The gut microbiome plays a vital role in numerous aspects of physiology, including functions related to metabolism, the immune system, behaviour, brain structure and function. Furthermore, it is now becoming increasingly clear that alterations in microbial composition or diversity are implicated in several disease states, including anxiety, depression, autism spectrum disorder (ASD), Alzheimer's disease (AD), Parkinson's disease (PD), obesity, and diabetes. Therefore, therapeutic targeting of the gut microbiota has the potential to be useful in the treatment of both stress-related disorders and metabolic diseases. An important method by which the gut microbiome can influence the gut-brain axis is through microbial production of psychoactive metabolites. Several bacteria have been shown to produce metabolites which can impact host health, such as short-chain fatty acids, conjugated linoleic acid, antimicrobials, exopolysaccharides, and vitamins. Furthermore, several molecules with neuroactive functions, including serotonin, gamma-aminobutyric acid, catecholamines, and acetylcholine, have been isolated from bacteria within the human gut. This review aims to explore the psychoactive metabolites reported to be produced by gut bacteria, particularly those of relevance to stress-related disorders. Screening methods for psychoactive metabolite production, as well as the challenges and limitations of this research, will also be addressed. Finally, the implications of metabolite production for neuropsychiatric disorders such as depression, anxiety, and stress, behavioural disorders such as ASD, and neurodegenerative disorders such as AD and PD will be discussed.
The gut-brain axis is a bidirectional communication system which allows the central nervous system and gastrointestinal tract to interact with and respond to each other rapidly and effectively. It is becoming increasingly clear that major players in this complex system are gut bacteria. The mechanisms of signal transmission from bacteria to the brain are complex and not fully elucidated, but include neural, endocrine, immune, and metabolic pathways. It was initially demonstrated in a rodent model of depression that the gut microbiota was altered. This observation has been replicated in patients with major depression who show decreased microbial diversity. Furthermore, when rodents receive a microbiota transplant from a depressed patient their behaviour alters, as does their tryptophan metabolism and immune status. Several studies of psychobiotics (bacteria with a potential mental health benefit) have been conducted in healthy populations and in patients with depression. While some psychobiotics have shown efficacy in treating depression, other bacteria have yielded negative findings. Larger-scale, well-designed studies are required. EU-funded guidelines recommend that patients with depression or vulnerability to depression should be encouraged to enhance a plant-based diet with a high content of grains/fibres, fermented foods, and fish. A significant impact of such a diet is likely mediated through the gut microbiota.
The human gut microbiome plays a key role in host physiology in health and disease. There is a growing emphasis on the bidirectional interaction between various medications and the gut microbiome. Here, we will first review how drugs can affect microbiome composition and how the microbiome can alter the pharmacodynamics and potentially pharmacokinetics of psychotropic medications. We will take into consideration different classes of psychotropics, including antipsychotics, antidepressants, antianxiety drugs, anticonvulsants/mood stabilisers, opioid analgesics, drugs of abuse, alcohol, nicotine, and xanthines. The varying effects of these widely used medications on microorganisms are becoming apparent from in vivo and in vitro studies. This has important implications for future drug discovery in psychiatry which will need to consider the host microbiome as a major potential target.
The dynamic population of microbes that reside in the gastrointestinal tract plays a pivotal role in orchestrating several aspects of host physiology and health, including but not limited to nutrient extraction and metabolism, as well as the regulation of intestinal epithelial barrier integrity. Gut microbes interact with the host in a bi-directional manner as the microbiota can support the development and education of the innate and adaptive immune systems, thereby conferring protection against pathogens and harmful stimuli while training the host to maintain a homeostatic tolerance towards commensal symbiotics. Recent advances in the field have highlighted the importance of the host-microbiota relationship in neurodevelopment and behaviour, with relevant implications for the onset and progression of brain disorders of inflammatory origin. Microbial modulation of brain function is achieved throughout complex neuro-immune-endocrine pathways of the microbiome-gut-brain axis. Changes in the composition of the gut microbiota or perturbation in microbial-derived metabolites and neuroactive compounds are sensed by the afferent branches of the sympathetic and vagal innervation and transmitted to the central nervous system, which in turn produces behavioural responses. Here, we focus on how the crosstalk between the gut microbiota and the immune system modulates the development and function of the peripheral and central nervous systems. Specific attention is afforded to the involvement of host-microbe neuroimmune interactions in the pathogenesis of neuro-psychiatric and neuroinflammatory disorders such as autism spectrum disorders, anxiety, and depression, as well as Parkinson's and Alzheimer's diseases.
