scholarly journals Gut Microbiome Regulation of Autophagic Flux and Neurodegenerative Disease Risks

2021 ◽  
Vol 12 ◽  
Author(s):  
Andrew P. Shoubridge ◽  
Célia Fourrier ◽  
Jocelyn M. Choo ◽  
Christopher G. Proud ◽  
Timothy J. Sargeant ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Cell Damage ◽  
Short Chain Fatty Acids ◽  
Autophagic Flux ◽  
Potential Contribution ◽  
Intestinal Microbiology ◽  
Immune Mediated ◽  
Cellular Debris ◽  
The Central Nervous System ◽  
Disease Risks

The gut microbiome-brain axis exerts considerable influence on the development and regulation of the central nervous system. Numerous pathways have been identified by which the gut microbiome communicates with the brain, falling largely into the two broad categories of neuronal innervation and immune-mediated mechanisms. We describe an additional route by which intestinal microbiology could mediate modifiable risk for neuropathology and neurodegeneration in particular. Autophagy, a ubiquitous cellular process involved in the prevention of cell damage and maintenance of effective cellular function, acts to clear and recycle cellular debris. In doing so, autophagy prevents the accumulation of toxic proteins and the development of neuroinflammation, both common features of dementia. Levels of autophagy are influenced by a range of extrinsic exposures, including nutrient deprivation, infection, and hypoxia. These relationships between exposures and rates of autophagy are likely to be mediated, as least in part, by the gut microbiome. For example, the suppression of histone acetylation by microbiome-derived short-chain fatty acids appears to be a major contributor to upregulation of autophagic function. We discuss the potential contribution of the microbiome-autophagy axis to neurological health and examine the potential of exploiting this link to predict and prevent neurodegenerative diseases.

scholarly journals Implications of Diet and The Gut Microbiome in Neuroinflammatory and Neurodegenerative Diseases

2019 ◽  
Vol 20 (12) ◽  
pp. 3109 ◽  
Author(s):  
Sarah Hirschberg ◽  
Barbara Gisevius ◽  
Alexander Duscha ◽  
Aiden Haghikia
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Gut Microbiome ◽  
Human Life ◽  
Microbiome Composition ◽  
Immune Mediated ◽  
The Central Nervous System ◽  
The Impact ◽  
The Relationship

Within the last century, human lifestyle and dietary behaviors have changed dramatically. These changes, especially concerning hygiene, have led to a marked decrease in some diseases, i.e., infectious diseases. However, other diseases that can be attributed to the so-called ‘Western’ lifestyle have increased, i.e., metabolic and cardiovascular disorders. More recently, multifactorial disorders, such as autoimmune and neurodegenerative diseases, have been associated with changes in diet and the gut microbiome. In particular, short chain fatty acid (SCFA)-producing bacteria are of high interest. SCFAs are the main metabolites produced by bacteria and are often reduced in a dysbiotic state, causing an inflammatory environment. Based on advanced technologies, high-resolution investigations of the abundance and composition of the commensal microbiome are now possible. These techniques enable the assessment of the relationship between the gut microbiome, its metabolome and gut-associated immune and neuronal cells. While a growing number of studies have shown the indirect impact of gut metabolites, mediated by alterations of immune-mediated mechanisms, the direct influence of these compounds on cells of the central nervous system needs to be further elucidated. For instance, the SCFA propionic acid (PA) increases the amount of intestine-derived regulatory T cells, which furthermore can positively affect the central nervous system (CNS), e.g., by increasing remyelination. However, the question of if and how PA can directly interact with CNS-resident cells is a matter of debate. In this review, we discuss the impact of an altered microbiome composition in relation to various diseases and discuss how the commensal microbiome is shaped, starting from the beginning of human life.

Resolution-Associated Molecular Patterns (RAMPs) as Endogenous Regulators of Glia Functions in Neuroinflammatory Disease

2020 ◽  
Vol 19 (7) ◽  
pp. 483-494
Author(s):  
Tyler J. Wenzel ◽  
Evan Kwong ◽  
Ekta Bajwa ◽  
Andis Klegeris
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Bioactive Lipids ◽  
Prothymosin Α ◽  
Neuroinflammatory Disease ◽  
Cellular Debris ◽  
Αb Crystallin ◽  
Endogenous Regulators ◽  
The Central Nervous System ◽  
Molecular Patterns

