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Bipolar Disorder and Immune Dysfunction: Epidemiological Findings, Proposed Pathophysiology and Clinical Implications.
Bipolar disorder (BD) is strongly associated with immune dysfunction. Replicated epidemiological studies have demonstrated that BD has high rates of inflammatory medical comorbidities, including autoimmune disorders, chronic infections, cardiovascular disease and metabolic disorders. Cytokine studies have demonstrated that BD is associated with chronic low-grade inflammation with further increases in pro-inflammatory cytokine levels during mood episodes. Several mechanisms have been identified to explain the bidirectional relationship between BD and immune dysfunction. Key mechanisms include cytokine-induced monoamine changes, increased oxidative stress, pathological microglial over-activation, hypothalamic-pituitary-adrenal (HPA) axis over-activation, alterations of the microbiome-gut-brain axis and sleep-related immune changes. The inflammatory-mood pathway presents several potential novel targets in the treatment of BD. Several proof-of-concept clinical trials have shown a positive effect of anti-inflammatory agents in the treatment of BD; however, further research is needed to determine the clinical utility of these treatments. Immune dysfunction is likely to only play a role in a subset of BD patients and as such, future clinical trials should also strive to identify which specific group(s) of BD patients may benefit from anti-inflammatory treatments.
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Agathobaculum butyriciproducens improves ageing-associated cognitive impairment in mice.
AIMS: The gut microbiota is increasingly recognised as a pivotal regulator of immune system homeostasis and brain health. Recent research has implicated the gut microbiota in age-related cognitive impairment and dementia. Agathobaculum butyriciproducens SR79 T (SR79), which was identified in the human gut, has been reported to be beneficial in addressing cognitive deficits and pathophysiologies in a mouse model of Alzheimer's disease. However, it remains unknown whether SR79 affects age-dependent cognitive impairment. MAIN METHOD: To explore the effects of SR79 on cognitive function during ageing, we administered SR79 to aged mice. Ageing-associated behavioural alterations were examined using the open field test (OFT), tail suspension test (TST), novel object recognition test (NORT), Y-maze alternation test (Y-maze), and Morris water maze test (MWM). We investigated the mechanisms of action in the gut and brain using molecular and histological analyses. KEY FINDINGS: Administration of SR79 improved age-related cognitive impairment without altering general locomotor activity or depressive behaviour in aged mice. Furthermore, SR79 increased mature dendritic spines in the pyramidal cells of layer III and phosphorylation of CaMKIIα in the cortex of aged mice. Age-related activation of astrocytes in the cortex of layers III-V of the aged brain was reduced following SR79 administration. Additionally, SR79 markedly increased IL-10 production and Foxp3 and Muc2 mRNA expression in the colons of aged mice. SIGNIFICANCE: These findings suggest that treatment with SR79 may be a beneficial microbial-based approach for enhancing cognitive function during ageing.
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Regulation of prefrontal cortex myelination by the microbiota.
The prefrontal cortex (PFC) is a key region implicated in a range of neuropsychiatric disorders such as depression, schizophrenia and autism. In parallel, the role of the gut microbiota in contributing to these disorders is emerging. Germ-free (GF) animals, microbiota-deficient throughout life, have been instrumental in elucidating the role of the microbiota in many aspects of physiology, especially the role of the microbiota in anxiety-related behaviours, impaired social cognition and stress responsivity. Here we aim to further elucidate the mechanisms of the microbial influence by investigating changes in the homeostatic regulation of neuronal transcription of GF mice within the PFC using a genome-wide transcriptome profiling approach. Our results reveal a marked, concerted upregulation of genes linked to myelination and myelin plasticity. This coincided with upregulation of neural activity-induced pathways, potentially driving myelin plasticity. Subsequent investigation at the ultrastructural level demonstrated the presence of hypermyelinated axons within the PFC of GF mice. Notably, these changes in myelin and activity-related gene expression could be reversed by colonization with a conventional microbiota following weaning. In summary, we believe we demonstrate for the first time that the microbiome is necessary for appropriate and dynamic regulation of myelin-related genes with clear implications for cortical myelination at an ultrastructural level. The microbiota is therefore a potential therapeutic target for psychiatric disorders involving dynamic myelination in the PFC.
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Loss of diurnal behavioral rhythms and impaired lipid metabolism in growing pigs with mistimed feeding.
