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An updated overview on the relationship between human gut microbiome dysbiosis and psychiatric and psychological disorders.
There is a lot of evidence establishing that nervous system development is related to the composition and functions of the gut microbiome. In addition, the central nervous system (CNS) controls the imbalance of the intestinal microbiota, constituting a bidirectional communication system. At present, various gut-brain crosstalk routes have been described, including immune, endocrine and neural circuits via the vagal pathway. Several empirical data have associated gut microbiota alterations (dysbiosis) with neuropsychiatric diseases, such as Alzheimer's disease, autism and Parkinson's disease, and with other psychological disorders, like anxiety and depression. Fecal microbiota transplantation (FMT) therapy has shown that the gut microbiota can transfer behavioral features to recipient animals, which provides strong evidence to establish a causal-effect relationship. Interventions, based on prebiotics, probiotics or synbiotics, have demonstrated an important influence of microbiota on neurological disorders by the synthesis of neuroactive compounds that interact with the nervous system and by the regulation of inflammatory and endocrine processes. Further research is needed to demonstrate the influence of gut microbiota dysbiosis on psychiatric and psychological disorders, and how microbiota-based interventions may be used as potential therapeutic tools.
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Never fear, the gut bacteria are here: Estrogen and gut microbiome-brain axis interactions in fear extinction.
Sex differences in the prevalence, symptomatology, severity, and other aspects of various neuropsychiatric diseases have been consistently reported. Stress and fear-related psychopathologies, such as anxiety disorders, depression, and post-traumatic stress disorder, are more prevalent in women. Investigations of the mechanisms underlying this sex disparity have described the influence of gonadal hormones in both humans and animal models. However, gut microbial communities are also likely to play a role, as these communities differ between the sexes, are involved in a bidirectional cycling of sex hormones and their metabolites, and are associated with changes in fear-related psychopathologies when gut microbiota are altered or removed. Here, we focus our review on: (1) the role of gut microbiota-brain connections in stress- and fear-based psychiatric disorders, (2) gut microbiota interactions with sex hormones with a particular focus on estrogen, and (3) investigations of these estrogen-gut microbiome interactions in fear extinction, a laboratory model of exposure therapy, to elucidate potential targets for psychiatric treatment. Finally, we call for more mechanistic research using female rodent models and humans.
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Steroids, stress and the gut microbiome-brain axis.
It is becoming well established that the gut microbiome has a profound impact on human health and disease. In this review, we explore how steroids can influence the gut microbiota and, in turn, how the gut microbiota can influence hormone levels. Within the context of the gut microbiome-brain axis, we discuss how perturbations in the gut microbiota can alter the stress axis and behaviour. In addition, human studies on the possible role of gut microbiota in depression and anxiety are examined. Finally, we present some of the challenges and important questions that need to be addressed by future research in this exciting new area at the intersection of steroids, stress, gut-brain axis and human health.
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Substance use, microbiome and psychiatric disorders.
Accumulating evidence from several studies has shown association between substance use, dysregulation of the microbiome and psychiatric disorders such as depression, anxiety, and psychosis. Many of the abused substances such as cocaine and alcohol have been shown to alter immune signaling pathways and cause inflammation in both the periphery and the central nervous system (CNS). In addition, these substances of abuse also alter the composition and function of the gut microbiome which is known to play important roles such as the synthesis of neurotransmitters and metabolites, that affect the CNS homeostasis and consequent behavioral outcomes. The emerging interactions between substance use, microbiome and CNS neurochemical alterations could contribute to the development of psychiatric disorders. This review provides an overview of the associative effects of substance use such as alcohol, cocaine, methamphetamine, nicotine and opioids on the gut microbiome and psychiatric disorders involving anxiety, depression and psychosis. Understanding the relationship between substance use, microbiome and psychiatric disorders will provide insights for potential therapeutic targets, aimed at mitigating these adverse outcomes.
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Sleep and Microbiome in Psychiatric Diseases.
