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1.
Gut Microbes and Neuropathology: Is There a Causal Nexus?
Dinan, K, Dinan, TG
Pathogens (Basel, Switzerland). 2022;(7)
Abstract
The gut microbiota is a virtual organ which produces a myriad of molecules that the brain and other organs require. Humans and microbes are in a symbiotic relationship, we feed the microbes, and in turn, they provide us with essential molecules. Bacteroidetes and Firmicutes phyla account for around 80% of the total human gut microbiota, and approximately 1000 species of bacteria have been identified in the human gut. In adults, the main factors influencing microbiota structure are diet, exercise, stress, disease and medications. In this narrative review, we explore the involvement of the gut microbiota in Parkinson's disease, Alzheimer's disease, multiple sclerosis and autism, as these are such high-prevalence disorders. We focus on preclinical studies that increase the understanding of disease pathophysiology. We examine the potential for targeting the gut microbiota in the development of novel therapies and the limitations of the currently published clinical studies. We conclude that while the field shows enormous promise, further large-scale studies are required if a causal link between these disorders and gut microbes is to be definitively established.
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A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials.
Sforzini, L, Worrell, C, Kose, M, Anderson, IM, Aouizerate, B, Arolt, V, Bauer, M, Baune, BT, Blier, P, Cleare, AJ, et al
Molecular psychiatry. 2022;(3):1286-1299
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Abstract
Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.
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Personalized Nutrition for Depression: Impact on the Unholy Trinity.
Duarte-Silva, E, Clarke, G, Dinan, TG, Peixoto, CA
Neuroimmunomodulation. 2021;(2):47-51
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Abstract
Major depressive disorder (MDD) is a chronic affective disorder that has a strong neuroinflammatory component underpinning its etiology. Recent studies indicate that MDD is also associated with changes in the gut microbiota and that the latter is mainly modulated by diet. Microbiota-based personalized nutrition aims to provide an individual-specific diet that will yield the maximum benefit from a given diet since the gut microbiota is accounted for the variations that individuals present in response to a given food. In this review, we present and discuss 5 possible outcomes of using microbiota-based personalized nutrition. Harnessing this approach is essential to design more accurate therapies to prevent and treat MDD or to even help in drug metabolism, especially in the case of antidepressants.
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Production of Psychoactive Metabolites by Gut Bacteria.
Wiley, NC, Cryan, JF, Dinan, TG, Ross, RP, Stanton, C
Modern trends in psychiatry. 2021;:74-99
Abstract
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.
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Mining microbes for mental health: Determining the role of microbial metabolic pathways in human brain health and disease.
Spichak, S, Bastiaanssen, TFS, Berding, K, Vlckova, K, Clarke, G, Dinan, TG, Cryan, JF
Neuroscience and biobehavioral reviews. 2021;125:698-761
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The microbiota-gut-brain axis is an emerging area of focus for mental health and disease. Metabolic products from gut microbiota exert direct and indirect effects on the brain through various body systems. The aim of this study was to review the evidence on these metabolic pathways and utilise new predictive tools to assess metabolic signatures of various disease states. This review included 278 studies and, despite the weak evidence, identified new links between gut microbial metabolic pathways in schizophrenia, Alzheimer’s disease, and anxiety and depression. The authors conclude this review provides a novel approach for understanding the mechanisms behind the bidirectional communication between the gut and brain. They also suggest guidelines for analysing and interpreting metadata of human-microbiome-brain studies and provide a framework for better understanding these metabolic pathways in relation to the brain.
Abstract
There is increasing knowledge regarding the role of the microbiome in modulating the brain and behaviour. Indeed, the actions of microbial metabolites are key for appropriate gut-brain communication in humans. Among these metabolites, short-chain fatty acids, tryptophan, and bile acid metabolites/pathways show strong preclinical evidence for involvement in various aspects of brain function and behaviour. With the identification of neuroactive gut-brain modules, new predictive tools can be applied to existing datasets. We identified 278 studies relating to the human microbiota-gut-brain axis which included sequencing data. This spanned across psychiatric and neurological disorders with a small number also focused on normal behavioural development. With a consistent bioinformatics pipeline, thirty-five of these datasets were reanalysed from publicly available raw sequencing files and the remainder summarised and collated. Among the reanalysed studies, we uncovered evidence of disease-related alterations in microbial metabolic pathways in Alzheimer's Disease, schizophrenia, anxiety and depression. Amongst studies that could not be reanalysed, many sequencing and technical limitations hindered the discovery of specific biomarkers of microbes or metabolites conserved across studies. Future studies are warranted to confirm our findings. We also propose guidelines for future human microbiome analysis to increase reproducibility and consistency within the field.