The misalignment of eating time and the endogenous circadian rhythm impairs the body's ability to maintain homeostasis. Although it is well established that children and growing animals differ from adults in their energy metabolism and behavioral patterns, little is known about how mistimed feeding disturbs the diurnal rhythms of behavior and metabolism in children and growing diurnal animals. In this study, growing pigs (diurnal animal) were randomly assigned to the daytime-restricted feeding (DRF) and nighttime-restricted feeding (NRF) groups for 5 weeks. Compared with observations in the DRF group, NRF disrupted the diurnal rhythm of behavior and clock genes and lowered the serum ghrelin, dopamine, and serotonin levels during the daytime and nighttime. Microbiome analysis results suggested that NRF altered the diurnal rhythm and composition of the gut microbiota, and increased log-ratios of Catenibacterium:Butyrivibrio and Streptococcus:Butyrivibrio. Based on the serum proteome, the results further revealed that rhythmic and upregulated proteins in NRF were mainly involved in oxidative stress, lipid metabolism, immunity, and cancer biological pathways. Serum physiological indicators further confirmed that NRF decreased the concentration of melatonin and fibroblast growth factor 21 during the daytime and nighttime, increased the diurnal amplitude and concentrations of very-low-density lipoprotein cholesterol, triglyceride, and total cholesterol, and increased the apolipoprotein B/ApoA1 ratio, which is a marker of metabolic syndrome. Taken together, this study is the first to reveal that mistimed feeding disrupts the behavioral rhythms of growing pigs, reprograms gut microbiota composition, reduces the serum levels of hormones associated with fighting depression and anxiety, and increases the risk of lipid metabolic dysregulation.
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The Role of Nutraceutical Supplements in the Treatment of Irritable Bowel Syndrome: A Mini Review.
BACKGROUND: Irritable bowel syndrome (IBS) is a prolonged bowel illness that is generally stress-related and is characterized by a variety of gastrointestinal problems, the most prominent of which is chronic visceral abdominal discomfort. As a result, IBS typically impacts sufferers' standard of living, and it is typically associated with depression and anxiety symptoms. IBS medication is based mostly on symptom alleviation. However, no effective medicines have been discovered too far. As a result, it is essential to discover novel anti-IBS medications. OBJECTIVE: The purpose of this brief review is to describe the existing research on nutraceutical supplements in irritable bowel syndrome management, including probiotics, prebiotics, symbiotics, herbal products, and dietary fibers. METHODS: This review covered the relevant papers from the previous twenty years that were available in different journals such as Science Direct, Elsevier, NCBI, and Web of Science that were related to the role and function of nutraceuticals in Irritable Bowel Syndrome. RESULTS: Nutraceutical substances have a variety of modes of action, including restoring the healthy microbiome, improving the function of the gastrointestinal barrier, immunomodulatory, antiinflammatory, and antinociceptive properties. According to the literature, these substances not only can improve irritable bowel syndrome symptomatology but also have an excellent long-term safety profile. CONCLUSION: Irritable bowel syndrome is a prolonged bowel illness with a lot of gastrointestinal problems. The nutraceuticals treatment works as an anti-IBS intervention and enhances patient compliance with minimum side effects since patients take it better than pharmaceutical treatments.
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The Interaction of HIV With Mental Health in the Modern Antiretroviral Therapy Era.
People with HIV (PWH) receiving effective antiretroviral therapy (ART) continue to display residual immune dysregulation that amplifies the risk for neuropsychiatric comorbidities. At the same time, PWH commonly experience intersectional stigma and other psychosocial stressors that are linked to neuroendocrine stress responses, potentiate residual immune dysregulation, and alter other biobehavioral processes relevant to health outcomes. This special issue of Psychosomatic Medicine seeks to advance our understanding of the intersection of HIV with mental health in the modern ART era. Several articles cover topics related to the prevalence and treatment of psychiatric comorbidities among PWH such as depression, suicidality, and substance use disorders. Other articles delineate biobehavioral mechanisms relevant to mental health in PWH such as inflammation, immune activation, neuroendocrine signaling, cellular aging, the microbiome-gut-brain axis, and neurobehavioral processes. Collectively, the articles in this special issue highlight the continued importance of biobehavioral and neurobehavioral mental health research in the modern ART era.
