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Microbe-Immune-Stress Interactions Impact Behaviour during Postnatal Development.
Decades of research have established the role of microbiota-brain communication in behaviour and brain function. Studies have shown that microbiota composition and diversity are influenced by a variety of factors including host genetics, diet, and other environmental exposures, with implications for the immunological and neurobiological development of the host organism. To further understand early-life interactions between environment, genetic factors, the microbiome and the central nervous system, we investigated the impact of postnatal stress in C57Bl/6 wild type and T-cell deficient mice on microbe-brain interactions and behaviour. Mice were exposed to immune challenge with lipopolysaccharide (LPS) at postnatal day (P) 3 and maternal separation at P9 (16 h overnight). Behavioural assessment of growth and development as well as behaviour (righting reflex, ultrasonic vocalizations in response to brief maternal separation, open field, sociability, and grooming) was conducted. Microbiota diversity and composition of fecal samples collected at P24 revealed reduced alpha diversity in T-cell-deficient mice as well as genotype- and stress-related taxa. Notably, integrated analyses of microbiota and behaviour in the context of immunocompromise revealed key behavioural related taxa that may be important to brain development. These findings are important to determining the influence of genetic and environmental factors on gut microbiota and advances our understanding microbiome-brain signaling pathways on neurodevelopment and behaviour.
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Exploring Therapeutic Potential of Phytoconstituents as a Gut Microbiota Modulator in the Management of Neurological and Psychological Disorders.
The functioning of the brain and its impact on behavior, emotions, and cognition can be affected by both neurological and psychiatric disorders that impose a significant burden on global health. Phytochemicals are helpful in the treatment of several neurological and psychological disorders, including anxiety, depression, Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), and autism spectrum disorder (ASD), because they have symptomatic benefits with few adverse reactions. Changes in gut microbiota have been associated with many neurological and psychiatric conditions. This review focuses on the potential efficacy of phytochemicals such as flavonoids, terpenoids, and polyphenols in regulating gut flora and providing symptomatic relief for a range of neurological and psychological conditions. Evidence-based research has shown the medicinal potentials of these phytochemicals, but additional study is required to determine whether altering gut microbiota might slow the advancement of neurological and psychological problems.
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One Giant Leap from Mouse to Man: The Microbiota-Gut-Brain Axis in Mood Disorders and Translational Challenges Moving towards Human Clinical Trials.
The microbiota-gut-brain axis is a bidirectional communication pathway that enables the gut microbiota to communicate with the brain through direct and indirect signaling pathways to influence brain physiology, function, and even behavior. Research has shown that probiotics can improve several aspects of health by changing the environment within the gut, and several lines of evidence now indicate a beneficial effect of probiotics on mental and brain health. Such evidence has prompted the arrival of a new term to the world of biotics research: psychobiotics, defined as any exogenous influence whose effect on mental health is bacterially mediated. Several taxonomic changes in the gut microbiota have been reported in neurodevelopmental disorders, mood disorders such as anxiety and depression, and neurodegenerative disorders such as Alzheimer's disease. While clinical evidence supporting the role of the gut microbiota in mental and brain health, and indeed demonstrating the beneficial effects of probiotics is rapidly accumulating, most of the evidence to date has emerged from preclinical studies employing different animal models. The purpose of this review is to focus on the role of probiotics and the microbiota-gut-brain axis in relation to mood disorders and to review the current translational challenges from preclinical to clinical research.
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Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration.
There is a growing realisation that the gut-brain axis and its regulation by the microbiota may play a key role in the biological and physiological basis of neurodevelopmental, age-related and neurodegenerative disorders. The routes of communication between the microbiota and brain are being unravelled and include the vagus nerve, gut hormone signalling, the immune system, tryptophan metabolism or by way of microbial metabolites such as short chain fatty acids. The importance of early life gut microbiota in shaping future health outcomes is also emerging. Disturbances of this composition by way of antibiotic exposure, lack of breastfeeding, infection, stress and the environmental influences coupled with the influence of host genetics can result in long-term effects on physiology and behaviour, at least in animal models. It is also worth noting that mode of delivery at birth influences microbiota composition with those born by Caesarean section having a distinctly different microbiota in early life to those born per vaginum. At the other extreme of life, ageing is associated with a narrowing in microbial diversity and healthy ageing correlates with a diverse microbiome. Recently, the gut microbiota has been implicated in a variety of conditions including depression, autism, schizophrenia and Parkinson's disease. There is still considerable debate as to whether or not the gut microbiota changes are core to the pathophysiology of such conditions or are merely epiphenomenal. It is plausible that such neuropsychiatric disorders might be treated in the future by targeting the microbiota either by microbiota transplantation, antibiotics or psychobiotics.
