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The Gut Microbiome in Early Life Stress: A Systematic Review.
Agusti, A, Lamers, F, Tamayo, M, Benito-Amat, C, Molina-Mendoza, GV, Penninx, BWJH, Sanz, Y
Nutrients. 2023;15(11)
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Children exposed to early life stress (ELS) show alterations in brain development and are at increased risk of developing mental illness. This study aims to clarify whether ELS influences the gut microbiome and whether this can be a predictor for the development of mental disorders. 13 articles were included in this systemic review. 4 looked at pre-natal stress and 9 at post-natal stress. Prenatal stress (via maternal stress) may be associated with an increase in Proteobacteria phylum and with a lower abundance of Bifidobacterium and lactic acid bacteria. In the postnatal group, greater microbiome diversity was related to lower depression and anxiety. In boys scores for adaptive skills were higher in those with good levels of Bifidobacterium. A positive association was found between EA (early adversity) experiences and gastrointestinal symptoms and anxiety. This review demonstrates links between ELS and gut microbiome changes. Further research will be necessary to draw more robust conclusions.
Expert Review
Conflicts of interest:
None
Take Home Message:
- This systematic review consolidated and discussed existing evidence on the link between early life stress (ELS) and changes to the human microbiome
- Exposure to ELS, prenatal or postnatal during childhood and adolescence, may impact mental and physical health.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
A systematic review was conducted to consolidate clinical evidence examining the impact of early life stress (ELS) on the human intestinal microbiome.
Method
Thirteen observational studies were included in the review, sourced from Pubmed, Scopus, Web of Science, and EMBASE. Methodological quality was assessed using the Newcastle-Ottawa Assessment Scale (NOS), with most studies scoring seven or eight out of nine stars.
Study designs varied, including prospective prenatal studies, postnatal longitudinal studies, case-control studies, and cross-sectional studies. Four prenatal studies were prospective in design. The other nine postnatal studies included one longitudinal study, five case-control studies, and three cross-sectional studies. All 13 studies were published between 2015 and 2022. Because study designs and outcome assessments varied, the results were presented in a narrative form. Data was extracted by 2 independent authors.
Results
The primary findings from the review were as follows:
- Four longitudinal stress studies indicated that pregnant mothers experiencing psychological stress, increased cortisol levels, HIV, and lack of social support exhibited a lower abundance of beneficial Bifidobacterium and an increased abundance of Enterobacter genus.
- One postnatal stress longitudinal study (n=260) demonstrated lower depression and anxiety and improved internalising behaviour in patients with high microbiome diversity.
- . One postnatal stress case-control study (n=344) showed changes in the microbiome and an abundance of several bacterial taxa in stressed groups, including genera Prevotella, Bacteroides (Bacteroidetes), Coprococcus, Streptococcus, and Escherichia.
- One cross-sectional study of 128 adults without psychiatric conditions revealed that higher stress correlated with increased levels of Bacteroides, Parabacteroides, Rhodococcus, Methanobrevibacter, and Roseburia at the genus level, as well as lower Phascolarcto bacterium and Firmicutes at the phylum level.
- One large prospective study (n=446) found infants exposed to higher cumulative stress exhibited an increased relative abundance of Proteobacteria groups and lower Bifidobacterium.
Conclusion:
Due to the inconsistency of study designs and their results this review failed to find consensus microbiome signatures associated with pre- or postnatal stress, or both.
Clinical practice applications:
- Early life stress, and alterations in the gut microbiome, have been linked to mental health conditions
- Maternal prenatal stress may be linked to emotional, behavioural, and cognitive outcomes in infants.
Considerations for future research:
- Future research should standardise questionnaires, to ensure consistency and comparability across studies
- Additionally, future studies should consider using standard procedures and specific species and strain resolution shotgun metagenomics sequencing
- Consideration should be given to the influence of environmental variables (diet, physical activity, etc.) and sex in gut microbiome analysis.