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A multi-omics analysis of gut bacteriome, virome, and serum metabolome in bipolar depression.
The involvement of microbiota-gut-brain axis in bipolar disorder (BD) has been uncovered, yet the specific tripartite interplay between the gut bacteriome, virome, and serum metabolome remains to be elucidated. We conducted a cross-sectional multi-omics analysis on 90 drug-free patients with bipolar depression and 30 healthy controls. A significant between-group difference in gut bacterial α-diversity was observed. Non-parametric test revealed 1929 bacterial and 134 viral species with significant inter-group difference, among which 249 bacterial and 7 viral species remained significant after FDR correction (Padjusted < 0.05). Metabolomic analysis identified 261 significantly differential serum metabolites, which were enriched in 70 biological pathways and 40 pathways remained significant after correction. Integration of the datasets revealed strong cross-omic correlations, while only eight significant viral-metabolic correlations were detected. Post-FDR significant correlations with clinical features were exclusively observed between differential metabolites and scores of disease severity, with a predominance of negative correlations. Clinically, a random forest model integrating bacteriome, virome, and metabolome features achieved superior discriminative power (AUC = 0.986) compared to single-omics models (metabolites: 0.970; bacteria: 0.823; viruses: 0.732). This work demonstrated a dysregulated bacteriome-virome-metabolome network of patients with bipolar depression, providing a robust panel of candidate biomarkers for the precise diagnosis of BD.
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Microbial composition, functionality, and stress resilience or susceptibility: unraveling sex-specific patterns.
BACKGROUND: Following exposure to traumatic stress, women are twice as likely as men to develop mood disorders. Yet, individual responses to such stress vary, with some people developing stress-induced psychopathologies while others exhibit resilience. The factors influencing sex-related disparities in affective disorders as well as variations in resilience remain unclear; however, emerging evidence suggests differences in the gut microbiota play a role. In this study, using the single prolonged stress (SPS) model of post-traumatic stress disorder, we investigated pre- and post-existing differences in microbial composition, functionality, and metabolites that affect stress susceptibility or resilience in each sex. METHODS: Male and female Sprague-Dawley rats were randomly assigned to control or SPS groups. Two weeks following SPS, the animals were exposed to a battery of behavioral tests and decapitated a day later. Based on their anxiety index, they were further categorized as SPS-resilient (SPS-R) or SPS-susceptible (SPS-S). On the day of dissection, cecum, and selected brain tissues were isolated. Stool samples were collected before and after SPS, whereas urine samples were taken before and 30 min into the SPS. RESULTS: Before SPS exposure, the sympathoadrenal axis exhibited alterations within male subgroups only. Expression of tight junction protein claudin-5 was lower in brain of SPS-S males, but higher in SPS-R females following SPS. Across the study, alpha diversity remained consistently lower in males compared to females. Beta diversity revealed distinct separations between male and female susceptible groups before SPS, with this separation becoming evident in the resilient groups following SPS. At the genus level, Lactobacillus, Lachnospiraceae_Incertae_Sedis, and Barnesiella exhibited sex-specific alterations, displaying opposing abundances in each sex. Additionally, sex-specific changes were observed in microbial predictive functionality and targeted functional modules both before and after SPS. Alterations in the microbial short-chain fatty acids (SCFAs), were also observed, with major and minor SCFAs being lower in SPS-susceptible males whereas branched-chain SCFAs being higher in SPS-susceptible females. CONCLUSION: This study highlights distinct pre- and post-trauma differences in microbial composition, functionality, and metabolites, associated with stress resilience in male and female rats. The findings underscore the importance of developing sex-specific therapeutic strategies to effectively address stress-related disorders. Highlights SPS model induces divergent anxiety and social behavioral responses to traumatic stress in both male and female rodents. SPS-resilient females displayed less anxiety-like behavior and initiated more interactions towards a juvenile rat than SPS-resilient males. Sex-specific pre-existing and SPS-induced differences in the gut microbial composition and predictive functionality were observed in susceptible and resilient rats. SPS-resilient males displayed elevated cecal acetate levels, whereas SPS-susceptible females exhibited heightened branched-chain SCFAs.
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Effectiveness of Probiotic, Prebiotic, and Synbiotic Supplementation to Improve Perinatal Mental Health in Mothers: A Systematic Review and Meta-Analysis.