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Gut Microbiota: A Perspective for Psychiatrists.
Rea, K, Dinan, TG, Cryan, JF
Neuropsychobiology. 2020;(1):50-62
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Abstract
There is mounting evidence that the trillions of microbes that inhabit our gut are a substantial contributing factor to mental health and, equally, to the progression of neuropsychiatric disorders. The extraordinary complexity of the gut ecosystem, and how it interacts with the intestinal epithelium to manifest physiological changes in the brain to influence mood and behaviour, has been the subject of intense scientific scrutiny over the last 2 decades. To further complicate matters, we each harbour a unique microbiota community that is subject to change by a number of factors including diet, exercise, stress, health status, genetics, medication, and age, amongst others. The microbiota-gut-brain axis is a dynamic matrix of tissues and organs including the gastrointestinal (GI) microbiota, immune cells, gut tissue, glands, the autonomic nervous system (ANS), and the brain that communicate in a complex multidirectional manner through a number of anatomically and physiologically distinct systems. Long-term perturbations to this homeostatic environment may contribute to the progression of a number of disorders by altering physiological processes including hypothalamic-pituitary-adrenal axis activation, neurotransmitter systems, immune function, and the inflammatory response. While an appropriate, co-ordinated physiological response, such as an immune or stress response, is necessary for survival, a dysfunctional response can be detrimental to the host, contributing to the development of a number of central nervous system disorders.
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Man and the Microbiome: A New Theory of Everything?
Butler, MI, Cryan, JF, Dinan, TG
Annual review of clinical psychology. 2019;:371-398
Abstract
The gut microbiome is implicated in the pathophysiology of a wide range of psychological disorders. Preclinical studies have provided us with key insights into the mechanisms by which the microbiome influences bidirectional gut-brain communication. There are many signaling pathways involved, including the hypothalamic-pituitary-adrenal axis, immune modulation, tryptophan and serotonin metabolism, bile acid transformation, microbial production of neuroactive compounds, and regulation of the endocannabinoid system. The complex and widespread influence of the microbiome on many physiological and psychological processes has generated a keen interest in its therapeutic potential for depression, anxiety, autism, and other psychiatric disorders. It has been shown that the microbiome composition of people suffering with such conditions differs significantly from that of healthy controls, and although the area is in its infancy, interventional studies that alter a person's microbiome through the use of probiotics, prebiotics, or dietary change can alleviate psychopathological symptoms.
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Psychotropics and the Microbiome: a Chamber of Secrets….
Cussotto, S, Clarke, G, Dinan, TG, Cryan, JF
Psychopharmacology. 2019;(5):1411-1432
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Abstract
The human gut contains trillions of symbiotic bacteria that play a key role in programming different aspects of host physiology in health and disease. Psychotropic medications act on the central nervous system (CNS) and are used in the treatment of various psychiatric disorders. There is increasing emphasis on the bidirectional interaction between drugs and the gut microbiome. An expanding body of evidence supports the notion that microbes can metabolise drugs and vice versa drugs can modify the gut microbiota composition. In this review, we will first give a comprehensive introduction about this bidirectional interaction, then 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 the future of psychopharmacology pipelines that will routinely need to consider the host microbiome during drug discovery and development.
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The Gut Microbiome and Mental Health: What Should We Tell Our Patients?: Le microbiote Intestinal et la Santé Mentale : que Devrions-Nous dire à nos Patients?
Butler, MI, Mörkl, S, Sandhu, KV, Cryan, JF, Dinan, TG
Canadian journal of psychiatry. Revue canadienne de psychiatrie. 2019;64(11):747-760
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The gut-brain axis is the bi-directional communication pathway and increasing evidence indicates its impact in neural health and disease. With the field of nutritional psychiatry actively developing, psychiatric patients have become increasingly aware of the therapeutic use of probiotics and mental health. This review aims to inform psychiatrists about the communication between the microbiome and brain and discuss its relevance to the management and treatment of psychiatric illness. In reviewing the common psychiatric illnesses, the current literature shows inconsistent results on specific microbiome compositions related to specific illnesses, yet shows promising effects for probiotic use in many disorders. These findings offer a novel paradigm for approaching mental illness through the lens of nutritional psychiatry. Authors conclude there is much work to be done translating laboratory findings into clinical practice, and highlight the necessity for clinicians to stay informed of the literature and make accurate recommendations to patients.