Abstract
Exposure to early life stress (ELS), prenatal or postnatal during childhood and adolescence, can significantly impact mental and physical health. The role of the intestinal microbiome in human health, and particularly mental health, is becoming increasingly evident. This systematic review aims to summarize the clinical data evaluating the effect of ELS on the human intestinal microbiome. The systematic review (CRD42022351092) was performed following PRISMA guidelines, with ELS considered as exposure to psychological stressors prenatally and during early life (childhood and adolescence). Thirteen articles met all inclusion criteria, and all studies reviewed found a link between ELS and the gut microbiome in both prenatal and postnatal periods. However, we failed to find consensus microbiome signatures associated with pre- or postnatal stress, or both. The inconsistency of results is likely attributed to various factors such as different experimental designs, ages examined, questionnaires, timing of sample collection and analysis methods, small population sizes, and the type of stressors. Additional studies using similar stressors and validated stress measures, as well as higher-resolution microbiome analytical approaches, are needed to draw definitive conclusions about the links between stress and the human gut microbiome.
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Brain Neurotransmitter Modulation by Gut Microbiota in Anxiety and Depression.
Huang, F, Wu, X
Frontiers in cell and developmental biology. 2021;9:649103
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The causes of anxiety and depression are unclear, but growing evidence points to a role of the gut microbiota. One possible way that the gut microbiota may have an influence on mental health is through a group of chemical messengers in the brain, known as neurotransmitters. This review summarised the research surrounding neurotransmitters and gut microbiota. The review began by looking at research in animal models and the roles of various neurotransmitters and how they may be influenced by the gut microbiota. The neurotransmitters outlined were serotonin, dopamine, and noradrenaline and it was stated that there is evidence that gut microbiota may be able to influence them alleviating anxiety and/or depression, however there was limited evidence with noradrenaline. It was concluded that there is a close connection between the gut microbiota and anxiety and depression. There is more research needed in humans, as most work has been completed in animal models. This paper could be used by healthcare professionals to understand the role of the gut microbiota in mental health disorders and the importance of gut health in individuals suffering from these.
Abstract
Anxiety and depression are highly prevalent mental illnesses worldwide and have long been thought to be closely associated to neurotransmitter modulation. There is growing evidence indicating that changes in the composition of the gut microbiota are related to mental health including anxiety and depression. In this review, we focus on combining the intestinal microbiota with serotonergic, dopaminergic, and noradrenergic neurotransmission in brain, with special emphasis on the anxiety- and depression-like behaviors in stress-related rodent models. Therefore, we reviewed studies conducted on germ-free rodents, or in animals subjected to microbiota absence using antibiotics, as well as via the usage of probiotics. All the results strongly support that the brain neurotransmitter modulation by gut microbiota is indispensable to the physiopathology of anxiety and depression. However, a lot of work is needed to determine how gut microbiota mediated neurotransmission in human brain has any physiological significance and, if any, how it can be used in therapy. Overall, the gut microbiota provides a novel way to alter neurotransmitter modulation in the brain and treat gut-brain axis diseases, such as anxiety and depression.
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Effects of Microbiota Imbalance in Anxiety and Eating Disorders: Probiotics as Novel Therapeutic Approaches.
Navarro-Tapia, E, Almeida-Toledano, L, Sebastiani, G, Serra-Delgado, M, García-Algar, Ó, Andreu-Fernández, V
International journal of molecular sciences. 2021;22(5)
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The interest in mental health has increased recently. Anxiety and mood disorders are associated with many disabilities and there is a close relationship between eating disorders and anxiety. Although current medical treatments for anxiety disorders are safer than a few decades ago; the effectiveness in some of them has not improved, they have side effects and can cause addiction. Therefore, the development of new tools to restore mental health without the undesired effects is necessary. Recent studies indicate that patients with generalized anxiety or eating disorders (anorexia nervosa, bulimia nervosa, and binge-eating disorders) show a specific gut microbiota profile, and this imbalance can be partially restored after a single or multi-strain probiotic supplementation. The purpose of this review is to look at the main microbial patterns seen in patients with generalized anxiety and/or eating disorders as well as the importance of probiotics as a preventive or a therapeutic tool in these pathologies. The studies reviewed showed an imbalance of microbial communities in patients with anxiety and with eating disorders. The effect of probiotics in reducing anxiety seems to be more effective the higher the baseline anxiety level of the individual. For eating disorders, the correction of dysbiosis may be associated with the physical and emotional well-being of these subjects. Further study of the intestinal microbiota will enable progress in the study of therapeutic approaches of these areas.