OBJECTIVES: Disturbances in the gut-brain barrier play an essential role in the development of mental disorders. There is considerable evidence showing that the gut microbiome not only affects digestive, metabolic and immune functions of the host but also regulates host sleep and mental states through the microbiota-gut-brain axis. The present review summarizes the role of the gut microbiome in the context of circadian rhythms, nutrition and sleep in psychiatric disorders. METHODS: A PubMed search (studies published between April 2015-April 2020) was conducted with the keywords: "sleep, microbiome and psychiatry"; "sleep, microbiome and depression"; "sleep, microbiome and bipolar disorder", "sleep, microbiome and schizophrenia", "sleep, microbiome and anorexia nervosa", "sleep, microbiome and substance use disorder", "sleep, microbiome and anxiety"; "clock gene expression and microbiome", "clock gene expression and nutrition". Only studies investigating the relationship between sleep and microbiome in psychiatric patients were included in the review. RESULTS: Search results yielded two cross-sectional studies analyzing sleep and gut microbiome in 154 individuals with bipolar disorder and one interventional study analyzing the effect of fecal microbiota transplantation in 17 individuals with irritable bowel syndrome on sleep. In patients with bipolar disorder, Faecalibacterium was significantly associated with improved sleep quality scores and a significant correlation between Lactobacillus counts and sleep. CONCLUSION: Translational research on this important field is limited and further investigation of the bidirectional pathways on sleep and the gut microbiome in mood disorders is warranted.
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Potential therapeutic applications of the gut microbiome in obesity: from brain function to body detoxification.
The prevalence of obesity is rising every year and associated comorbidities such as cardiovascular diseases are among the leading causes of death worldwide. The gut microbiota has recently emerged as a potential target for therapeutic applications to prevent and treat those comorbidities. In this review, we focus on three conditions related to obesity in which the use of gut microbiota modulators could have benefits; mood disorders, eating behaviors, and body detoxification of persistent organic pollutants (POPs). On one hand, modulation of gut-derived signals to the brain in a context of obesity is involved in the development of neuroinflammation and can subsequently alter behaviors. An altered gut microbiome could change these signals and alleviate their consequences. On the other hand, obesity is associated with an increased accumulation of lipophilic contaminants, such as POPs. Targeting the microbiota could help body detoxication by reducing bioavailability, enhancing degradation by bioremediation or their excretion through the enterohepatic circulation. Thus, a supplementation of prebiotics, probiotics, or synbiotics could represent a complementary strategy to current ones, such as medication and lifestyle modifications, to decrease depression, alter eating behaviors, and lower body burden of pollutants considering the actual obesity epidemic our society is facing.
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Differences in gut microbiome composition between persons with chronic schizophrenia and healthy comparison subjects.
Intestinal microbiome and gut-brain axis have been receiving increasing attention for their role in the regulation of brain/behavior and possible biological basis of psychiatric disorders. Several recent clinical studies have linked the microbiome with neuropsychiatric conditions, although the literature on schizophrenia is quite limited. This study investigated gut microbiome composition in 50 individuals, including 25 persons with chronic schizophrenia and 25 demographically-matched non-psychiatric comparison subjects (NCs). Stool samples were collected and assayed using 16S rRNA sequencing of the V4 region. Examination of unweighted UniFrac and Bray-Curtis dissimilarity revealed significant community-level separation in microbiome composition between the two subject groups. At the phylum level, Proteobacteria were found to be relatively decreased in schizophrenia subjects compared to NCs. At the genus level, Anaerococcus was relatively increased in schizophrenia while Haemophilus, Sutterella, and Clostridium were decreased. Within individuals with schizophrenia, abundance of Ruminococcaceae was correlated with lower severity of negative symptoms; Bacteroides was associated with worse depressive symptoms; and Coprococcus was related to greater risk for developing coronary heart disease. Our findings provide evidence of altered gut microbial composition in persons with chronic schizophrenia and suggest a need for larger and longitudinal studies of microbiome in schizophrenia.
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Improving Mental Health for the Mother-Infant Dyad by Nutrition and the Maternal Gut Microbiome.
