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Journal ArticleDOI: 10.1016/J.PNPBP.2020.110112

Emerging role of gut microbiota in modulation of neuroinflammation and neurodegeneration with emphasis on Alzheimer's disease.

02 Mar 2021-Progress in Neuro-psychopharmacology & Biological Psychiatry (Elsevier)-Vol. 106, pp 110112
Abstract: Alzheimer's disease (AD) is a complex multifactorial disease involving chronic neuroinflammation and neurodegeneration. It has been recently recognized that gut microbiota interacts with the brain, and it is termed as microbiota-gut-brain axis. Modulation of this axis has been recently reported to affect the pathogenesis of neurodegenerative diseases, such as AD. Gut microbiota has a pivotal role in regulating multiple neuro-chemical pathways through the highly interconnected gut-brain axis. Recent emerging evidences have highlighted that the intestinal microflora takes part in bidirectional communication between the gut and the brain. Due to this, the researchers have suggested that human gut microflora may even act as the "second brain" and may be responsible for neurodegenerative disorders like Alzheimer's disease. Dysbiosis of gut microbiota can induce increased intestinal permeability and systemic inflammation. This may lead to the development of AD pathologies and cognitive impairment via the neural, immune, endocrine, and metabolic pathways. Thus, the modulation of gut microbiota through personalized diet, oral bacteriotherapy may lead to alteration of gut microbiota their products including amyloid protein. It has been demonstrated that modulation of the gut microbiota induces beneficial effects on neuronal pathways consequently leading to delay the progression of Alzheimer's disease. Thus, this approach may provide a novel therapeutic option for treatment of AD.

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Topics: Dysbiosis (61%), Gut flora (58%), Intestinal permeability (57%) ... read more

22 results found

Open accessJournal ArticleDOI: 10.3390/IJMS21228751
Abstract: Alzheimer's disease (AD), considered the most common type of dementia, is characterized by a progressive loss of memory, visuospatial, language and complex cognitive abilities. In addition, patients often show comorbid depression and aggressiveness. Aging is the major factor contributing to AD; however, the initial cause that triggers the disease is yet unknown. Scientific evidence demonstrates that AD, especially the late onset of AD, is not the result of a single event, but rather it appears because of a combination of risk elements with the lack of protective ones. A major risk factor underlying the disease is neuroinflammation, which can be activated by different situations, including chronic pathogenic infections, prolonged stress and metabolic syndrome. Consequently, many therapeutic strategies against AD have been designed to reduce neuro-inflammation, with very promising results improving cognitive function in preclinical models of the disease. The literature is massive; thus, in this review we will revise the translational evidence of these early strategies focusing in anti-diabetic and anti-inflammatory molecules and discuss their therapeutic application in humans. Furthermore, we review the preclinical and clinical data of nutraceutical application against AD symptoms. Finally, we introduce new players underlying neuroinflammation in AD: the activity of the endocannabinoid system and the intestinal microbiota as neuroprotectors. This review highlights the importance of a broad multimodal approach to treat successfully the neuroinflammation underlying AD.

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Topics: Dementia (53%)

10 Citations

Open accessJournal ArticleDOI: 10.3390/BIOM11020262
10 Feb 2021-
Abstract: Alzheimer’s disease (AD) is the most common cause of dementia Epidemiological studies show the association between AD and type 2 diabetes (T2DM), although the mechanisms are not fully understood Dietary habits and lifestyle, that are risk factors in both diseases, strongly modulate gut microbiota composition Also, the brain-gut axis plays a relevant role in AD, diabetes and inflammation, through products of bacterial metabolism, like short-chain fatty acids We provide a comprehensive review of current literature on the relation between dysbiosis, altered inflammatory cytokines profile and microglia in preclinical models of AD, T2DM and models that reproduce both diseases as commonly observed in the clinic Increased proinflammatory cytokines, such as IL-1β and TNF-α, are widely detected Microbiome analysis shows alterations in Actinobacteria, Bacteroidetes or Firmicutes phyla, among others Altered α- and β-diversity is observed in mice depending on genotype, gender and age; therefore, alterations in bacteria taxa highly depend on the models and approaches We also review the use of pre- and probiotic supplements, that by favoring a healthy microbiome ameliorate AD and T2DM pathologies Whereas extensive studies have been carried out, further research would be necessary to fully understand the relation between diet, microbiome and inflammation in AD and T2DM