Abstract
Anxiety and eating disorders produce a physiological imbalance that triggers alterations in the abundance and composition of gut microbiota. Moreover, the gut-brain axis can be altered by several factors such as diet, lifestyle, infections, and antibiotic treatment. Diet alterations generate gut dysbiosis, which affects immune system responses, inflammation mechanisms, the intestinal permeability, as well as the production of short chain fatty acids and neurotransmitters by gut microbiota, which are essential to the correct function of neurological processes. Recent studies indicated that patients with generalized anxiety or eating disorders (anorexia nervosa, bulimia nervosa, and binge-eating disorders) show a specific profile of gut microbiota, and this imbalance can be partially restored after a single or multi-strain probiotic supplementation. Following the PRISMA methodology, the current review addresses the main microbial signatures observed in patients with generalized anxiety and/or eating disorders as well as the importance of probiotics as a preventive or a therapeutic tool in these pathologies.
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Evolution of the Human Diet and Its Impact on Gut Microbiota, Immune Responses, and Brain Health.
González Olmo, BM, Butler, MJ, Barrientos, RM
Nutrients. 2021;13(1)
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One explanation for the increased prevalence in chronic disease and mental illness is from the evolutionary perspective. This suggests the rapid shift in diet towards processed foods in the past 200 years has not allowed for sufficient adaptation of the gut microbiome. The gut microbiome plays an important role in the digestive, immune and nervous systems via the gut-brain axis, and may be a key factor in modulating inflammation and disease. The aim of this review is to discuss how what we eat affects the immune system and impacts our brain health. The literature currently shows significant associations between the Western diet and its impact on the health of the gut microbiome and the brain. Increased intake of saturated fats, refined carbohydrates and sugar, coupled with a reduction in fiber, negatively impacts the digestive system and elicits an immune response. This response can lead to neuroinflammation, which is now found to be associated with deficits in learning and memory, as well as increased rates of neurodegenerative disease and depression. Based on the existing literature, the authors conclude the human gut microbiome has not had sufficient time to adapt to many modern foods, thus leading to inflammation and disease. The authors recommend that a diet composed of natural whole foods with minimal processing can help prevent and alleviate some of the burden caused by chronic disease, and suggest future studies focus on improving techniques to evaluate neuroinflammation in humans.
Abstract
The relatively rapid shift from consuming preagricultural wild foods for thousands of years, to consuming postindustrial semi-processed and ultra-processed foods endemic of the Western world less than 200 years ago did not allow for evolutionary adaptation of the commensal microbial species that inhabit the human gastrointestinal (GI) tract, and this has significantly impacted gut health. The human gut microbiota, the diverse and dynamic population of microbes, has been demonstrated to have extensive and important interactions with the digestive, immune, and nervous systems. Western diet-induced dysbiosis of the gut microbiota has been shown to negatively impact human digestive physiology, to have pathogenic effects on the immune system, and, in turn, cause exaggerated neuroinflammation. Given the tremendous amount of evidence linking neuroinflammation with neural dysfunction, it is no surprise that the Western diet has been implicated in the development of many diseases and disorders of the brain, including memory impairments, neurodegenerative disorders, and depression. In this review, we discuss each of these concepts to understand how what we eat can lead to cognitive and psychiatric diseases.
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Role of the Intestinal Microbiome, Intestinal Barrier and Psychobiotics in Depression.
Trzeciak, P, Herbet, M
Nutrients. 2021;13(3)
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Major depressive disorder (MDD) is a disorder with feelings of depressed mood or loss of interest or pleasure alongside several other symptoms such as weight or appetite changes, difficulty sleeping and an inability to think or concentrate. The development of MDD is not fully understood and may involve several different factors such as the gut microbiome. The gut microbiome may be involved as it can communicate with the brain in a bidirectional fashion, known as the gut-brain axis. This review study aimed to summarise the data on the use of probiotics thought to confer benefits in the brain, known as psychobiotics. Depression is thought to involve aspects of imbalances in brain signalling molecules, stress hormones, and free radicals and inflammation. One of the newest ideas suggests that the gut microbiome may have a role. Individuals with depression have shown to have altered composition of gut microbiota, which may have an impact in several ways. Alterations in vitamin production, altered intestinal barrier function and poor diet during disease, may all contribute to the development of MDD. Psychobiotics may be of benefit to symptoms of depression shown in numerous animal and human studies. It was concluded that there are several ways that the microbiota may be involved in the development of depression. This study could be used by healthcare professionals to justify the introduction of psychobiotics as an adjuvant to standard therapy for MDD, to relieve symptoms.
