The role of microbiota-gut-brain axis in neuropsychiatric and neurological disorders.

Alzheimer's disease (AD) is an incurable, neuropsychiatric, pathological condition that deteriorates the worth of geriatric lives. AD is characterized by aggregated senile amyloid plaques, neurofibrillary tangles, neuronal loss, gliosis, oxidative stress, neurotransmitter dysfunction, and bioenergetic deficits. The changes in GIT composition and harmony have been recognized as a decisive and interesting player in neuronal pathologies including AD. Microbiota control and influence the oxidoreductase status, inflammation, immune system, and the endocrine system through which it may have an impact on the cognitive domain. The altered and malfunctioned state of microbiota is associated with minor infections to complicated illnesses that include psychosis and neurodegeneration, and several studies show that microbiota regulates neuronal plasticity and neuronal development. The altered state of microbiota (dysbiosis) may affect behavior, stress response, and cognitive functions. Chronic stress-mediated pathological progression also has a well-defined role that intermingles at various physiological levels and directly impacts the pathological advancement of AD. Chronic stress-modulated alterations affect the well-established pathological markers of AD but also affect the gut-brain axis through the mediation of various downstream signaling mechanisms that modulate the microbial commensals of GIT. The extensive literature reports that chronic stressors affect the composition, metabolic activities, and physiological role of microbiota in various capacities. The present manuscript aims to elucidate mechanistic pathways through which stress induces dysbiosis, which in turn escalates the neuropathological cascade of AD. The stress-dysbiosis axis appears a feasible zone of work in the direction of treatment of AD.

https://www.mdpi.com/2218-273X/11/5/678/pdf

Dysbiosis and Alzheimer's Disease: A Role for Chronic Stress?

The gut microbiome has a tremendous influence on human physiology, including the nervous system. During fetal development, the initial colonization of the microbiome coincides with the development of the nervous system in a timely, coordinated manner. Emerging studies suggest an active involvement of the microbiome and its metabolic by-products in regulating early brain development. However, any disruption during this early developmental process can negatively impact brain functionality, leading to a range of neurodevelopment and neuropsychiatric disorders (NPD). In this review, we summarize recent evidence as to how the gut microbiome can influence the process of early human brain development and its association with major neurodevelopmental psychiatric disorders such as autism spectrum disorders, attention-deficit hyperactivity disorder, and schizophrenia. Further, we discuss how gut microbiome alterations can also play a role in inducing drug resistance in the affected individuals. We propose a model that establishes a direct link of microbiome dysbiosis with the exacerbated inflammatory state, leading to functional brain deficits associated with NPD. Based on the existing research, we discuss a framework whereby early diet intervention can boost mental wellness in the affected subjects and call for further research for a better understanding of mechanisms that govern the gut-brain axis may lead to novel approaches to the study of the pathophysiology and treatment of neuropsychiatric disorders.

Understanding the Role of the Gut Microbiome in Brain Development and Its Association With Neurodevelopmental Psychiatric Disorders

The gut microbiota is involved in metabolic and immune disorders associated with obesity and type 2 diabetes. We previously demonstrated that prebiotic treatment may significantly improve host health by modulating bacterial species related to the improvement of gut endocrine, barrier and immune functions. An analysis of the gut metagenome is needed to determine which bacterial functions and taxa are responsible for beneficial microbiota–host interactions upon nutritional intervention. We subjected mice to prebiotic (Pre) treatment under physiological (control diet: CT) and pathological conditions (high-fat diet: HFD) for 8 weeks and investigated the production of intestinal antimicrobial peptides and the gut microbiome. HFD feeding significantly decreased the expression of regenerating islet-derived 3-gamma (Reg3g) and phospholipase A2 group-II (PLA2g2) in the jejunum. Prebiotic treatment increased Reg3g expression (by ∼50-fold) and improved intestinal homeostasis as suggested by the increase in the expression of intectin, a key protein involved in intestinal epithelial cell turnover. Deep metagenomic sequencing analysis revealed that HFD and prebiotic treatment significantly affected the gut microbiome at different taxonomic levels. Functional analyses based on the occurrence of clusters of orthologous groups (COGs) of proteins also revealed distinct profiles for the HFD, Pre, HFD-Pre and CT groups. Finally, the gut microbiota modulations induced by prebiotics counteracted HFD-induced inflammation and related metabolic disorders. Thus, we identified novel putative taxa and metabolic functions that may contribute to the development of or protection against the metabolic alterations observed during HFD feeding and HFD-Pre feeding.