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Topics: Microbiome (58%), Dysbiosis (56%), Gut flora (55%) ... read more

9 Citations

Open access
01 Jan 2018-
Abstract: BACKGROUND Alzheimer's disease is characterized by amyloid‐beta (Aβ) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aβ, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid. METHODS We conducted a double‐blind, placebo‐controlled, phase 3 trial involving patients with mild dementia due to Alzheimer's disease, defined as a Mini–Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron‐emission tomography or Aβ1‐42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14‐item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS‐cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment). RESULTS A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS‐cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between‐group difference at week 80 (difference, ‐0.80; 95% confidence interval, ‐1.73 to 0.14; P=0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was ‐3.17 in the solanezumab group and ‐3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group. CONCLUSIONS Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer's disease did not significantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3 number, NCT01900665.)

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Topics: Solanezumab (71%), Dementia (64%)

7 Citations

Journal ArticleDOI: 10.1021/ACS.JAFC.1C00923
Abstract: Today, neurodegenerative diseases have become a remarkable public health challenge due to their direct relation with aging. Accordingly, understanding the molecular and cellular mechanisms occurring in the pathogenesis of them is essential. Both protein aggregations as a result of the ubiquitin-proteasome system (UPS) inefficiency and gut microbiota alternation are the main pathogenic hallmarks. Polyphenols upregulating this system may decrease the developing rate of neurodegenerative diseases. Most of the dietary intake of polyphenols is converted into other microbial metabolites, which have completely different biological properties from the original polyphenols and should be thoroughly investigated. Herein, several prevalent neurodegenerative diseases are pinpointed to explain the role of gut microbiota alternations and the role of molecular changes, especially UPS down-regulation in their pathogenesis. Some of the most important polyphenols found in our diet are explained along with their microbial metabolites in the body.

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Topics: Gut flora (52%)

3 Citations

Open accessJournal ArticleDOI: 10.14336/AD.2021.0122
01 Aug 2021-Aging and Disease
Abstract: Neuroinflammation is a biological process by which the central nervous system responds to stimuli/injuries affecting its homeostasis. So far as this reactive response becomes exacerbated and uncontrolled, it can lead to neurodegeneration, compromising the cognitive and neuropsychiatric domains. Parallelly, modifications in the hypothalamic signaling of neuroprotective hormones linked also to the inflammatory responses of microglia and astrocytes can exacerbate these processes. To complicate the picture, modulations in the gut microbiota (GM) can induce changes in neuroinflammation, altering cognitive and neuropsychiatric functioning. We conducted a web-based search on PubMed. We described studies regarding the cross-talk among microglia and astrocytes in the neuroinflammation processes, along with the role played by the steroid hormones, and how this can reflect on cognitive decline/neurodegeneration, in particular on Alzheimer's Disease (AD) and its neuropsychiatric manifestations. We propose and support the huge literature showing the potentiality of complementary/alternative therapeutic approaches (nutraceuticals) targeting the sustained inflammatory response, the dysregulation of hypothalamic system and the GM composition. NF-κB and Keap1/Nrf2 are the main molecular targets on which a list of nutraceuticals can modulate the altered processes. Since there are some limitations, we propose a new intervention natural treatment in terms of Oxygen-ozone (O2-O3) therapy that could be potentially used for AD pathology. Through a meta-analytic approach, we found a significant modulation of O3 on inflammation-NF-κB/NLRP3 inflammasome/Toll-Like Receptor 4 (TLR4)/Interleukin IL-17α signalling, reducing mRNA (p<0.00001 Odd Ratio (OR)=-5.25 95% CI:-7.04/-3.46) and protein (p<0.00001 OR=-4.85 95%CI:-6.89/-2.81) levels, as well as on Keap1/Nrf2 pathway. Through anti-inflammatory, immune, and steroid hormones modulation and anti-microbial activities, O3 at mild therapeutic concentrations potentiated with nutraceuticals and GM regulators could determine combinatorial effects impacting on cognitive and neurodegenerative domains, neuroinflammation and neuroendocrine signalling, directly or indirectly through the mediation of GM.