Abstract
The intestinal microbiota plays an important role in the pathophysiology of depression. As determined, the microbiota influences the shaping and modulation of the functioning of the gut-brain axis. The intestinal microbiota has a significant impact on processes related to neurotransmitter synthesis, the myelination of neurons in the prefrontal cortex, and is also involved in the development of the amygdala and hippocampus. Intestinal bacteria are also a source of vitamins, the deficiency of which is believed to be related to the response to antidepressant therapy and may lead to exacerbation of depressive symptoms. Additionally, it is known that, in periods of excessive activation of stress reactions, the immune system also plays an important role, negatively affecting the tightness of the intestinal barrier and intestinal microflora. In this review, we have summarized the role of the gut microbiota, its metabolites, and diet in susceptibility to depression. We also describe abnormalities in the functioning of the intestinal barrier caused by increased activity of the immune system in response to stressors. Moreover, the presented study discusses the role of psychobiotics in the prevention and treatment of depression through their influence on the intestinal barrier, immune processes, and functioning of the nervous system.
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Towards Tailored Gut Microbiome-Based and Dietary Interventions for Promoting the Development and Maintenance of a Healthy Brain.
Larroya, A, Pantoja, J, Codoñer-Franch, P, Cenit, MC
Frontiers in pediatrics. 2021;9:705859
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The cause of neurodevelopmental disorders (NDDs) is complex and multifactorial. Recent studies have indicated that early life disturbances of the gut microbiome can impact neurodevelopment, suggesting this critical window may play a key role in the prevention or progression of neurological disease. The growing field of personalized nutrition works on the basis of tailored dietary intervention strategies that consider individual variability based on genetics, diet, and the environment. The aim of this paper is to review the current evidence on the neurodevelopmental interaction between the gut microbiota, environment and host, and assess the efficacy of tailored, personalized nutrition interventions aimed at preventing or treating NDDs. The literature provides evidence that the gut microbiota is susceptible to influence by various factors early in life, and the health of the microbiome may modulate mental health consequences later in life. Additionally, key nutritional deficiencies and microbiome alterations have been linked to NDDs, suggesting potential markers that may lead to improved prevention and treatment. Based on the current literature, the authors emphasize the need for further research during the critical window of microbiome development in order to target the cause of neurodevelopmental impairments. They suggest these findings could help progress the field of Nutritional Psychiatry towards effective tailored nutrition and personalized medicine.
Abstract
Mental health is determined by a complex interplay between the Neurological Exposome and the Human Genome. Multiple genetic and non-genetic (exposome) factors interact early in life, modulating the risk of developing the most common complex neurodevelopmental disorders (NDDs), with potential long-term consequences on health. To date, the understating of the precise etiology underpinning these neurological alterations, and their clinical management pose a challenge. The crucial role played by diet and gut microbiota in brain development and functioning would indicate that modulating the gut-brain axis may help protect against the onset and progression of mental-health disorders. Some nutritional deficiencies and gut microbiota alterations have been linked to NDDs, suggesting their potential pathogenic implications. In addition, certain dietary interventions have emerged as promising alternatives or adjuvant strategies for improving the management of particular NDDs, at least in particular subsets of subjects. The gut microbiota can be a key to mediating the effects of other exposome factors such as diet on mental health, and ongoing research in Psychiatry and Neuropediatrics is developing Precision Nutrition Models to classify subjects according to a diet response prediction based on specific individual features, including microbiome signatures. Here, we review current scientific evidence for the impact of early life environmental factors, including diet, on gut microbiota and neuro-development, emphasizing the potential long-term consequences on health; and also summarize the state of the art regarding the mechanisms underlying diet and gut microbiota influence on the brain-gut axis. Furthermore, we describe the evidence supporting the key role played by gut microbiota, diet and nutrition in neurodevelopment, as well as the effectiveness of certain dietary and microbiome-based interventions aimed at preventing or treating NDDs. Finally, we emphasize the need for further research to gain greater insight into the complex interplay between diet, gut microbiome and brain development. Such knowledge would help towards achieving tailored integrative treatments, including personalized nutrition.