: Glial cells, including microglia and astrocytes, facilitate the survival and health of all cells within the Central Nervous System (CNS) by secreting a range of growth factors and contributing to tissue and synaptic remodeling. Microglia and astrocytes can also secrete cytotoxins in response to specific stimuli, such as exogenous Pathogen-Associated Molecular Patterns (PAMPs), or endogenous Damage-Associated Molecular Patterns (DAMPs). Excessive cytotoxic secretions can induce the death of neurons and contribute to the progression of neurodegenerative disorders, such as Alzheimer’s disease (AD). The transition between various activation states of glia, which include beneficial and detrimental modes, is regulated by endogenous molecules that include DAMPs, cytokines, neurotransmitters, and bioactive lipids, as well as a diverse group of mediators sometimes collectively referred to as Resolution-Associated Molecular Patterns (RAMPs). RAMPs are released by damaged or dying CNS cells into the extracellular space where they can induce signals in autocrine and paracrine fashions by interacting with glial cell receptors. While the complete range of their effects on glia has not been described yet, it is believed that their overall function is to inhibit adverse CNS inflammatory responses, facilitate tissue remodeling and cellular debris removal. This article summarizes the available evidence implicating the following RAMPs in CNS physiological processes and neurodegenerative diseases: cardiolipin (CL), prothymosin α (ProTα), binding immunoglobulin protein (BiP), heat shock protein (HSP) 10, HSP 27, and αB-crystallin. Studies on the molecular mechanisms engaged by RAMPs could identify novel glial targets for development of therapeutic agents that effectively slow down neuroinflammatory disorders including AD.

Associations between gut microbiome, short chain fatty acids and blood pressure across ethnic groups: the HELIUS study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
B Verhaar ◽  
D Collard ◽  
A Prodan ◽  
J.H.M Levels ◽  
A.H Zwinderman ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Fatty Acids ◽  
Ethnic Groups ◽  
Gut Microbiome ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Funding Source ◽  
Microbiome Composition ◽  
Helius Study ◽  
Chain Fatty Acids

Abstract Background Gut microbiome composition is shaped by a combination of host genetic make-up and dietary habits. In addition, large ethnic differences exist in microbiome composition. Several studies in humans and animals have shown that differences in gut microbiota and its metabolites, including short chain fatty acids (SCFA), are associated with blood pressure (BP). We hypothesized that gut microbiome composition and its metabolites may be differently associated with BP across ethnic groups. Purpose To investigate associations of gut microbiome composition and fecal SCFA levels with BP across different ethnic groups. Methods We assessed the association between gut microbiome composition and office BP among 4672 subjects (mean age 49.8±11.7 years, 52%F) of 6 different ethnic groups participating in the HELIUS study. Gut microbiome composition was determined using 16S rRNA sequencing. Associations between microbiome composition and blood pressure were assessed using machine learning prediction models. The resulting best predictors were correlated with BP using Spearman's rank correlations. Fecal SCFA levels were measured with high-performance liquid chromatography in an age- and body mass index (BMI)-matched subgroup of 200 participants with either extreme low or high systolic BP. Differences in abundances of best predictors and fecal SCFA levels between high and low BP groups were assessed with Mann-Whitney U tests. Results Gut microbiome composition explained 4.4% of systolic BP variance. Best predictors for systolic BP included Roseburia spp. (ρ −0.15, p<0.001), Clostridium spp. (ρ −0.14, p<0.001), Romboutsia spp. (ρ −0.10, p<0.001), and Ruminococceae spp. (ρ −0.15, p<0.001) (Figure 1). Explained variance of the microbiome composition was highest in Dutch subjects (4.8%), but very low in African Surinamese, Ghanaian, and Turkish ethnic groups (ranging from 0–0.77%) Hence, we selected only participants with Dutch ethnicity for the matched subgroup. Participants with high BP had lower abundance of Roseburia hominis (p<0.01) and Roseburia spp. (p<0.05) compared to participants with low BP. However, fecal acetate (p<0.05) and propionate (p<0.01) levels were higher in participants with high BP. Conclusions In this cross-sectional study, gut microbiome composition was moderately associated with BP. Associations were strongly divergent between ethnic groups, with strongest associations in Dutch participants. Intriguingly, while Dutch participants with high BP had lower abundances of several SCFA-producing microbes, they had higher fecal SCFA levels. Intervention studies with SCFAs could provide more insight in the effects of these metabolites on BP. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): The Academic Medical Center (AMC) of Amsterdam and the Public Health Service of Amsterdam (GGD Amsterdam) provided core financial support for HELIUS. The HELIUS study is also funded by research grants of the Dutch Heart Foundation (Hartstichting; grant no. 2010T084), the Netherlands Organization for Health Research and Development (ZonMw; grant no. 200500003), the European Integration Fund (EIF; grant no. 2013EIF013) and the European Union (Seventh Framework Programme, FP-7; grant no. 278901).

