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Deciphering microbiome and neuroactive immune gene interactions in schizophrenia.
The body's microbiome represents an actively regulated network of novel mechanisms that potentially underlie the etiology and pathophysiology of a wide range of diseases. For complex brain disorders such as schizophrenia, understanding the cellular and molecular pathways that intersect the bidirectional gut-brain axis is anticipated to lead to new methods of treatment. The means by which the microbiome might differ across neuropsychiatric and neurological disorders are not known. Brain disorders as diverse as schizophrenia, major depression, Parkinson's disease and multiple sclerosis appear to share a common pathology of an imbalanced community of commensal microbiota, often measured in terms of a leaky gut phenotype accompanied by low level systemic inflammation. While environmental factors associated with these disease states might contribute to intestinal pathologies, products from a perturbed microbiome may also directly promote specific signs, symptoms and etiologies of individual disorders. We hypothesize that in schizophrenia, it is the putatively unique susceptibility related to genes that modulate the immune system and the gut-brain pleiotropy of these genes which leads to a particularly neuropathological response when challenged by a microbiome in dysbiosis. Consequences from exposure to this dysbiosis may occur during pre- or post-natal time periods and thus may interfere with normal neurodevelopment in those who are genetically predisposed. Here, we review the evidence from the literature which supports the idea that the intersection of the microbiome and immune gene susceptibility in schizophrenia is relevant etiologically and for disease progression. Figuring prominently at both ends of the gut-brain axis and at points in between are proteins encoded by genes found in the major histocompatibility complex (MHC), including select MHC as well as non-MHC complement pathway genes.
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Microbial genes, brain & behaviour - epigenetic regulation of the gut-brain axis.
To date, there is rapidly increasing evidence for host-microbe interaction at virtually all levels of complexity, ranging from direct cell-to-cell communication to extensive systemic signalling, and involving various organs and organ systems, including the central nervous system. As such, the discovery that differential microbial composition is associated with alterations in behaviour and cognition has significantly contributed to establishing the microbiota-gut-brain axis as an extension of the well-accepted gut-brain axis concept. Many efforts have been focused on delineating a role for this axis in health and disease, ranging from stress-related disorders such as depression, anxiety and irritable bowel syndrome to neurodevelopmental disorders such as autism. There is also a growing appreciation of the role of epigenetic mechanisms in shaping brain and behaviour. However, the role of epigenetics in informing host-microbe interactions has received little attention to date. This is despite the fact that there are many plausible routes of interaction between epigenetic mechanisms and the host-microbiota dialogue. From this new perspective we put forward novel, yet testable, hypotheses. Firstly, we suggest that gut-microbial products can affect chromatin plasticity within their host's brain that in turn leads to changes in neuronal transcription and eventually alters host behaviour. Secondly, we argue that the microbiota is an important mediator of gene-environment interactions. Finally, we reason that the microbiota itself may be viewed as an epigenetic entity. In conclusion, the fields of (neuro)epigenetics and microbiology are converging at many levels and more interdisciplinary studies are necessary to unravel the full range of this interaction.
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Persistent exercise fatigue and associative learning deficits in combination with transient glucose dyshomeostasis in a mouse model of Gulf War Illness.