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Associations among diet, the gastrointestinal microbiota, and negative emotional states in adults.
Objective: Habitual diet impacts mood and the human gastrointestinal (GI) microbiota. Yet, studies infrequently control for diet when evaluating associations between mood and GI microbiota. Accordingly, we aimed to investigate relationships among diet, GI microbiota, and mood in adults without mood disorders by conducting a cross-sectional examination of dietary intake, subjective emotional state, and fecal microbial taxa abundances. Methods: Adults (N = 133; 25-45 years of age) without physician-diagnosed mood disorders were studied. Fecal DNA was extracted, and the V4 region of the 16S rRNA gene was sequenced. Sequences were analyzed using QIIME2. Subjective mood state was assessed using the 42-item Depression, Anxiety, and Stress Scale (DASS-42). Habitual dietary intake was measured with the National Cancer Institute's Diet History Questionnaire II, and diet quality was evaluated with the 2010 Healthy Eating Index (HEI). Results: Relationships were observed between 28 bacterial taxa and DASS-42 scores. Sex-dependent associations were observed among 21 bacterial taxa and DASS-42 scores, including an inverse relationship between Anxiety scale scores and Bifidobacterium in females and an inverse relationship between Depression scale scores and Lactobacillus in males. HEI total fruit and dairy components were inversely associated with Depression and Stress scales, respectively. Conclusions: These results suggest GI microbes are related to mood in adults without diagnosed mood disorders and that these relationships differ by sex and are influenced by dietary fiber intake. Incorporating dietary intake data in gut-microbiota-brain studies may help clarify the roles of specific microbes and dietary components in mental health symptoms.
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Gut microbiota profiles associated with temporal lobe epilepsy and psychiatric comorbidities: a family-matched case-control 16S rRNA study.
We investigated alterations in the intestinal microbiota of patients with temporal lobe epilepsy (TLE) and their associations with drug resistance and psychiatric comorbidities. Thirty TLE patients and 30 family-matched healthy controls sharing the same household diet were recruited, and fecal samples were analyzed by high-throughput 16S rDNA sequencing on the Illumina MiSeq [Formula: see text] bp platform. Differential abundance was assessed using Metastats and LEfSe with Benjamini-Hochberg false-discovery-rate correction, and independently validated using ANCOM-BC to account for the compositional nature of microbiome data. Community α- and β-diversity indices showed no significant differences between groups; however, ANCOM-BC identified species-level signatures in drug-resistant epilepsy, including significant depletion of Bacteroides plebeius and Coprococcus comes. Among psychiatric subgroups, Ruminococcus was significantly reduced in patients with comorbid depression, while Bilophila was enriched in those with comorbid anxiety and depression. Bacteroides stercoris distinguished the anxiety-plus-depression subgroup from the depression-only subgroup with robust support from both ANCOM and ANCOM-BC. Given the modest overall sample size ([Formula: see text] per arm) and small psychiatric and drug-resistance subgroups, these findings should be regarded as exploratory and hypothesis-generating associations rather than definitive biomarkers. They identify candidate microbial taxa warranting validation in larger, longitudinal cohorts combined with metagenomic and metabolomic approaches.
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A systematic review of microbiome changes and impact of probiotic supplementation in children and adolescents with neuropsychiatric disorders.