scholarly journals Cannabidiol induces autophagy via ERK1/2 activation in neural cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Talita A. M. Vrechi ◽  
Anderson H. F. F. Leão ◽  
Ingrid B. M. Morais ◽  
Vanessa C. Abílio ◽  
Antonio W. Zuardi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Neurodegenerative Disorders ◽  
Molecular Mechanisms ◽  
Cannabis Sativa ◽  
Autophagic Flux ◽  
Neural Cells ◽  
Human Neuroblastoma ◽  
Trpv1 Receptor ◽  
The Central Nervous System ◽  
Catabolic Process

AbstractAutophagy is a lysosomal catabolic process essential to cell homeostasis and is related to the neuroprotection of the central nervous system. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid present in Cannabis sativa. Many therapeutic actions have been linked to this compound, including autophagy activation. However, the precise underlying molecular mechanisms remain unclear, and the downstream functional significance of these actions has yet to be determined. Here, we investigated CBD-evoked effects on autophagy in human neuroblastoma SH-SY5Y and murine astrocyte cell lines. We found that CBD-induced autophagy was substantially reduced in the presence of CB1, CB2 and TRPV1 receptor antagonists, AM 251, AM 630 and capsazepine, respectively. This result strongly indicates that the activation of these receptors mediates the autophagic flux. Additionally, we demonstrated that CBD activates autophagy through ERK1/2 activation and AKT suppression. Interestingly, CBD-mediated autophagy activation is dependent on the autophagy initiator ULK1, but mTORC1 independent. Thus, it is plausible that a non-canonical pathway is involved. Our findings collectively provide evidence that CBD stimulates autophagy signal transduction via crosstalk between the ERK1/2 and AKT kinases, which represent putative regulators of cell proliferation and survival. Furthermore, our study sheds light on potential therapeutic cannabinoid targets that could be developed for treating neurodegenerative disorders.

Gut microbiome–short-chain fatty acids interplay in the context of iron deficiency anaemia

2021 ◽  
Author(s):  
Ana Soriano-Lerma ◽  
María García-Burgos ◽  
María J.M. Alférez ◽  
Virginia Pérez-Carrasco ◽  
Victoria Sanchez-Martin ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Iron Deficiency ◽  
Gut Microbiome ◽  
Iron Deficiency Anaemia ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Deficiency Anaemia ◽  
Chain Fatty Acids

scholarly journals Meta-analysis of the Parkinson’s disease gut microbiome suggests alterations linked to intestinal inflammation

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Stefano Romano ◽  
George M. Savva ◽  
Janis R. Bedarf ◽  
Ian G. Charles ◽  
Falk Hildebrand ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Fatty Acids ◽  
Parkinson's Disease ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Intestinal Inflammation ◽  
Meta Analysis ◽  
Gastrointestinal Symptoms ◽  
Short Chain Fatty Acids ◽  
Inflammatory Status

AbstractThe gut microbiota is emerging as an important modulator of neurodegenerative diseases, and accumulating evidence has linked gut microbes to Parkinson’s disease (PD) symptomatology and pathophysiology. PD is often preceded by gastrointestinal symptoms and alterations of the enteric nervous system accompany the disease. Several studies have analyzed the gut microbiome in PD, but a consensus on the features of the PD-specific microbiota is missing. Here, we conduct a meta-analysis re-analyzing the ten currently available 16S microbiome datasets to investigate whether common alterations in the gut microbiota of PD patients exist across cohorts. We found significant alterations in the PD-associated microbiome, which are robust to study-specific technical heterogeneities, although differences in microbiome structure between PD and controls are small. Enrichment of the genera Lactobacillus, Akkermansia, and Bifidobacterium and depletion of bacteria belonging to the Lachnospiraceae family and the Faecalibacterium genus, both important short-chain fatty acids producers, emerged as the most consistent PD gut microbiome alterations. This dysbiosis might result in a pro-inflammatory status which could be linked to the recurrent gastrointestinal symptoms affecting PD patients.

scholarly journals Acute Disseminated Encephalomyelitis (ADEM): A Demyelinating Disease with Specific Morphological Features

2021 ◽  
pp. 106689692199356
Author(s):  
Fleur Cordier ◽  
Lars Velthof ◽  
David Creytens ◽  
Jo Van Dorpe
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Differential Diagnosis ◽  
Clinical Case ◽  
Demyelinating Disease ◽  
Acute Disseminated Encephalomyelitis ◽  
Demyelinating Diseases ◽  
Demyelinating Disorder ◽  
Immune Mediated ◽  
The Central Nervous System

Acute disseminated encephalomyelitis (ADEM) is a rare immune-mediated inflammatory and demyelinating disorder of the central nervous system. Its characteristic perivenular demyelination and inflammation aid in the differential diagnosis with other inflammatory demyelinating diseases. Here, we present a clinical case of ADEM, summarize its histological hallmarks, and discuss pitfalls concerning the most important neuropathological differential diagnoses.