Perinatal mood and anxiety disorders (PMAD) have significant negative impacts on mother and child, yet treatments are limited. Adequate nutrition during the perinatal period is essential to maternal and infant health, including maternal mental health and the child's neurologic and neuropsychiatric development. Nutrition holds promise to improve prevention and treatment of PMAD. The ability to manipulate the gut microbiota composition and structure through host nutrition and to harness the gut microbes for improved individualized nutrition may be an important new direction for prevention and treatment of PMAD, thus improving the mental health of mother and child.
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Effect of icariin on depressive behaviour in rat pups. Evidences for its mechanism of action by integrating network pharmacology, metabolomics and gut microbiota composition.
BACKGROUND: Prenatal stress (PS) can cause cognitive disorder and a range of psychological illnesses, including anxiety and depression. Icariin (ICA) has shown promising effects in improving PS-induced depressive behaviour. However, its mechanism of action remains unclear. PURPOSE: This study was performed to reveal the key targets, metabolites and gut microbiota for ICA in improving depressive behaviour in PS rat pups. METHODS: A prenatal restraint stress animal model was established for Sprague-Dawley (SD) rats in late pregnancy. Male pups were randomly divided into six groups: no stress group (NS), PS group, PS + saline group (PS_S), PS + high-dose ICA group (ICAH, 80 mg/kg*day), PS + low-dose ICA group (ICAL, 40 mg/kg*day) and PS + fluoxetine group (FLU, 10 mg/kg*day). The depressive behaviour of each group of rat pups was evaluated using open field test, forced swimming test and sucrose preference test. Different metabolites were identified using untargeted metabolomics of serum and faeces, and metabolic pathways were analyzed through MetaboAnalyst. Targets for ICA acting on depression were determined after network pharmacology was applied. An integrated network of network pharmacology and metabolomics were constructed using Cytoscape software, and molecular docking were performed to verify the interactions between ICA and key targets. Finally, gut microbiota of rat pups in each group were analyzed after 16S rDNA sequencing. RESULTS: PS could cause rat pups to exhibit depressive behaviour, and ICA could significantly improve this depressive behaviour. A total of 49 differential metabolites were found in serum and 23 differential metabolites were found in faeces, and 24 metabolites in serum and 6 metabolites in faeces could be reversed following ICA administration. Integrated analysis focused on five key targets (i.e. adenosyl homocysteinase; medium-chain specific acyl-CoA dehydrogenase, mitochondrial; thymidine phosphorylase; cGMP-specific 3',5'-cyclic phosphodiesterase and xanthine dehydrogenase/oxidase) and three metabolites (i.e. palmitoylcarnitine, methionine and hypoxanthine). Molecular docking indicated that ICA combined well with key targets. Gut microbiota analysis showed that g_Bacteroides, f_Bacteroidaceae and s_Lactobacillus reuteri were required for ICA to improve depressive behaviour. CONCLUSION: In this study, the antidepressant mechanism of ICA was clarified with a strategy of integrating metabolomics, network pharmacology and gut microbiota. ICA has a good effect on improving metabolism and increasing the abundance of probiotics in the intestine. The present research provided new insights into the anti-depressant mechanism of ICA.
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The Microbiota-Gut-Brain Axis in Neuropsychiatric Disorders: Pathophysiological Mechanisms and Novel Treatments.
BACKGROUND: The human gut microbiome comprise a huge number of microorganisms with co-evolutionary associations with humans. It has been repeatedly revealed that bidirectional communication exists between the brain and the gut and involves neural, hormonal, and immunological pathways. Evidences from neuroscience researches over the past few years suggest that microbiota is essential for the development and maturation of brain systems that are associated to stress responses. METHOD: This review provides that the summarization of the communication among microbiota, gut and brain and the results of preclinical and clinical studies on gut microbiota used in treatments for neuropsychiatric disorders. RESULT: Recent studies have reported that diverse forms of neuropsychiatric disorders (such as autism, depression, anxiety, and schizophrenia) are associated with or modulated by variations in the microbiome, by microbial substrates, and by exogenous prebiotics, antibiotics, and probiotics. CONCLUSION: The microbiota-gut-brain axis might provide novel targets for prevention and treatment of neuropsychiatric disorders. However, further studies are required to substantiate the clinical use of probiotics, prebiotics and FMT.