Microbiome of prebiotic treated mice reveals novel targets involved in host response during obesity and diabetes

Purpose of review Accumulating evidence indicates that there are bidirectional interactions between the gut microbiota and functioning of the central nervous system. Consequently, it has been proposed that gut microbiota alterations might play an important role in the pathophysiology of schizophrenia. Therefore, in this article, we aimed to perform a narrative review of studies addressing gut microbiota alterations in patients with schizophrenia that were published in the years 2019-2020. Recent findings Several studies have shown a number of gut microbiota alterations at various stages of schizophrenia. Some of them can be associated with neurostructural abnormalities, psychopathological symptoms, subclinical inflammation and cardiovascular risk. Experimental studies clearly show that transplantation of gut microbiota from unmedicated patients with schizophrenia to germ-free mice results in a number of behavioural impairments accompanied by altered neurotransmission. However, findings from clinical trials do not support the use of probiotics as add-on treatments in schizophrenia. Summary Gut microbiota alterations are widely observed in patients with schizophrenia and might account for various biological alterations involved in the cause of psychosis. However, longitudinal studies are still needed to conclude regarding causal associations. Well designed clinical trials are needed to investigate safety and efficacy of probiotics and prebiotics in schizophrenia.

Gut microbiota and microbiome in schizophrenia.

Schizophrenia (SZ) is a psychiatric disorder that constitutes one of the top 10 global causes of disability. More recently, a potential pathogenic role for the gut microbial community (microbiota) has been highlighted, with numerous studies describing dysregulated microbial profiles in SZ patients when compared to healthy controls. However, no animal model of SZ has previously recapitulated the gut dysbiosis observed clinically. Since the metabotropic glutamate receptor 5 (mGlu5) knockout mice provide a preclinical model of SZ with strong face and predictive validity, in the present study we performed gut microbiome profiling of mGlu5 knockout (KO) and wild-type (WT) mice by 16S rRNA sequencing of bacterial genomic DNA from fecal samples, analyzing bacterial diversity and taxonomic composition, as well as gastrointestinal parameters as indicators of gut function. We found a significant genotype difference in microbial beta diversity. Analysis of composition of microbiomes (ANCOM) models were performed to evaluate microbiota compositions, which identified a decreased relative abundance of the Erysipelotrichaceae family and Allobaculum genus in this mouse model of SZ. We also identified a signature of bacteria discriminating between the genotypes (KO and WT), consisting of the Erysipelotrichales, Bacteroidales, and Clostridiales orders and macroscopic gut differences. We thus uncovered global differential community composition in the gut microbiota profile between mGlu5 KO and WT mice, outlining the first evidence for gut dysbiosis in a genetic animal model of SZ. Our findings suggest that this widely used preclinical model of SZ also has substantial utility for investigations of gut dysbiosis and associated signaling via the microbiota-gut-brain axis, as potential modulators of SZ pathogenesis. Our discovery opens up new avenues to explore gut dysbiosis and its proposed links to brain dysfunction in SZ, as well as novel therapeutic approaches to this devastating disorder.

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Microbiome Profiling Reveals Gut Dysbiosis in the Metabotropic Glutamate Receptor 5 Knockout Mouse Model of Schizophrenia

Glutamate is the major excitatory neurotransmitter in the central nervous system, and there is evidence that Group-I metabotropic glutamate receptors (mGlu1 and mGlu5) have established roles in excitatory neurotransmission and synaptic plasticity. While glutamate is abundantly present in the gut, it plays a smaller role in neurotransmission in the enteric nervous system. In this study, we examined the roles of Group-I mGlu receptors in gastrointestinal function. We investigated the expression of Grm1 (mGlu1) and Grm5 (mGlu5) in the mouse myenteric plexus using RNAscope in situ hybridization. Live calcium imaging and motility analysis were performed on ex vivo preparations of the mouse colon. mGlu5 was found to play a role in excitatory enteric neurotransmission, as electrically-evoked calcium transients were sensitive to the mGlu5 antagonist MPEP. However, inhibition of mGlu5 activity did not affect colonic motor complexes (CMCs). Instead, inhibition of mGlu1 using BAY 36-7620 reduced CMC frequency but did not affect enteric neurotransmission. These data highlight complex roles for Group-I mGlu receptors in myenteric neuron activity and colonic function.

/pdf/group-i-metabotropic-glutamate-receptors-modulate-motility-3on3vjct.pdf

Group I Metabotropic Glutamate Receptors Modulate Motility and Enteric Neural Activity in the Mouse Colon

/pdf/novel-antidepressant-like-properties-of-the-iron-chelator-1yttsqy9.pdf

Volkan Uzungil

Papers

Microbiome Profiling Reveals Gut Dysbiosis in the Metabotropic Glutamate Receptor 5 Knockout Mouse Model of Schizophrenia

Group I Metabotropic Glutamate Receptors Modulate Motility and Enteric Neural Activity in the Mouse Colon

Novel Antidepressant-Like Properties of the Iron Chelator Deferiprone in a Mouse Model of Depression