Developmental Signatures of Microbiota-Derived Metabolites in the Mouse Brain

The gut microbiome is recognized to exert a wide-ranging influence on host health and disease, including brain development and behavior. Commensal bacteria can produce bioactive molecules that enter the circulation and impact host physiology and homeostasis. However, little is known about the potential for these metabolites to cross the blood–brain barrier and enter the developing brain under normal physiological conditions. In this study, we used a liquid chromatography–mass spectrometry-based metabolomic approach to characterize the developmental profiles of microbial-derived metabolites in the forebrains of mice across three key postnatal developmental stages, co-occurring with the maturation of the gut microbiota. We demonstrate that direct metabolites of the gut microbiome (e.g., imidazole propionate) or products of the combinatorial metabolism between the microbiome and host (e.g., 3-indoxyl-sulfate, trimethylamine-N-oxide, and phenylacetylglycine) are present in the forebrains of mice as early as the neonatal period and remain into adulthood. These findings demonstrate that microbial-associated molecules can cross the BBB either in their detected form or as precursor molecules that undergo further processing in the brain. These chemical messengers are able to bind receptors known to be expressed in the brain. Alterations in the gut microbiome may therefore influence neurodevelopmental trajectories via the regulation of these microbial-associated metabolites.

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The Gut Microbiome as a Regulator of the Neuroimmune Landscape

Annual Review of Immunology ◽

10.1146/annurev-immunol-101320-014237 ◽

2022 ◽

Vol 40 (1) ◽

Author(s):

Lewis W. Yu ◽

Gulistan Agirman ◽

Elaine Y. Hsiao

Keyword(s):

Gut Microbiome ◽

Neurological Disorders ◽

Annual Review ◽

Publication Date ◽

Immune Mediated ◽

Health And Disease ◽

And Behavior ◽

Bidirectional Interactions ◽

The Brain ◽

Microbial Effects

The gut microbiome influences many host physiologies, spanning gastrointestinal function, metabolism, immune homeostasis, neuroactivity, and behavior. Many microbial effects on the host are orchestrated by bidirectional interactions between the microbiome and immune system. Imbalances in this dialogue can lead to immune dysfunction and immune-mediated conditions in distal organs including the brain. Dysbiosis of the gut microbiome and dysregulated neuroimmune responses are common comorbidities of neurodevelopmental, neuropsychiatric, and neurological disorders, highlighting the importance of the gut microbiome–neuroimmune axis as a regulator of central nervous system homeostasis. In this review, we discuss recent evidence supporting a role for the gut microbiome in regulating the neuroimmune landscape in health and disease. Expected final online publication date for the Annual Review of Immunology, Volume 40 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Role of Biological Sex in the Cardiovascular-Gut Microbiome Axis

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.759735 ◽

2022 ◽

Vol 8 ◽

Author(s):

Shuangyue Li ◽

Georgios Kararigas

Keyword(s):

Gut Microbiota ◽

Gut Microbiome ◽

Microbial Composition ◽

Biological Sex ◽

Technological Advances ◽

Host Health ◽

Health And Disease ◽

And Function ◽

Insight Into

There has been a recent, unprecedented interest in the role of gut microbiota in host health and disease. Technological advances have dramatically expanded our knowledge of the gut microbiome. Increasing evidence has indicated a strong link between gut microbiota and the development of cardiovascular diseases (CVD). In the present article, we discuss the contribution of gut microbiota in the development and progression of CVD. We further discuss how the gut microbiome may differ between the sexes and how it may be influenced by sex hormones. We put forward that regulation of microbial composition and function by sex might lead to sex-biased disease susceptibility, thereby offering a mechanistic insight into sex differences in CVD. A better understanding of this could identify novel targets, ultimately contributing to the development of innovative preventive, diagnostic and therapeutic strategies for men and women.

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Glucocorticoid receptor action in metabolic and neuronal function

F1000Research ◽

10.12688/f1000research.11375.1 ◽

2017 ◽

Vol 6 ◽

pp. 1208 ◽

Cited By ~ 19

Author(s):

Michael J. Garabedian ◽

Charles A. Harris ◽

Freddy Jeanneteau

Keyword(s):

Gene Expression ◽

Glucocorticoid Receptor ◽

Metabolic Diseases ◽

Cell Types ◽

Health And Disease ◽

And Behavior ◽

External Signals ◽

The Brain

Glucocorticoids via the glucocorticoid receptor (GR) have effects on a variety of cell types, eliciting important physiological responses via changes in gene expression and signaling. Although decades of research have illuminated the mechanism of how this important steroid receptor controls gene expression using in vitro and cell culture–based approaches, how GR responds to changes in external signals in vivo under normal and pathological conditions remains elusive. The goal of this review is to highlight recent work on GR action in fat cells and liver to affect metabolism in vivo and the role GR ligands and receptor phosphorylation play in calibrating signaling outputs by GR in the brain in health and disease. We also suggest that both the brain and fat tissue communicate to affect physiology and behavior and that understanding this “brain-fat axis” will enable a more complete understanding of metabolic diseases and inform new ways to target them.

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Drosophila as a Model for Microbiota Studies of Neurodegeneration

Journal of Alzheimer s Disease ◽

10.3233/jad-215031 ◽

2021 ◽

pp. 1-12

Author(s):

Fukiko Kitani-Morii ◽

Robert P. Friedland ◽

Hideki Yoshida ◽

Toshiki Mizuno

Keyword(s):

Gut Microbiota ◽

Molecular Mechanisms ◽

Environmental Changes ◽

Fruit Fly ◽

Endocrine Regulation ◽

Nutrient Metabolism ◽

Host Health ◽

And Behavior ◽

The Brain ◽

Lateral Sclerosis

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.