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Updated Review and Meta-Analysis of Probiotics for the Treatment of Clinical Depression: Adjunctive vs. Stand-Alone Treatment.
Nikolova, VL, Cleare, AJ, Young, AH, Stone, JM
Journal of clinical medicine. 2021;10(4)
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Major depressive disorder is a common, complex, and heterogeneous illness that is characterized by persistent low mood and anhedonia, and a combination of sleep disturbances, changes in appetite, feelings of worthlessness or guilt, poor concentration, and suicidal ideation. The aim of this study was to identify and evaluate all current evidence from randomised controlled trials on the efficacy of probiotics in reducing depressive symptoms among people with clinical depression. This study is a review and meta-analysis of randomised controlled trials which included seven studies for qualitative and quantitative analysis. Results demonstrate that probiotics significantly reduce depressive symptoms after eight weeks of use, but only when used in addition to an approved antidepressant. Authors conclude that their findings support the clinical use of probiotics in depressed populations and provides an insight into the mode of administration more likely to yield antidepressant effects.
Abstract
Recent years have seen a rapid increase in the use of gut microbiota-targeting interventions, such as probiotics, for the treatment of psychiatric disorders. The objective of this update review was to evaluate all randomised controlled clinical trial evidence on the efficacy of probiotics for clinical depression. Cochrane guidelines for updated reviews were followed. By searching PubMed and Web of Science databases, we identified 546 new records since our previous review. A total of seven studies met selection criteria, capturing 404 people with depression. A random effects meta-analysis using treatment type (stand-alone vs. adjunctive) as subgroup was performed. The results demonstrated that probiotics are effective in reducing depressive symptoms when administered in addition to antidepressants (SMD = 0.83, 95%CI 0.49-1.17), however, they do not seem to offer significant benefits when used as stand-alone treatment (SMD = -0.02, 95%CI -0.34-0.30). Potential mechanisms of action may be via increases in brain-derived neurotrophic factor (BDNF) and decreases in C-reactive protein (CRP), although limited evidence is available at present. This review offers stronger evidence to support the clinical use of probiotics in depressed populations and provides an insight into the mode of administration more likely to yield antidepressant effects.
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Exploring the Role and Potential of Probiotics in the Field of Mental Health: Major Depressive Disorder.
Johnson, D, Thurairajasingam, S, Letchumanan, V, Chan, KG, Lee, LH
Nutrients. 2021;13(5)
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A bi-directional communication between the brain and the microbiome of the gut may exist, known as the microbiome-gut-brain axis (MGBA). The role of this and the use of probiotics in relation to many psychiatric and neurological disorders is being increasingly researched. This review aimed to summarise the research on the use of probiotics for the treatment of mental health disorders and major depressive disorder (MDD). Probiotics and their use were summarised concluding that they have a diverse range of health benefits due to their anti-inflammatory, antipathogenic and antimicrobial actions. Imbalances in the four major phyla of gut bacteria; Bacteroidetes, Firmicutes, Proteobacteria and Actinobacteria may have a major role in the development of MDD. Probiotics may have several mechanisms through which they benefit MDD and decreased inflammation in the brain, increased production of chemicals involved in brain signalling and decreased stress hormones, were all implicated. It was concluded that probiotics have mental health benefits, however gaps in the evidence from studies needs to be addressed. This study could be used by healthcare professionals to understand the role of probiotics in the treatment of mental health disorders and in particular MDD.
Abstract
The field of probiotic has been exponentially expanding over the recent decades with a more therapeutic-centered research. Probiotics mediated microbiota modulation within the microbiota-gut-brain axis (MGBA) have been proven to be beneficial in various health domains through pre-clinical and clinical studies. In the context of mental health, although probiotic research is still in its infancy stage, the promising role and potential of probiotics in various mental disorders demonstrated via in-vivo and in-vitro studies have laid a strong foundation for translating preclinical models to humans. The exploration of the therapeutic role and potential of probiotics in major depressive disorder (MDD) is an extremely noteworthy field of research. The possible etio-pathological mechanisms of depression involving inflammation, neurotransmitters, the hypothalamic-pituitary-adrenal (HPA) axis and epigenetic mechanisms potentially benefit from probiotic intervention. Probiotics, both as an adjunct to antidepressants or a stand-alone intervention, have a beneficial role and potential in mitigating anti-depressive effects, and confers some advantages compared to conventional treatments of depression using anti-depressants.