AIMS: To characterize exercise fatigue, metabolic phenotype and cognitive and mood deficits correlated with brain neuroinflammatory and gut microbiome changes in a chronic Gulf War Illness (GWI) mouse model. The latter have been described in an accompanying paper [1]. MAIN METHODS: Adult male C57Bl/6N mice were exposed for 28 days (5 days/week) to pyridostigmine bromide: 6.5 mg/kg, b.i.d., P.O. (GW1) or 8.7 mg/kg, q.d., P.O. (GW2); topical permethrin (1.3 mg/kg in 100% DMSO) and N,N-diethyl-meta-toluamide (DEET 33% in 70% EtOH) and restraint stress (5 min). Exercise, metabolic and behavioral endpoints were compared to sham stress control (CON/S). KEY FINDINGS: Relative to CON/S, GW2 presented persistent exercise intolerance (through post-treatment (PT) day 161), deficient associative learning/memory, and transient insulin insensitivity. In contrast to GW2, GW1 showed deficient long-term object recognition memory, milder associative learning/memory deficit, and behavioral despair. SIGNIFICANCE: Our findings demonstrate that GW chemicals dose-dependently determine the presentation of exercise fatigue and severity/type of cognitive/mood-deficient phenotypes that show persistence. Our comprehensive mouse model of GWI recapitulates the major multiple symptom domains characterizing GWI, including fatigue and cognitive impairment that can be used to more efficiently develop diagnostic tests and curative treatments for ill Gulf War veterans.
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Social isolation during adolescence alters novel object recognition memory, brain and gut gene expression, and microbiota composition in a sex-specific manner.
Adolescent social isolation is a known risk factor for anxiety and depression related disorders, yet its effects on brain-gut communication and potential sex differences remain unclear. We hypothesised that isolation would heighten anxiety- and depression-related behaviors and consequently impair memory in both sexes. To investigate this we exposed male (M) and female (F) rats to four weeks of social isolation beginning at 3 weeks of age and assessed behavior, brain and gut gene expression and microbiota, in single- (S) or pair-housed (P) animals. Contrary to our hypothesis, the results showed higher novel object recognition memory in socially-isolated females (FS vs FP). No isolation-induced changes in anxiety-related behaviours were detected in either sex. Social isolation in females (FS vs FP) increased expression of hippocampal Grik5 (glutamate receptor/memory/learning), and decreased expression of prefrontal cortex genes: Mbp, Mobp, Plp1 (neuroplasticity), Cnp (neuroprotection) and Tph2 (serotonin synthesis). There was a trend toward lower microbial diversity in socially-isolated females (FS vs FP). Although no behaviour change was detected in isolated males, amygdala c-Fos (neuronal activity) and prefrontal cortex Gabbr1 (inhibitory) expression were decreased. Il6r, Tgfb1, Tlr9 (immune-related) were increased in the colon (MS vs MP). In both sexes, social isolation increased Tph1 expression in the colon (FS vs FP; MS vs MP). These findings indicate sex-specific responses to adolescent social isolation, with females showing enhanced novel object recognition memory performance alongside changes in genes linked to neuroplasticity and memory, while males showed altered brain and gut gene expression linked to brain neuro-activity and gut-immune function.
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Gulf War Illness: Mechanisms Underlying Brain Dysfunction and Promising Therapeutic Strategies.
Gulf War Illness (GWI), a chronic multisymptom health problem, afflicts ~30% of veterans served in the first GW. Impaired brain function is among the most significant symptoms of GWI, which is typified by persistent cognitive and mood impairments, concentration problems, headaches, chronic fatigue, and musculoskeletal pain. This review aims to discuss findings from animal prototypes and veterans with GWI on mechanisms underlying its pathophysiology and emerging therapeutic strategies for alleviating brain dysfunction in GWI. Animal model studies have linked brain impairments to incessantly elevated oxidative stress, chronic inflammation, inhibitory interneuron loss, altered lipid metabolism and peroxisomes, mitochondrial dysfunction, modified expression of genes relevant to cognitive function, and waned hippocampal neurogenesis. Furthermore, the involvement of systemic alterations such as the increased intensity of reactive oxygen species and proinflammatory cytokines in the blood, transformed gut microbiome, and activation of the adaptive immune response have received consideration. Investigations in veterans have suggested that brain dysfunction in GWI is linked to chronic activation of the executive control network, impaired functional connectivity, altered blood flow, persistent inflammation, and changes in miRNA levels. Lack of protective alleles from Class II HLA genes, the altered concentration of phospholipid species and proinflammatory factors in the circulating blood have also been suggested as other aiding factors. While some drugs or combination therapies have shown promise for alleviating symptoms in clinical trials, larger double-blind, placebo-controlled trials are needed to validate such findings. Based on improvements seen in animal models of GWI, several antioxidants and anti-inflammatory compounds are currently being tested in clinical trials. However, reliable blood biomarkers that facilitate an appropriate screening of veterans for brain pathology need to be discovered. A liquid biopsy approach involving analysis of brain-derived extracellular vesicles in the blood appears efficient for discerning the extent of neuropathology both before and during clinical trials.