There is currently enormous interest in the impact of the intestinal microbiota on the development and function of the brain via activity of the microbiota-gut-brain axis. It has long been recognised that symbiotic microorganisms influence host behaviour, but in recent years evidence has accumulated that this can, in fact, be beneficial to the host. Indeed, substantial research has now demonstrated an influence of the intestinal microbiota on a wide range of mammalian behaviours. Here, we review what is currently known about the influence of intestinal microbiota on learning and memory, olfaction, social behaviours, and circadian processes. While work in animal models is compelling, further work is required to elucidate mechanisms whereby bacterial influence is occurring, as well as to determine the extent to which gut microbiota can influence similar phenotypes in humans.
Understanding how the microbiome influences health and disease has emerged as an important area of research across all domains of biomedical and health sciences. An extensive body of work in animal models has established a link between the gut microbiome and anxiety-like behaviour. Foundational work on germ-free mice provided the catalyst for neuroscientists to consider the microbiota-brain axis and brain health. Research manipulating the microbiome, including use of germ-free mice, antibiotics, and probiotics, provide evidence that the microbiota influences stress systems and in particular anxiety-like behaviour. Consideration of anxiety-like behaviour in animal models of metabolic and inflammatory disorders expands the scope of the work and correlates in clinical studies are emerging. This chapter highlights the work done to date in animal studies and reviews the recent clinical literature translating these observations to anxiety disorders.
There is accumulating evidence from observational and intervention studies in nutritional psychiatry regarding the importance of diet for mental health outcomes across the lifespan. Here, we synthesise this evidence, including findings from large meta-analyses showing cross-sectional and prospective associations between diet quality and mental health, even following adjustment for relevant confounding factors. Potential mechanistic pathways underpinning these associations include those of the gut-brain axis, demonstrated mostly in animal models. Dietary fibre is an important component of healthy diet and may be relevant for common mental disorders, with some studies showing a dose-dependent relationship between fibre intake and risk of depression. The potential contribution of nutraceuticals is also discussed, such as omega-3 fatty acids, vitamins, minerals, and psychobiotics. We consider the relevance of special diets such as the ketogenic diet and food sensitivities in the management of severe mental illness (e.g., anorexia nervosa) and brain disease (e.g., Alzheimer's disease). Given the relatively early nature of research in nutritional psychiatry, there remain a number of challenges to its translation into clinical practice. These span individual, clinical, and societal domains. We conclude with a discussion of micro- and macroeconomic factors which may be considered in the successful application of nutritional psychiatry research to improve public health.
Psychosocial stress, driven by a variety of sources and influences, can be ubiquitous in our modern society. Prolonged exposure to these stressors can have detrimental biological and psychological effects; extant findings in childhood adversity indicate that the cumulative effects of exposure to childhood adversity increase risk for developmental delays, altered immune responses, and psychopathology later in life. The pathways by which these effects are conferred continue to be studied. Given that pregnancy is a critical period during which susceptibility to lifetime health and illness are programmed, this chapter will focus on the impacts of maternal history of childhood adversity on offspring mental health, including the role of the microbiota-gut-brain axis. One of the most commonly used frameworks of the last several decades for measuring childhood adversity is the Adverse Childhood Experiences (ACEs) psychometric. We provide an overview of the possible mechanisms through which maternal stress, including the cumulative effects of maternal ACEs, may increase susceptibility to disease in offspring. These include altered epigenetic regulation, hypothalamic-pituitary-adrenal axis function and peripheral inflammation, and gut microbial composition. Finally, we conclude with clinical considerations, including possible future therapeutic interventions.