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Topics: Neuroinflammation (56%), Cognitive decline (53%), Neuroprotection (52%) ... read more

3 Citations


112 results found

Journal ArticleDOI: 10.1126/SCIENCE.1072994
John Hardy1, Dennis J. Selkoe2Institutions (2)
19 Jul 2002-Science
Abstract: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer9s disease (AD) may be caused by deposition of amyloid β-peptide (Aβ) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Aβ production and Aβ clearance.

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Topics: Amyloid beta (67%), Biochemistry of Alzheimer's disease (66%), Senile plaques (65%) ... read more

11,721 Citations

Open accessJournal ArticleDOI: 10.1126/SCIENCE.1104816
25 Mar 2005-Science
Abstract: The distal human intestine represents an anaerobic bioreactor programmed with an enormous population of bacteria, dominated by relatively few divisions that are highly diverse at the strain/subspecies level. This microbiota and its collective genomes (microbiome) provide us with genetic and metabolic attributes we have not been required to evolve on our own, including the ability to harvest otherwise inaccessible nutrients. New studies are revealing how the gut microbiota has coevolved with us and how it manipulates and complements our biology in ways that are mutually beneficial. We are also starting to understand how certain keystone members of the microbiota operate to maintain the stability and functional adaptability of this microbial organ.

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Topics: Microbiome (55%), Population (52%)

4,005 Citations

Open accessJournal ArticleDOI: 10.1126/SCIENCE.1124234
Steven R. Gill, Mihai Pop, Robert T. DeBoy, Paul B. Eckburg1  +8 moreInstitutions (4)
02 Jun 2006-Science
Abstract: The human intestinal microbiota is composed of 10(13) to 10(14) microorganisms whose collective genome ("microbiome") contains at least 100 times as many genes as our own genome. We analyzed approximately 78 million base pairs of unique DNA sequence and 2062 polymerase chain reaction-amplified 16S ribosomal DNA sequences obtained from the fecal DNAs of two healthy adults. Using metabolic function analyses of identified genes, we compared our human genome with the average content of previously sequenced microbial genomes. Our microbiome has significantly enriched metabolism of glycans, amino acids, and xenobiotics; methanogenesis; and 2-methyl-d-erythritol 4-phosphate pathway-mediated biosynthesis of vitamins and isoprenoids. Thus, humans are superorganisms whose metabolism represents an amalgamation of microbial and human attributes.

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Topics: Human Microbiome Project (65%), Microbiome (63%), Metagenomics (58%) ... read more

3,636 Citations

Journal ArticleDOI: 10.1038/35013070
25 May 2000-Nature
Abstract: Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. Endotoxin (lipopolysaccharide), produced by all gram-negative bacteria, activates macrophages to release cytokines that are potentially lethal. The central nervous system regulates systemic inflammatory responses to endotoxin through humoral mechanisms. Activation of afferent vagus nerve fibres by endotoxin or cytokines stimulates hypothalamic-pituitary-adrenal anti-inflammatory responses. However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. Here, we describe a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to endotoxin. Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1beta, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.

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Topics: Inflammatory reflex (64%), Vagus nerve stimulation (61%), Proinflammatory cytokine (61%) ... read more

3,128 Citations

Journal ArticleDOI: 10.1038/NATURE11552
13 Sep 2012-Nature
Abstract: The link between the microbes in the human gut and the development of obesity, cardiovascular disease and metabolic syndromes, such as type 2 diabetes, is becoming clearer. However, because of the complexity of the microbial community, the functional connections are less well understood. Studies in both mice and humans are helping to show what effect the gut microbiota has on host metabolism by improving energy yield from food and modulating dietary or the host-derived compounds that alter host metabolic pathways. Through increased knowledge of the mechanisms involved in the interactions between the microbiota and its host, we will be in a better position to develop treatments for metabolic disease.

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Topics: Gut flora (56%)

2,875 Citations

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