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The Brain, Seizures and Epilepsy Throughout Life: Understanding a Moving Target

Epilepsy Currents ◽

10.5698/1535-7511-12.4s.7 ◽

2012 ◽

Vol 12 (4_suppl) ◽

pp. 7-12 ◽

Cited By ~ 18

Author(s):

Tallie Z. Baram

Keyword(s):

Temporal Evolution ◽

Three Dimensional ◽

Epileptic Activity ◽

Dimensional Structure ◽

Moving Target ◽

Neuronal Structure ◽

Health And Disease ◽

Dimension One ◽

And Behavior ◽

The Brain

The human brain is a tremendously complex and still enigmatic three-dimensional structure, composed of countless interconnected neurons and glia. The temporal evolution of the brain throughout life provides a fourth dimension, one that influences every element of the brain's function in health and disease. This temporal evolution contributes to the probability of seizure generation and to the type and the nature of these seizures. The age-specific properties of the brain also influence the consequences of seizures on neuronal structure and behavior. These, in turn, govern epileptic activity and cognitive and emotional functions, contributing to the diverse consequences of seizures and epilepsy throughout life.

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Consumption of Butylated Starch Alleviates the Chronic Restraint Stress-Induced Neurobehavioral and Gut Barrier Deficits Through Reshaping the Gut Microbiota

Frontiers in Immunology ◽

10.3389/fimmu.2021.755481 ◽

2021 ◽

Vol 12 ◽

Author(s):

Peijun Tian ◽

Huiyue Zhu ◽

Xin Qian ◽

Ying Chen ◽

Zheng Wang ◽

...

Keyword(s):

Beneficial Effect ◽

Gut Microbiome ◽

Short Chain Fatty Acids ◽

Host Health ◽

Microbiome Research ◽

The Brain ◽

Targeted Release ◽

Junction Proteins ◽

Microbial Effects

The beneficial effect of short-chain fatty acids (SCFAs) on host health has been well recognized based on the booming knowledge from gut microbiome research. The role of SCFA in influencing psychological function is highlighted in recent years but has not been fully elucidated. In this study, the SCFA-acylated starches were used to accomplish a sizeable intestine-targeted release of the SCFAs, and the neurobehavioral, immunological, and microbial effects were further investigated. Acetylated-, butylated-, and isobutylated-starch could attenuate the depression-like behaviors and excessive corticosterone production in chronically stressed mice. Butylated- starch significantly reduced the colonic permeability via increasing the tight junction proteins (including ZO-1, Claudin, and Occludin) gene expression and reduced the level of the inflammatory cytokines (including IL-1β and IL-6). The butylated starch’s neurological and immunological benefits may be derived from the gut microbiome modifications, including normalizing the abundance of certain beneficial microbes (Odoribacter and Oscillibacter) and metabolomic pathways (Tryptophan synthesis and Inositol degradation). The present findings further validate the brain-beneficial effect of butyrate and offer novel guidance for developing novel food or dietary supplements for improving mental health.

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A Review of Traumatic Brain Injury and the Gut Microbiome: Insights into Novel Mechanisms of Secondary Brain Injury and Promising Targets for Neuroprotection

Brain Sciences ◽

10.3390/brainsci8060113 ◽

2018 ◽

Vol 8 (6) ◽

pp. 113 ◽

Cited By ~ 29

Author(s):

Caroline Zhu ◽

Ramesh Grandhi ◽

Thomas Patterson ◽

Susannah Nicholson

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Gut Microbiome ◽

The Body ◽

Secondary Brain Injury ◽

Major Focus ◽

Inflammatory State ◽

The Central Nervous System ◽

Health And Disease ◽

The Brain

The gut microbiome and its role in health and disease have recently been major focus areas of research. In this review, we summarize the different ways in which the gut microbiome interacts with the rest of the body, with focus areas on its relationships with immunity, the brain, and injury. The gut–brain axis, a communication network linking together the central and enteric nervous systems, represents a key bidirectional pathway with feed-forward and feedback mechanisms. The gut microbiota has a central role in this pathway and is significantly altered following injury, leading to a pro-inflammatory state within the central nervous system (CNS). Herein, we examine traumatic brain injury (TBI) in relation to this axis and explore potential interventions, which may serve as targets for improving clinical outcomes and preventing secondary brain injury.

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Role of Maternal Microbiota and Nutrition in Early-Life Neurodevelopmental Disorders

Nutrients ◽

10.3390/nu13103533 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3533

Author(s):

Anissa Daliry ◽

Evelyn Nunes Goulart da Silva Pereira

Keyword(s):

Neurodevelopmental Disorders ◽

Early Life ◽

Maternal Nutrition ◽

Metabolic Diseases ◽

Developmental Stages ◽

Mechanistic Pathway ◽

Prevalence Of Obesity ◽

Health And Disease ◽

And Behavior ◽

Early Developmental

The rise in the prevalence of obesity and other related metabolic diseases has been paralleled by an increase in the frequency of neurodevelopmental problems, which has raised the likelihood of a link between these two phenomena. In this scenario, maternal microbiota is a possible linking mechanistic pathway. According to the “Developmental Origins of Health and Disease” paradigm, environmental exposures (in utero and early life) can permanently alter the body’s structure, physiology, and metabolism, increasing illness risk and/or speeding up disease progression in offspring, adults, and even generations. Nutritional exposure during early developmental stages may induce susceptibility to the later development of human diseases via interactions in the microbiome, including alterations in brain function and behavior of offspring, as explained by the gut–brain axis theory. This review provides an overview of the implications of maternal nutrition on neurodevelopmental disorders and the establishment and maturation of gut microbiota in the offspring.

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