Since the beginning of life on earth, microorganisms have played a significant role in evolution. Throughout the history of Homo sapiens and its precursor humanoid forms, microorganisms have been present at birth and proliferated until death. It is at these extremes of life that the microbiome, especially that within the gastrointestinal tract, is most dynamic and perhaps has its greatest influence on host health. Here, we focus on the role of the gut microbiome as a regulator of brain and behaviour through key points in the human lifespan. We first describe trajectories of the microbiome in early life and ageing, before providing evidence for the existence of sensitive periods in the microbiome-gut-brain axis at these extremes of the lifespan. Finally, we briefly examine potential mechanisms for interactions between the microbiome and the brain during development and ageing.
New neurons are continuously formed in the adult hippocampus of the human, nonhuman primate, and rodent throughout life though rates of neurogenesis precipitously decline with age to near zero levels at the end of the natural life span. Since its discovery in the 1960s, a large number of studies have documented numerous environmental and genetic factors which regulate adult neurogenesis. Chief among the positive regulators of neurogenesis are exercise and antidepressant drugs. Chief among the negative regulators of neurogenesis besides age are stress and inflammation. To the extent that many psychiatric disorders are comorbid with or causally related to stress and inflammation, decreased neurogenesis could be a partial contributor to the pathophysiology of the disorders. However, the functional significance of new neurons in behavior has yet to be established and is currently a hotly debated topic. Therefore, it is not clear whether changes in neurogenesis that occur alongside psychiatric illnesses are a cause or a consequence of the mediating factors such as stress, drug abuse, and inflammation, which are complexly involved in the disorders. It will be important moving forward to use modern technologies capable of instantaneously inactivating cohorts of new neurons to test their functional significance in behavior and the etiology of mental illnesses.
Traditionally, the neurobiology of major depressive disorder (MDD) has been largely considered from the perspective of the state of major depressive episodes (MDE) versus being in remission, but the current accumulation of disease markers, largely acquired cross-sectionally, is strongly suggestive of neuroprogressive aspects of MDD. This chapter focuses on the changes in disease markers involved in the reorganization of the nervous system in MDD, including the translocator protein (TSPO; an index of microglial activation), glial fibrillary acidic protein (GFAP; an index of astroglial activation), [11C]harmine (a marker of monoamine oxidase A; MAO-A), and several other indices (metabotropic glutamate receptor 5 [mGluR5], excitatory amino acid transporters, and magnetic resonance imaging spectroscopy measurements) of glutamate dysregulation. These are markers of processes involved in immune activation, oxidative stress, and chronic glucocorticoid exposure. Positron emission tomography studies of the TSPO distribution volume, a marker of microglial activation, provide strong evidence for microglial activation throughout the gray matter of the brain during MDE of MDD. In postmortem studies, GFAP reductions in the orbitofrontal cortex, anterior cingulate cortex, and hippocampus indicate a deficit in reactive astroglia. Elevated MAO-A levels are present throughout the gray matter of the brain, including affect-modulating brain regions, starting in high-risk states for MDE such as the early postpartum period, perimenopause, heavy cigarette smoking, heavy alcohol intake, and prior to MDE recurrence. Evidence is accumulating for glutamate dysregulation, with some findings of reduced glutamate transporter density in the orbitofrontal cortex, and decreased mGluR5 density. Collectively, these changes suggest an imbalance in the immune system with increased microglial activation and decreased astroglial activation, continued elevations of the MAO-A level, and, likely, the development of extracellular glutamate dysregulation. Many of these imbalances involve processes implicated in increased oxidative stress, apoptosis, and neurodegeneration. Future studies are required to assess potential therapeutics targeting these processes to ameliorate progression of MDD.
