pathway (SP). Human cells lack SP, which is found in human gut bacteria exclusively using SP to produce aromatic amino acids (AAA). This study is a first attempt toward gene-targeted analysis of human gut microbiota in AD fecal samples. The oligonucleotide primers newly-designed for this work target SP-AAA in environmental bacteria associated with human activity. Using polymerase chain reaction (PCR), we found unique gut bacterial sequence in most AD patients (18 of 20), albeit rarely in controls (1 of 13). Cloning and sequencing AD-associated PCR products (ADPP) enables identification of Na(+)-transporting NADH: Ubiquinone reductase (NQR) in Clostridium sp. The ADPP of unrelated AD patients possess near identical sequences. NQR substrate, ubiquinone is a SP product and human neuroprotectant. A defici in ubiquinone has been determined in a number of neuromuscular and neurodegenerative disorders. Antibacterial therapy prompted an ADPP reduction in an ADPP-positive control person who was later diagnosed with AD-dementia. We explored the gut microbiome databases and uncovered a sequence similarity (up to 97%) between ADPP and some healthy individuals from different geographical locations. Importantly, our main findin of the significan difference in the gut microbial genotypes between the AD and control human populations is a breakthrough.

Recently, the concept of the brain-gut-microbiota (BGM) axis disturbances in the pathogenesis of Alzheimer’s disease (AD) has been receiving growing attention. At the same time, accumulating data revealing complex interplay between bile acids (BAs), gut microbiota, and host metabolism have shed new light on a potential impact of BAs on the BGM axis. The crosstalk between BAs and gut microbiota is based on reciprocal interactions since microbiota determines BA metabolism, while BAs affect gut microbiota composition. Secondary BAs as microbe-derived neuroactive molecules may affect each of three main routes through which interactions within the BGM axis occur including neural, immune, and neuroendocrine pathways. BAs participate in the regulation of multiple gut-derived molecule release since their receptors are expressed on various cells. The presence of BAs and their receptors in the brain implies a direct effect of BAs on the regulation of neurological functions. Experimental and clinical data confirm that disturbances in BA signaling are present in the course of AD. Disturbed ratio of primary to secondary BAs as well as alterations in BA concertation in serum and brain samples have been reported. An age-related shift in the gut microbiota composition associated with its decreased diversity and stability observed in AD patients may significantly affect BA metabolism and signaling. Given recent evidence on BA neuroprotective and anti-inflammatory effects, new therapeutic targets have been explored including gut microbiota modulation by probiotics and dietary interventions, ursodeoxycholic acid supplementation, and use of BA receptor agonists.

Animal studies increasingly indicate that the gut microbiota composition and function can be involved in the pathophysiology and progression of Alzheimer’s disease (AD) at multiple levels. However, few studies have investigated this putative gut-brain axis in human beings, and none of them considered diet as a determinant of intestinal microbiota composition. Epidemiological studies highlight that a high intake of fruit and vegetables, such as that typical of the Mediterranean diet, can modulate AD progression. Thus, nutritional interventions are being increasingly studied as a possible non-pharmacological strategy to slow down the progression of AD. In particular, polyphenols and fibers represent the nutritional compounds with the higher potential of counterbalancing the pathophysiological mechanisms of dementia due to their antioxidant, anti-inflammatory, and anti-apoptotic properties. These actions are mediated by the gut microbiota, that can transform polyphenols and fibers into biologically active compounds including, among others, phenyl-γ-valerolactones, urolithins, butyrate, and other short-chain fatty acids. In this review, the complex mechanisms linking nutrition, gut microbiota composition, and pathophysiology of cognitive decline in AD are discussed, with a particular focus on the role of polyphenols and fibers. The gaps between pre-clinical and clinical studies are particularly emphasized, as well as the urgent need for studies comprehensively evaluating the link between nutrition, microbiome, and clinical aspects of AD.

Alzheimer’s disease (AD), the most common neurodegenerative disorder, is accompanied by cognitive impairment and shows representative pathological features, including senile plaques and neurofibrillary tangles in the brain. Recent evidence suggests that several systemic changes outside the brain are associated with AD and may contribute to its pathogenesis. Among the factors that induce systemic changes in AD, the gut microbiota is increasingly drawing attention. Modulation of gut microbiome, along with continuous attempts to remove pathogenic proteins directly from the brain, is a viable strategy to cure AD. Seeking a holistic understanding of the pathways throughout the body that can affect the pathogenesis, rather than regarding AD solely as a brain disease, may be key to successful therapy. In this review, we focus on the role of the gut microbiota in causing systemic manifestations of AD. The review integrates recently emerging concepts and provides potential mechanisms about the involvement of the gut-brain axis in AD, ranging from gut permeability and inflammation to bacterial translocation and cross-seeding.

Background:

Recent studies had explored that gut microbiota was associated with neurodegenerative diseases (including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS)) through the gut-brain axis, among which metabolic pathways played an important role. However, the underlying causality remained unclear.

Objective:

Our study aimed to evaluate potential causal relationships between gut microbiota, metabolites, and neurodegenerative diseases through Mendelian randomization (MR) approach.

Methods:

We selected genetic variants associated with gut microbiota traits (N = 18,340) and gut microbiota-derived metabolites (N = 7,824) from genome-wide association studies. Summary statistics of neurodegenerative diseases were obtained from IGAP (AD, 17,008 cases; 37,154 controls), IPDGC (PD, 37,688 cases; 141,779 controls), and IALSC (ALS, 20,806 cases; 59,804 controls) respectively.

Results:

Greater abundance of Ruminococcus (OR, 1.245; 95%CI, 1.103–1.405; p = 0.0004) was found significantly related to higher risk of ALS. Besides, our study found suggestive associations of Actinobacteria, Lactobacillaceae, Faecalibacterium, Ruminiclostridium, and Lachnoclostridium with AD, of Lentisphaerae, Lentisphaeria, Oxalobacteraceae, Victivallales, Bacillales, Eubacteriumhalliigroup, Anaerostipes, and Clostridiumsensustricto1 with PD, and of Lachnospira, Fusicatenibacter, Catenibacterium, and Ruminococcusgnavusgroup with ALS. Our study also revealed suggestive associations between 12 gut microbiome-dependent metabolites and neurodegenerative diseases. Glutamine was related to lower risk of AD. For the serotonin pathway, serotonin was found as a protective factor of PD, while kynurenine as a risk factor for ALS.

Conclusion:

Our study firstly applied a two-sample MR approach to detect causal relationships among gut microbiota, gut metabolites, and neurodegenerative diseases. Our findings may provide new targets for treatments and may offer valuable insights for further studies on the underlying mechanisms.

Background:

In recent years, scientific research on the gut microbiota and their relationship with some diseases, including neurological ones, has notably increased. As a result of these investigations, the so-called gut-brain axis arises. Despite its influence on the evolution and development of cognitive impairment, the gut-brain axis is little defined and demonstrated.

Objective:

To provide the best scientific evidence available on the relationship between the gut microbiota and Alzheimer’s disease.

Method:

Systematic and narrative review of the information generated in the last 5 years in national and international databases, in English and Spanish.

Results:

Eight observational studies were selected, carried out in humans and, therefore, suitable for inclusion in this review.

Conclusion:

The results of these studies support the hypothesis that there is a relationship between the gut microbiota and cognitive disorders through the gut-brain axis. However, today, there is a substantial lack of human studies, especially clinical trials, which makes it difficult to formulate clinical recommendations on this topic.