Deciphering the role of microbially-derived metabolites on the microbiota-gut-brain axis

The trillions of microbial organisms residing in the gut, microbiota, are now recognized as major modulators of physiology and health, quickly becoming one of the most exciting emerging areas in neuroscience. Preclinical and clinical research alike suggests that the metabolites produced by these gut microbes modulate brain, behavior and disease. Short-chain fatty acids, tryptophan metabolites and bile acids are promising targets for new microbiome-based therapies. But, little is known about their mechanisms. To this end, the second chapter of the thesis collates 278 studies relating to the human microbiota-gut-brain axis, identifying trends and technical/bioinformatics limitations. These studies across different disorders of the brain as well as healthy human behavioral functions. Then a 35 of these studies was reanalyzed with an up-to-date bioinformatics pipeline. New tools, mainly the gut-brain modules provide a predictive framework for identifying whether these gut microbial metabolic pathways are dysregulated in brain diseases and disorders. We uncovered evidence of disease-related alterations in microbial metabolic pathways in Alzheimer’s Disease, schizophrenia, anxiety and depression. Previous human studies suggest that astrocyte immunity and metabolism is affected by short-chain fatty acids. Thus we grew primary male and female mouse astrocyte cultures, treating them with acetate, butyrate and propionate. Butyrate treatment (0 – 25μM) increased gene expression of Bdnf and Pgc1-α expression, implicating histone-deacetylase inhibitor pathways only in female cells. Acetate (0 – 1500 μM) positively correlated with Ahr and Gfap expression in males, suggesting an immune modulatory role. These findings show a novel sex-dependent impact of acetate and butyrate, but not propionate on astrocyte gene expression. These studies increase understanding of microbial metabolites and how they might impact the brain. It also provides guidance to improve and direct future investigations aimed at identifying the mechanisms of other metabolites

Gut-neuroimmune interactions: The unexpected role of the immune system in brain development

How does the immune system impact brain development?The exciting and somewhat unexpected relationship between the immune system and the brain has become one of the most fascinating topics in neuroscience. Even though the immune system was initially implicated in resolving viral and bacterial threats, it is now becoming more evident that it also plays a role in processes in the brain, both under healthy and pathological conditions. This novel role of the immune system in brain health has been implicated in various psychopathologies where neurodevelopment, stress and mood are central. In particular, its role in healthy brain development is becoming more evident, and understanding neuroimmune communication is becoming crucial in treating neurodevelopmental and mood disorders in later life. In the brain, glia function as part of the innate immune system and are programmed to respond to pathogens and physical injury. They also play an important role in neuronal development and pruning. These cells communicate with and respond to chemical signals, such as cytokines and chemokines, which can then initiate or downregulate inflammatory responses. Finally, the trillions of microbes residing in the gut can also stimulate cytokine and chemokine responses in the periphery and play an important role in both immunity and brain development

You've got male: Sex and the microbiota-gut-brain axis across the lifespan

Sex is a critical factor in the diagnosis and development of a number of mental health disorders including autism, schizophrenia, depression, anxiety, Parkinson's disease, multiple sclerosis, anorexia nervosa and others; likely due to differences in sex steroid hormones and genetics. Recent evidence suggests that sex can also influence the complexity and diversity of microbes that we harbour in our gut; and reciprocally that our gut microbes can directly and indirectly influence sex steroid hormones and central gene activation. There is a growing emphasis on the role of gastrointestinal microbiota in the maintenance of mental health and their role in the pathogenesis of disease. In this review, we introduce mechanisms by which gastrointestinal microbiota are thought to mediate positive health benefits along the gut-brain axis, we report how they may be modulated by sex, the role they play in sex steroid hormone regulation, and their sex-specific effects in various disorders relating to mental health

Programming bugs: microbiota and the developmental origins of brain health and disease

It has been nearly 30 years since Dr. David Barker first highlighted the importance of prenatal factors in contributing to the developmental origins of adult disease. This concept was later broadened to include postnatal events. It is clear that the interaction between genetic predisposition and early life environmental exposures is key in this regard. However, recent research has also identified another important factor in the microbiota—the trillions of microorganisms that inhabit key body niches, including the vagina and gastrointestinal tract. Because the composition of these maternal microbiome sites has been linked to maternal metabolism and is also vertically transmitted to offspring, changes in the maternal microbiota are poised to significantly affect the newborn. In fact, several lines of evidence show that the gut microbiota interacts with diet, drugs, and stress both prenatally and postnatally and that these exogenous factors could also affect the dynamic changes in the microbiota composition occurring during pregnancy. Animal models have shown great utility in illuminating how these disruptions result in behavioral and brain morphological phenotypes reminiscent of psychiatric disorders (anxiety, depression, schizophrenia, and autism spectrum disorders). Increasing evidence points to critical interactions among the microbiota, host genetics, and both the prenatal and postnatal environments to temporally program susceptibility to psychiatric disorders later in life. Sex-specific phenotypes may be programmed through the influence of the microbiota on the hypothalamic-pituitary-adrenal axis and neuroimmune system

The microbiota-gut-brain axis

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders

You\u27ve got male: Sex and the microbiota-gut-brain axis across the lifespan

Sex is a critical factor in the diagnosis and development of a number of mental health disorders including autism, schizophrenia, depression, anxiety, Parkinson\u27s disease, multiple sclerosis, anorexia nervosa and others; likely due to differences in sex steroid hormones and genetics. Recent evidence suggests that sex can also influence the complexity and diversity of microbes that we harbour in our gut; and reciprocally that our gut microbes can directly and indirectly influence sex steroid hormones and central gene activation. There is a growing emphasis on the role of gastrointestinal microbiota in the maintenance of mental health and their role in the pathogenesis of disease. In this review, we introduce mechanisms by which gastrointestinal microbiota are thought to mediate positive health benefits along the gut-brain axis, we report how they may be modulated by sex, the role they play in sex steroid hormone regulation, and their sex-specific effects in various disorders relating to mental health

Programming bugs: microbiota and the developmental origins of brain health and disease

It has been nearly 30 years since Dr. David Barker first highlighted the importance of prenatal factors in contributing to the developmental origins of adult disease. This concept was later broadened to include postnatal events. It is clear that the interaction between genetic predisposition and early life environmental exposures is key in this regard. However, recent research has also identified another important factor in the microbiota—the trillions of microorganisms that inhabit key body niches, including the vagina and gastrointestinal tract. Because the composition of these maternal microbiome sites has been linked to maternal metabolism and is also vertically transmitted to offspring, changes in the maternal microbiota are poised to significantly affect the newborn. In fact, several lines of evidence show that the gut microbiota interacts with diet, drugs, and stress both prenatally and postnatally and that these exogenous factors could also affect the dynamic changes in the microbiota composition occurring during pregnancy. Animal models have shown great utility in illuminating how these disruptions result in behavioral and brain morphological phenotypes reminiscent of psychiatric disorders (anxiety, depression, schizophrenia, and autism spectrum disorders). Increasing evidence points to critical interactions among the microbiota, host genetics, and both the prenatal and postnatal environments to temporally program susceptibility to psychiatric disorders later in life. Sex-specific phenotypes may be programmed through the influence of the microbiota on the hypothalamic-pituitary-adrenal axis and neuroimmune system