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The role of the microbiota-gut-brain axis in neuropsychiatric disorders.
Generoso, JS, Giridharan, VV, Lee, J, Macedo, D, Barichello, T
Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999). 2021;43(3):293-305
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Metabolites produced by the gut microbiota have been shown to influence mood and behaviour via the microbiota-gut-brain axis, and there is increased interest in better understanding this interaction in the context of mental health. This review summarises the evidence around the influence of gut microbiota in various neuropsychiatric disorders, primarily focusing on the metabolic pathways that originate in the gut microbiota. Current research highlights an association between gut microbiota metabolites with neuropsychiatric disorders and that probiotics demonstrate a significant therapeutic role in many of these disorders. Based on the current literature, the authors conclude it is crucial to better understand the complex microbiota-host interaction in health and disease, leading to more targeted and improved therapeutic interventions.
Abstract
The microbiota-gut-brain axis is a bidirectional signaling mechanism between the gastrointestinal tract and the central nervous system. The complexity of the intestinal ecosystem is extraordinary; it comprises more than 100 trillion microbial cells that inhabit the small and large intestine, and this interaction between microbiota and intestinal epithelium can cause physiological changes in the brain and influence mood and behavior. Currently, there has been an emphasis on how such interactions affect mental health. Evidence indicates that intestinal microbiota are involved in neurological and psychiatric disorders. This review covers evidence for the influence of gut microbiota on the brain and behavior in Alzheimer disease, dementia, anxiety, autism spectrum disorder, bipolar disorder, major depressive disorder, Parkinson's disease, and schizophrenia. The primary focus is on the pathways involved in intestinal metabolites of microbial origin, including short-chain fatty acids, tryptophan metabolites, and bacterial components that can activate the host's immune system. We also list clinical evidence regarding prebiotics, probiotics, and fecal microbiota transplantation as adjuvant therapies for neuropsychiatric disorders.
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Probiotics, Prebiotics and Postbiotics on Mitigation of Depression Symptoms: Modulation of the Brain-Gut-Microbiome Axis.
Chudzik, A, Orzyłowska, A, Rola, R, Stanisz, GJ
Biomolecules. 2021;11(7)
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The bidirectional communication pathway between the gut microbiota and the central nervous system has been termed the brain-gut-microbiome axis. Increased investigation of this pathway has found the gut bacteria to impact metabolism and the brain, suggesting that modulating the microbiome may elicit change in mental health. The aim of this review is to discuss the current findings in both animal and human studies regarding the use of pro-, pre- and post-biotics in the prevention and treatment of depressive disorders. Studies show that modulating the bacteria in the gut may reduce inflammation, decrease stress hormone levels and adjust the levels of neurotransmitters in the brain. These changes consequently lead to the reduction of depressive symptoms and improvement in mood. While these results are promising, larger clinical trials are needed that include biochemical measurements and fecal microbiome analysis in addition to validated questionnaires. With this in mind, the authors conclude there is huge potential in the role of nutrition as a therapeutic target for neurological and mental health conditions.
Abstract
The brain-gut-microbiome axis is a bidirectional communication pathway between the gut microbiota and the central nervous system. The growing interest in the gut microbiota and mechanisms of its interaction with the brain has contributed to the considerable attention given to the potential use of probiotics, prebiotics and postbiotics in the prevention and treatment of depressive disorders. This review discusses the up-to-date findings in preclinical and clinical trials regarding the use of pro-, pre- and postbiotics in depressive disorders. Studies in rodent models of depression show that some of them inhibit inflammation, decrease corticosterone level and change the level of neurometabolites, which consequently lead to mitigation of the symptoms of depression. Moreover, certain clinical studies have indicated improvement in mood as well as changes in biochemical parameters in patients suffering from depressive disorders.