The concept of neuroprogression describes the progressive course of the disorder and stresses the progressive, recurrent, and chronic course of the disease entity under consideration. It subsumes clinical manifestations of the disease process and may also entail morphological, biochemical, neurochemical, immunological, physiological, and genetic aspects that contribute to the progressive course of the disease in question. In an attempt to identify the appropriate agent or method that could arrest neuroprogression in psychiatric patients, we conducted an evaluation of the use of anti-inflammatory drugs under the perspective of current pharmacological and neurophysiological data. This evaluation included the use of nonsteroidal anti-inflammatory drugs (NSAIDs) as adjunctive treatment to conventional pharmacotherapy as well as the use of natural products exerting anti-inflammatory properties (i.e., ω-3 fatty acids) given as adjunctive or monotherapeutic treatments in less severe cases. The therapeutic significance of nonpharmacological methods, such as psychotherapy, physical exercise, and body-mind therapies, was also considered and will be discussed in this chapter. In conclusion, the role of psychotropic and select anti-inflammatory drugs in arresting neuroprogression is a very promising new frontier in psychiatric research and clinical practice. Modulators of a specific prostanoid synthase or receptor across the cyclooxygenase (COX)-2 downstream pathway along with new multitarget NSAIDs are expected to be tested by the pharmaceutical industry as potential agents to antagonize neuroprogression. Meanwhile, salicylates and selective COX-2 inhibitors could still be used in carefully selected subgroups of patients. Psychotherapy and nonpharmacological, stress-relieving methods should be considered as adjunctive tools to aid in arresting neuroprogression.
Psychotic disorders are heterogeneous and complex, involving many putative causal factors interacting along the course of disease development. Many of the factors implicated in the pathogenesis of psychosis also appear to be involved in disease onset and subsequent neuroprogression. Herein, we highlight the pertinent literature implicating inflammation and oxidative stress in the pathogenesis of psychosis, and the potential contribution of N-methyl-D-aspartate receptors (NMDARs). We also emphasize the role of peripubertal social stress in psychosis, and the ways in which hippocampal dysfunction can mediate dysregulation of the hypothalamic-pituitary-adrenal axis and cortisol release. Finally, we propose a model wherein inflammation and oxidative stress act as a first hit, producing altered parvalbumin interneuron development, NMDAR hypofunction, microglial priming, and sensitivity to a second hit of peripubertal social stress. With a greater understanding of how these factors interact, it may be possible to detect, prevent, and treat psychosis more effectively.
Schizophrenia is a disorder that shows a progressive course in 30-50% of the people concerned. The biology of chronification and progression is unclear. Genetic aspects may play a role, but details are unresolved. The fact that immune-mediated and autoimmune disorders such as rheumatoid arthritis or multiple sclerosis have a very similar course as schizophrenia has focused the interest on the immunopathogenesis of schizophrenia. A clear immune marker for neuroprogression in schizophrenia or psychosis could not be identified up to now, but a proinflammatory immune state (increased markers of cellular immunity) is regularly found in schizophrenia, e.g., increased levels of cytokines such as interleukin-6 (IL-6). Moreover, the tryptophan/kynurenine metabolism is regulated via pro- and anti-inflammatory cytokines and is closely related to the glutamatergic neurotransmission. Certain molecules of this metabolism, such as quinolinic acid or 3OH-kynurenine, have neurotoxic effects and seem to play a role in chronification. Studies with immune/anti-inflammatory-based therapeutic approaches show that acuity or chronicity of the inflammation influence the outcome of therapeutic interventions.
Immunostimulatory insults such as stress and infection are risk factors for the development of several neuropsychiatric disorders characterized by neuroprogression. Inflammatory and neurotoxic molecules in the brain can cause disruptions in neurogenesis, neuronal excitability, synaptic transmission, synaptic plasticity, and neuronal survival - changes that characterize neuroprogression. We draw on recent findings in the immunology literature that peripheral innate immune cells are capable of retaining long-term memory of infectious insults and displaying long-lasting upregulated proinflammatory function in response to repeated infectious insults - a concept known as "innate immune memory." In turn, we hypothesize that microglia, the resident innate immune cells of the brain, are also capable of retaining long-term memory of infectious and noninfectious insults, including stress. Microglia are capable of producing a variety of proinflammatory neurotoxic cytokines and chemokines. Persistent upregulation of microglial proinflammatory function as a result of memory for immunostimulatory insults may therefore contribute to persistent and progressive inflammation in neuropsychiatric illnesses and be an important driver of neuroprogression.