scholarly journals Xylitol enhances synthesis of propionate in the colon via cross-feeding of gut microbiota

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Shasha Xiang ◽  
Kun Ye ◽  
Mian Li ◽  
Jian Ying ◽  
Huanhuan Wang ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Lactobacillus Reuteri ◽  
Carbon Sources ◽  
Short Chain Fatty Acids ◽  
Microbial Composition ◽  
Key Enzymes ◽  
Rrna Sequencing ◽  
Phosphate Acetyltransferase

Abstract Background Xylitol, a white or transparent polyol or sugar alcohol, is digestible by colonic microorganisms and promotes the proliferation of beneficial bacteria and the production of short-chain fatty acids (SCFAs), but the mechanism underlying these effects remains unknown. We studied mice fed with 0%, 2% (2.17 g/kg/day), or 5% (5.42 g/kg/day) (weight/weight) xylitol in their chow for 3 months. In addition to the in vivo digestion experiments in mice, 3% (weight/volume) (0.27 g/kg/day for a human being) xylitol was added to a colon simulation system (CDMN) for 7 days. We performed 16S rRNA sequencing, beneficial metabolism biomarker quantification, metabolome, and metatranscriptome analyses to investigate the prebiotic mechanism of xylitol. The representative bacteria related to xylitol digestion were selected for single cultivation and co-culture of two and three bacteria to explore the microbial digestion and utilization of xylitol in media with glucose, xylitol, mixed carbon sources, or no-carbon sources. Besides, the mechanisms underlying the shift in the microbial composition and SCFAs were explored in molecular contexts. Results In both in vivo and in vitro experiments, we found that xylitol did not significantly influence the structure of the gut microbiome. However, it increased all SCFAs, especially propionate in the lumen and butyrate in the mucosa, with a shift in its corresponding bacteria in vitro. Cross-feeding, a relationship in which one organism consumes metabolites excreted by the other, was observed among Lactobacillus reuteri, Bacteroides fragilis, and Escherichia coli in the utilization of xylitol. At the molecular level, we revealed that xylitol dehydrogenase (EC 1.1.1.14), xylulokinase (EC 2.7.1.17), and xylulose phosphate isomerase (EC 5.1.3.1) were key enzymes in xylitol metabolism and were present in Bacteroides and Lachnospiraceae. Therefore, they are considered keystone bacteria in xylitol digestion. Also, xylitol affected the metabolic pathway of propionate, significantly promoting the transcription of phosphate acetyltransferase (EC 2.3.1.8) in Bifidobacterium and increasing the production of propionate. Conclusions Our results revealed that those key enzymes for xylitol digestion from different bacteria can together support the growth of micro-ecology, but they also enhanced the concentration of propionate, which lowered pH to restrict relative amounts of Escherichia and Staphylococcus. Based on the cross-feeding and competition among those bacteria, xylitol can dynamically balance proportions of the gut microbiome to promote enzymes related to xylitol metabolism and SCFAs.

scholarly journals Current Evidence on the Role of the Gut Microbiome in ADHD Pathophysiology and Therapeutic Implications

Nutrients ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 249
Author(s):  
Ana Checa-Ros ◽  
Antonio Jeréz-Calero ◽  
Antonio Molina-Carballo ◽  
Cristina Campoy ◽  
Antonio Muñoz-Hoyos
Keyword(s):  
Gut Microbiome ◽  
Pediatric Patients ◽  
Neurodevelopmental Disorder ◽  
Current Evidence ◽  
Omega 3 ◽  
Therapeutic Implications ◽  
Neuropsychiatric Diseases ◽  
Bidirectional Relationship ◽  
The Central Nervous System

Studies suggest that the bidirectional relationship existent between the gut microbiome (GM) and the central nervous system (CNS), or so-called the microbiome–gut–brain axis (MGBA), is involved in diverse neuropsychiatric diseases in children and adults. In pediatric age, most studies have focused on patients with autism. However, evidence of the role played by the MGBA in attention deficit/hyperactivity disorder (ADHD), the most common neurodevelopmental disorder in childhood, is still scanty and heterogeneous. This review aims to provide the current evidence on the functioning of the MGBA in pediatric patients with ADHD and the specific role of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in this interaction, as well as the potential of the GM as a therapeutic target for ADHD. We will explore: (1) the diverse communication pathways between the GM and the CNS; (2) changes in the GM composition in children and adolescents with ADHD and association with ADHD pathophysiology; (3) influence of the GM on the ω-3 PUFA imbalance characteristically found in ADHD; (4) interaction between the GM and circadian rhythm regulation, as sleep disorders are frequently comorbid with ADHD; (5) finally, we will evaluate the most recent studies on the use of probiotics in pediatric patients with ADHD.

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