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Biogenic Amines: Signals Between Commensal Microbiota and Gut Physiology.
There is increasing interest in the interactions among the gut microbiota, gut, and brain, which is often referred to as the "microbiota-gut-brain" axis. Biogenic amines including dopamine, norepinephrine, serotonin, and histamines are all generated by commensal gut microorganisms and are suggested to play roles as signaling molecules mediating the function of the "microbiota-gut-brain" axis. In addition, such amines generated in the gut have attracted attention in terms of possible clues into the etiologies of depression, anxiety, and even psychosis. This review covers the latest research related to the potential role of microbe-derived amines such as catecholamine, serotonin, histamine, as well as other trace amines, in modulating not only gut physiology but also brain function of the host. Further attention in this field can offer not only insight into expanding the fundamental roles and impacts of the human microbiome, but also further offer new therapeutic strategies for psychological disorders based on regulating the balance of resident bacteria.
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The effects of exercise and diet on mental status, insulin signaling pathway, and microbiome in obese mice.
The aim of this study was to investigate the effects of exercise and diet on mental status, insulin signaling pathway, serotonin synthesis, and microbiome in high-fat-induced obesity mice. Before the start of this experiment, obesity groups made obese mice by administering a high-fat diet containing 60% fat for 12 weeks. In the obesity with exercise group, after a high-fat diet for 12 weeks, exercise was performed with high-fat diet for 8 weeks. In the obesity with diet group, a high-fat diet for 12 weeks followed by a normal diet for 8 weeks. Depression and anxiety were determined by open field test and elevated plus maze test. Immunohistochemistry for tryptophan hydroxylase (TPH) in the dorsal raphe, western blot analysis for phosphorylated protein kinase B (p-ATK), total AKT (t-AKT), phosphorylated phosphoinositide 3-kinase (p-PI3K), and total PI3K (t-PI3K) in the hippocampus were performed. Analysis of microbiome was also conducted. Obesity-induced depression and anxiety status, suppressed ratio of p-AKT/t-AKT and p-PI3K/t-PI3K, and inhibited TPH synthesis. Exercise and diet improved depression and anxiety status, activated p-AKT/t-AKT and p-PI3K/t-PI3K, and increased TPH synthesis. Exercise and diet improved depression and anxiety status by increasing the insulin signaling pathway and promoting serotonin production. These effects of exercise and diet were almost similar. In addition, exercise and diet regulated the composition of gut microbiota.
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1H Nuclear Magnetic Resonance: A Future Approach to the Metabolic Profiling of Psychedelics in Human Biofluids?
While psychedelics may have therapeutic potential for treating mental health disorders such as depression, further research is needed to better understand their biological effects and mechanisms of action when considering the development of future novel therapy approaches. Psychedelic research could potentially benefit from the integration of metabonomics by proton nuclear magnetic resonance (1H NMR) spectroscopy which is an analytical chemistry-based approach that can measure the breakdown of drugs into their metabolites and their metabolic consequences from various biofluids. We have performed a systematic review with the primary aim of exploring published literature where 1H NMR analysed psychedelic substances including psilocin, lysergic acid diethylamide (LSD), LSD derivatives, N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and bufotenin. The second aim was to assess the benefits and limitations of 1H NMR spectroscopy-based metabolomics as a tool in psychedelic research and the final aim was to explore potential future directions. We found that the most current use of 1H NMR in psychedelic research has been for the structural elucidation and analytical characterisation of psychedelic molecules and that no papers used 1H NMR in the metabolic profiling of biofluids, thus exposing a current research gap and the underuse of 1H NMR. The efficacy of 1H NMR spectroscopy was also compared to mass spectrometry, where both metabonomics techniques have previously shown to be appropriate for biofluid analysis in other applications. Additionally, potential future directions for psychedelic research were identified as real-time NMR, in vivo 1H nuclear magnetic resonance spectroscopy (MRS) and 1H NMR studies of the gut microbiome. Further psychedelic studies need to be conducted that incorporate the use of 1H NMR spectroscopy in the analysis of metabolites both in the peripheral biofluids and in vivo to determine whether it will be an effective future approach for clinical and naturalistic research.