Abstract
The gut microbiome as a potential therapeutic target for mental illness is a hot topic in psychiatry. Trillions of bacteria reside in the human gut and have been shown to play a crucial role in gut-brain communication through an influence on neural, immune, and endocrine pathways. Patients with various psychiatric disorders including depression, bipolar disorder, schizophrenia, and autism spectrum disorder have been shown to have significant differences in the composition of their gut microbiome. Enhancing beneficial bacteria in the gut, for example, through the use of probiotics, prebiotics, or dietary change, has the potential to improve mood and reduce anxiety in both healthy people and patient groups. Much attention is being given to this subject in the general media, and patients are becoming increasingly interested in the potential to treat mental illness with microbiome-based therapies. It is imperative that those working with people with mental illness are aware of the rationale and current evidence base for such treatment strategies. In this review, we provide an overview of the gut microbiome, what it is, and what it does in relation to gut-brain communication and psychological function. We describe the fundamental principles and basic techniques used in microbiome-gut-brain axis research in an accessible way for a clinician audience. We summarize the current evidence in relation to microbiome-based strategies for various psychiatric disorders and provide some practical advice that can be given to patients seeking to try a probiotic for mental health benefit.
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Anxiety, Depression, and the Microbiome: A Role for Gut Peptides.
Lach, G, Schellekens, H, Dinan, TG, Cryan, JF
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2018;15(1):36-59
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Hormones released in the gut can have an impact in the brain through a bidirectional relationship, known as the gut-brain axis. The release of these hormones may be controlled by the gut microbiota, however exact mechanisms are not fully understood. Most hormones originating in the gut may have a role in obesity development, which is often associated with psychiatric disorders. Understanding the relationship between gut microbiota and depression through gut derived signalling molecules may be of benefit and was the focus of this review. Diversity and stability of the gut microbiota is important for health, which is disrupted during depression and anxiety. The gut microbiota serves to produce brain, hormone and immune signals that can travel to the brain, and can be affected by poor gut health. For those with depression, side effects of anti-depressants can be a disruption of the gut microbiota, however how this impacts symptoms is not fully understood. It was concluded that although there is strong research on the gut microbiota and depression it is still in its infancy. The role of gut microbiota on signalling with the brain and the rest of the body seems to be important for depression and anxiety. This study could be used by healthcare professionals to understand how the gut microbiota can play a role in depression.
Abstract
The complex bidirectional communication between the gut and the brain is finely orchestrated by different systems, including the endocrine, immune, autonomic, and enteric nervous systems. Moreover, increasing evidence supports the role of the microbiome and microbiota-derived molecules in regulating such interactions; however, the mechanisms underpinning such effects are only beginning to be resolved. Microbiota-gut peptide interactions are poised to be of great significance in the regulation of gut-brain signaling. Given the emerging role of the gut-brain axis in a variety of brain disorders, such as anxiety and depression, it is important to understand the contribution of bidirectional interactions between peptide hormones released from the gut and intestinal bacteria in the context of this axis. Indeed, the gastrointestinal tract is the largest endocrine organ in mammals, secreting dozens of different signaling molecules, including peptides. Gut peptides in the systemic circulation can bind cognate receptors on immune cells and vagus nerve terminals thereby enabling indirect gut-brain communication. Gut peptide concentrations are not only modulated by enteric microbiota signals, but also vary according to the composition of the intestinal microbiota. In this review, we will discuss the gut microbiota as a regulator of anxiety and depression, and explore the role of gut-derived peptides as signaling molecules in microbiome-gut-brain communication. Here, we summarize the potential interactions of the microbiota with gut hormones and endocrine peptides, including neuropeptide Y, peptide YY, pancreatic polypeptide, cholecystokinin, glucagon-like peptide, corticotropin-releasing factor, oxytocin, and ghrelin in microbiome-to-brain signaling. Together, gut peptides are important regulators of microbiota-gut-brain signaling in health and stress-related psychiatric illnesses.