Introduction: There is an emerging interest in modulating the gut microbiota to target the gut-brain axis and improve maternal mental health in the perinatal period. This systematic review evaluated the effectiveness of prebiotics, probiotics, and synbiotics supplementation during pregnancy to reduce the risk of maternal mental health problems in the perinatal period. Methods: Electronic biomedical databases and clinical trial registries were searched from database inception through August 2020 to identify randomized controlled clinical trials (RCTs) evaluating the effect of probiotic, prebiotic, or synbiotic supplements administered to women during pregnancy on measures of perinatal depression, anxiety, and other mental health outcomes. Study selection, risk of bias appraisal, and data extraction were independently performed by two reviewers. Pooled mean differences (MD) and odds ratios (pOR) with 95% confidence intervals (CI) were calculated in random-effects meta-analyses for the outcomes of interest in the review. Results: From 3,868 studies identified through the search strategy, three RCTs of low risk of bias involving 713 participants were included, all three testing probiotics. There were no differences between probiotics and control groups in the mean depression scores (MD -0.46; 95% CI -2.16, 1.25) at end of follow-up. Although statistical significance was not achieved, probiotics showed an advantage in the proportion of participants scoring below an established cut-off for depression (pOR 0.68; 95% CI 0.43, 1.07). Compared to placebo, probiotics in pregnancy reduced anxiety symptoms (MD -0.99; 95% CI -1.80, -0.18); however, this advantage was not translated in a reduction in the proportion of participants scoring above an established cut-off for anxiety (pOR 0.65; 95% CI 0.23, 1.85). There were no differences between probiotics and control groups in global mental health scores at end of follow-up (MD 1.09; 95% CI -2.04, 4.22). Conclusion: There is limited but promising evidence about the effectiveness of probiotics during pregnancy to reduce anxiety symptoms and reduce the proportion of women scoring ABOVE a cut-off depression score. There is a lack of RCT evidence supporting prebiotics and synbiotics supplementation for similar purposes in the perinatal period. More research is needed before prebiotics, probiotics, and synbiotics are recommended to support maternal mental health and well-being in the perinatal period. Systematic Review Registration: PROSPERO, CRD42019137158.
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Chronic Δ9-Tetrahydrocannabinol Vapor Self-Administration Modulates Gut Microbiota and the Immune and Endocannabinoid Systems in Female Sprague- Dawley Rats.
Vaping of cannabis and its primary components, including Δ9- tetrahydrocannabinol (THC), has increased during the last decade, especially among adolescents and adults. While the behavioral consequences of THC, including anxiety, depression, and associated impacts on reward-related signaling, are well documented, evaluation of additional pathways that have implications for neuronal function remains relatively unexplored. Further, despite evidence of the impact of THC on several physiologic processes, most studies have focused on the brain even though the endocannabinoid system with which THC interacts has widespread expression and functions throughout the body. To address these gaps, we obtained biological samples from adult female Sprague-Dawley rats (N=5-6 per group; all females) that were passively exposed to THC or vehicle vapor and then allowed to self-administer vaporized THC or vehicle intermittently for nine months. Animals were euthanized, and brain and peripheral organs were collected for analyses. We evaluated genes of endocannabinoid system-related receptors, modulators, ion channels, and metabolic enzymes, along with immune and microbiome-related pathways in 9 peripheral organs, 14 brain regions, and plasma. We observed that rats exposed to chronic intermittent THC vapor administration had widespread modulation of several endocannabinoid- system genes only in the brain, with most changes occurring in the dorsal striatum and hippocampus. In contrast, endocannabinoid-system gene expression in all evaluated peripheral organs remained unchanged after THC exposure. Similar findings occurred with immune-relevant genes, where il-1β , il-6 , ccl2 , and mx1 were modulated only in the brain while expression in peripheral organs remained unchanged. Immune system modulation following chronic THC exposure significantly elevated plasma concentrations of IL-17A, gut microbiota dysbiosis, and global changes to circulating metabolites, including several amino acids, fatty acids, aminosugar, and nucleic acids. Our findings provide, for the first time, a whole-body evaluation of the molecular effects of chronic THC exposure throughout adulthood on the endocannabinoid and immune systems that have implications for cannabinoid-related behavioral effects.