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The Gut-Brain Axis: Literature Overview and Psychiatric Applications.
IMPORTANCE: Literature exploring the relationship between the intestinal microbiome and its effects on general health and well-being has grown significantly in recent years, and our knowledge of this subject continues to grow. Mounting evidence indicates that the intestinal microbiome is a potential target for therapeutic intervention in psychiatric illness and in neurodegenerative disorders such as Alzheimer disease. It is reasonable to consider modulating not just a patient's neurochemistry, behavior, or cognitive habits, but also their intestinal microbiome in an effort to improve psychiatric symptoms. OBSERVATIONS: In this review paper, we show that intestinal microbiota possess the ability to directly influence both physical and mental well-being; therefore, should be included in future discussions regarding psychiatric treatment. CONCLUSIONS: Clinicians are encouraged to consider patients' gut health when evaluating and treating psychiatric conditions, such as anxiety and depression. Optimization and diversification of gut flora through the use of psychobiotics-probiotics that confer mental health benefits-may soon become standard practice in conjunction with traditional psychiatric treatment modalities such as pharmacotherapy and psychotherapy.
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Nutrition during pregnancy and early development (NuPED) in urban South Africa: a study protocol for a prospective cohort.
BACKGROUND: Adequate nutrition during pregnancy is important to ensure optimal birth outcomes, maternal health and offspring development. However, little is known about the dietary intake and nutritional status of pregnant women residing in urban South Africa. Therefore, the Nutrition during Pregnancy and Early Development (NuPED) cohort study was initiated to assess early nutrition-related exposures predictive of early childhood development in urban South Africa. METHODS: The aims of this prospective cohort study are: 1) to assess dietary intake and nutritional status of urban pregnant women in Johannesburg, South Africa, and 2) to determine associations with birth outcomes, measures of maternal health, as well as measures of offspring health and development. Pregnant women (< 18 weeks' gestation) (n = 250) are being recruited from primary healthcare clinics in Johannesburg and are followed-up at a provincial hospital. Participants' dietary intake and nutrient status (focus on micronutrients and fatty acids) are assessed at < 18, 22 and 36 weeks' gestation. Additional assessments during pregnancy include anthropometric and blood pressure measurements, obstetric ultrasound screens, and assessments of food security, maternal fatigue, prenatal depression, allergy, immune function, morbidity and gestational diabetes. At birth, maternal and neonatal health is assessed and an umbilical cord blood sample collected. Maternal and offspring health is followed-up at 6 weeks, as well as at 6, ≈7.5 and 12 months after birth. Follow-up assessments of mothers include anthropometric measures, diet history, nutrient status, blood pressure, breast milk composition, and measures of postnatal depression and fatigue. Follow-up assessments of the offspring include feeding practices, nutrient status, measures of growth, psychomotor, socio-emotional and immune development, morbidity, allergy, as well as analysis of the gut microbiome and the epigenome. DISCUSSION: Ensuring adequate nutrition during pregnancy is one of the key actions endorsed by the South African Government to promote optimal early childhood development in an effort to eradicate poverty. The results from this study may serve as a basis for the development of context-specific nutritional interventions which can improve birth outcomes and long-term quality of life of the mother and her offspring.