OBJECTIVES: In recent decades, the diagnostic and therapeutic implications of the microbiome changes and the impact of probiotic supplementation have increased rapidly. However, the potential for clinical translation of microbiome research for children and adolescents with psychiatric disorders is unclear. This review examined available evidence related to gut microbiota as well as the impact of probiotic supplementation on psychiatric disorders in the pediatric population reported to date. METHODS: We performed a literature search for the gut microbiota in child and adolescent population (0-18 years old) with mental health disorders from July 1999 through July 2019 in several databases: ClinicalTrials.gov, Ovid EBM Reviews, Ovid Embase, Ovid Medline, Ovid PsycINFO, Scopus, and Web of Science. RESULTS: A total of 7 studies met inclusion criteria consisting of randomized controlled trials and cohort studies that examined various associations between psychiatric disorders and gut microbiota in youth. Six studies examined the effects of various treatment interventions such as probiotic supplementation on microbiota composition and behaviors. One study showed an increase in prosocial behavior in children with Autism Spectrum Disorder (ASD) and an increase in the Lachnospiraceae family following prebiotic supplementation. Another study suggested that prebiotic supplementation increased bifidobacterial populations for ASD and healthy controls. A study evaluating infant supplementation of prebiotics showed both a decreased likelihood of developing Attention Deficit Hyperactivity Disorder (ADHD) or ASD and decreased gut Bifidobacterium. One study did not find significant differences in microbiome composition after micronutrient treatment. CONCLUSION: The main goal of this systematic review was to comprehensively examine and summarize the current evidence focused on the potential effect of the relationship between microbiota gut composition as well as the effects of probiotic supplementation on psychiatric disorders in children and adolescents. This is a relatively new area of research and the number of included studies is limited. More studies are needed to determine whether gut dysbiosis leads to the development and/or contributes to the severity of mental disorders or whether gut dysbiosis is a result of other processes that accompany mental disorders. CLINICAL SIGNIFICANCE: A better understanding of the specific bacteria contributions, gut-brain pathways, and role in pathophysiological mechanisms in neuropsychiatric disorders in the child and adolescent populations can possibly provide alternative tools for a clinical psychiatrist. Moreover, it may ultimately aid the clinician with intervention strategies, or detect populations at risk for developing neuropsychiatric disorders.
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Ketamine enantiomers and the gut microbiota: mechanisms, clinical implications, and future directions.
There is a complex, bidirectional interaction between the gut microbiota and the central nervous system, known as the gut-brain axis. Esketamine, as the right-handed isomer of ketamine, has been approved by the US FDA for the treatment of treatment-resistant depression (TRD), and its rapid antidepressant effect may involve modulation of gut microbiota. In addition, other ketamine isomers (such as R-ketamine) and racemic mixtures (R, S-ketamine) may also affect the gut microbiota through different pathways. This article reviews the potential regulatory mechanisms of ketamine and its isomers on gut microbiota, including anti-inflammatory effects, regulation of neurotransmitter metabolism, and intestinal barrier repair. It discusses, their clinical implications and future research directions.
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Delivery of Metabolically Neuroactive Probiotics to the Human Gut.
The human microbiome is a rich factory for metabolite production and emerging data has led to the concept that orally administered microbial strains can synthesize metabolites with neuroactive potential. Recent research from ex vivo and murine models suggests translational potential for microbes to regulate anxiety and depression through the gut-brain axis. However, so far, less emphasis has been placed on the selection of specific microbial strains known to produce the required key metabolites and the formulation in which microbial compositions are delivered to the gut. Here, we describe a double-capsule technology to deliver high numbers of metabolically active cells derived from the 24-strain probiotic product SH-DS01 to the gastrointestinal tract, including the small intestine, where immune responses and adsorption of metabolites into the bloodstream occur. Based on its genome sequence, Limosilactobacillus reuteri SD-LRE2-IT was predicted to have the genetic capacity to de novo produce a specific metabolite of interest to brain health, vitamin B12, which could be confirmed in vitro. Taken together, our data conceptualizes the importance of rationally defined microbial strain characterization based on genomics and metabolomics data, combined with carefully designed capsule technology for delivery of live cells and concomitant functionality in and beyond the gut ecosystem.
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The Role of the Gut Microbiota in Individuals with Irritable Bowel Syndrome: A Scoping Review.
Irritable bowel syndrome (IBS) represents the most prevalent disorder of brain-gut interaction, affecting approximately 10% of the global population. The objective of this study was to examine the mechanisms by which the gut microbiota contributes to the development of IBS. To this end, a review of articles that examined the gut microbiota of IBS patients was conducted. A search was conducted using PubMed and J-STAGE for articles published over the past five years that relate to the gut microbiota in patients with IBS. Individuals diagnosed with IBS display a reduction in alpha diversity and a decline in butyrate-producing bacteria, which collectively indicate a state of dysbiosis within their gut microbiota. Butyrate plays a dual role in the body, acting as a source of nutrition for the intestinal epithelium while also regulating the expression of dopamine transporters and D2 receptors in the central nervous system through epigenetic mechanisms. These characteristics may be linked to dysfunction of the central dopamine D2 pathway and play a role in the formation of various symptoms in IBS.