Several studies suggest that major depressive disorder (MDD) and bipolar disorder (BPD) are neuroprogressive illnesses. Besides clinical features, neurobiological mechanisms have been suggested to contribute to the neuroprogression of mood disorders. Biological factors that have been shown to contribute significantly toward the neuroprogressive course of these disorders are inflammatory markers, such as cytokines. Cytokines have been extensively investigated, primarily in the serum of MDD and BPD patients, and these studies show cytokine abnormalities in both adolescent and adult patients with mood disorders. However, cytokine abnormalities in the brain may also contribute toward neuroprogression, but brain cytokines have not been adequately investigated. To examine the role of cytokines in neuroprogression, we have studied the markers of adaptive and innate immunity in postmortem brain obtained from teenage and adult suicide victims and gene expression of cytokines and their membrane-bound receptors in lymphocytes of MDD and BPD patients. Cytokines and Toll-like receptors (TLRs) were studied in 24 teenage suicide victims and 24 normal control (NC) subjects, and also in 22 adult depressed suicide victims and 20 adult NC subjects. We found that the protein and mRNA expression of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were significantly higher in the prefrontal cortex (PFC). We also found that the protein and mRNA expression of TLRs, which are major mediators of innate immunity, is increased in the PFC of adult depressed suicide victims and NC subjects. In patients, mRNA and protein expression of TNF-α, IL-1β, and IL-6 was significantly increased in both MDD and BPD patients. Similarly, mRNA expression of some specific membrane-bound receptors, such as IL1R1, TNFR1, IL1RA, were significantly increased in lymphocytes of MDD and BPD patients. These studies indicate the existence of abnormal cytokines and TLRs in the brain of teenage and adult suicide victims. Future studies, including both teenage and adult postmortem samples, will be needed to further clarify the role of cytokines and TLRs in neuroprogression.
Epidemiological studies implicate chronic depression as a predisposing factor for dementia in later life. However, the link is incompletely understood and controversial. The aim of this review is to consider some of the biological factors that contribute to neuroprogressive brain dysfunction in late life as a consequence of prolonged, low-grade inflammation in the course of depressive episodes. As chronic inflammation is known to precipitate increased apoptosis of neurons and astrocytes, this could be a contributing factor to brain dysfunction. In addition, certain proinflammatory cytokines activate the neurotoxic derivatives of the tryptophan-kynurenine pathway. This results in the synthesis of the NMDA glutamate agonist, quinolinic acid, and kynurenine metabolites which initiate oxidative stress and insulin receptor resistance. As a consequence of these changes, combined with a structural and functional defect in brain mitochondria, glucose transport into the brain is affected. Due to the ensuing reduction in the metabolic energy needed to sustain brain function, brain cells die prematurely. These changes could provide a link between chronic inflammation and dementia, at least in some patients with recurrent and chronic depression. This outcome may be particularly true in poor responders and treatment-resistant depression.
There is a growing emphasis on the relationship between the complexity and diversity of the microorganisms that inhabit our gut (human gastrointestinal microbiota) and brain health. The microbiota-gut-brain axis is a dynamic matrix of tissues and organs including the brain, glands, gut, immune cells, and gastrointestinal microbiota that communicate in a complex multidirectional manner to maintain homeostasis. Changes in this environment may contribute to the neuroprogression of stress-related disorders by altering physiological processes including hypothalamic-pituitary-adrenal axis activation, neurotransmitter systems, immune function, and inflammatory responses. While appropriate, coordinated physiological responses, such as immune or stress responses, are necessary for survival, the contribution of repeated or chronic exposure to stress may predispose individuals to a more vulnerable state leaving them more susceptible to stress-related disorders. In this chapter, the involvement of the gastrointestinal microbiota in stress- and immune-mediated modulation of neuroendocrine, immune, and neurotransmitter systems and the consequential behavior is considered. We also focus on the mechanisms by which commensal gut microbiota can regulate neuroinflammation and further aim to exploit our understanding of their role in the effects of the microbiota-gut-brain axis on the neuroprogression of stress-related disorders as a consequence of neuroinflammatory processes.
