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Linking nervous and immune systems in psychiatric illness: A meta-analysis of the kynurenine pathway.
Tryptophan is an essential amino acid absorbed by the gut depending on a homoeostatic microbiome. Up to 95% of unbound tryptophan is converted into tryptophan catabolites (TRYCATs) through the kynurenine system. Recent studies identified conflicting associations between altered levels of TRYCATs and genetic polymorphisms in major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD). This meta-analysis aimed to understand how tryptophan catabolic pathways are altered in MDD, SCZ, and BD. When compared to healthy controls, participants with MDD had moderately lower levels of tryptophan associated with a moderate increase of kynurenine/tryptophan ratios and no differences in kynurenine. While significant differences were found in SCZ for any of the TRYCATs, studies on kynurenic acid found opposing directions of effect sizes depending on the sample source. Unique changes in levels of TRYCATs were also observed in BD. Dynamic changes in levels of cytokines and other immune/inflammatory elements modulate the transcription and activity of kynurenine system enzymes, which lastly seems to be impacting glutamatergic neurotransmission via N-methyl-D-aspartate and α-7 nicotine receptors.
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Contextual & physiological markers for individual distress (CP-MIND). Brain health as a comprehensive framework for Mental-health equity.
Socioeconomic disadvantage shapes brain-mind health by intensifying exposures, resource scarcity, nutritional insecurity, violence, and weak social support, which dysregulate stress and immune systems. These conditions promote allostatic overload, whereby adaptive stress responses become maladaptive, degrading neural circuits for cognitive control and emotion regulation. In parallel, the microbiota-gut-brain axis links contextual adversity and diet quality to inflammation, barrier dysfunction, and neuroendocrine perturbations that further compromise resilience. Converging evidence connects these biological disruptions to structural and functional brain differences and higher risks of depression, anxiety, stress-related syndromes, and later neurodegeneration. While some sociocultural adaptations may bolster cooperation and communal coping, chronic physiological strain undermines durable resilience. This integrative review advances a combined framework, contextual & physiological markers for Individual distress, nested within a brain-mind health perspective, to organise how socioeconomic disadvantage-related exposures are embedded biologically via allostatic and microbiota-gut-brain axis pathways and manifest as social-cognitive difficulties and affective symptoms. We synthesise evidence across behaviour, neural systems, and systemic physiology to identify leverage points for intervention. Priorities include early multi-domain strategies that reduce chronic stressors; strengthen sleep, nutrition, and social cohesion; and test mechanistic interventions (e.g., allostatic regulation, psychobiotic or dietary modulation) within equity-focused, life-course designs. Understanding how contextual and physiological markers interact is essential for designing effective, scalable policies and clinical approaches that mitigate adversity's neurobiological impact and reduce long-term disparities in brain-mind health.
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Targeting the microbiota in pharmacology of psychiatric disorders.
There is increasing interest in the role of the gut microbiota in health and disease. In particular, gut microbiota influences the Central Nervous System (CNS) development and homeostasis through neural pathways or routes involving the immune and circulatory systems. The CNS, in turn, shapes the intestinal flora through endocrine or stress-mediated responses. These overall bidirectional interactions, known as gut microbiota-brain axis, profoundly affect some brain functions, such as neurogenesis and the production of neurotransmitters, up to influence behavioral aspects of healthy subjects. Consequently, a dysfunction within this axis, as observed in case of dysbiosis, can have an impact on the behavior of a given individual (e.g. anxiety and depression) or on the development of pathologies affecting the CNS, such as autism spectrum disorders and neurodegenerative diseases (e.g. Alzheimer's disease and Parkinson's disease). It should be considered that the whole microbiota has a significant role not only on aspects concerning human physiology, such as harvesting of nutrients and energy from the ingested food or production of a wide range of bioactive compounds, but also has positive effects on the gastrointestinal barrier function and actively contributes to the pharmacokinetics of several compounds including neuropsychiatric drugs. Indeed, the microbiota is able to affect drug absorption and metabolism up to have an impact on drug activity and/or toxicity. On the other hand, drugs are able to shape the human gut microbiota itself, where these changes may contribute to their pharmacologic profile. Therefore, the emerging picture on the complex drug-microbiota bidirectional interplay will have considerable implications in the future not only in terms of clinical practice but also, upstream, on drug development.
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A Pilot Randomized Controlled Trial to Explore Cognitive and Emotional Effects of Probiotics in Fibromyalgia.
It has recently been found that microbes in the gut may regulate brain processes through the gut microbiota-brain axis, which modulates affection, motivation and higher cognitive functions. According to this finding, the use of probiotics may be a potential treatment to improve physical, psychological and cognitive status in clinical populations with altered microbiota balance such as those with fibromyalgia (FMS). Thus, the aim of the present pilot study with a double-blind, placebo-controlled, randomised design was to test whether a multispecies probiotic may improve cognition, emotional symptoms and functional state in a sample of patients diagnosed with FMS. Pain, impact of FMS, quality of life, anxiety and depressive symptoms were measured during the pre- and post-intervention phases; participants also completed two computerised cognitive tasks to assess impulsive choice and decision-making. Finally, urinary cortisol concentration was determined. To our knowledge, this is the first study that explore the effect of a multispecies probiotic in FMS patients. Our results indicated that probiotics improved impulsivity and decision-making in these patients. However, more research is needed to further explore the potential effects of probiotics on other cognitive functions affected in FMS as well as in other clinical populations.
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Requirement of a Wnt5A-microbiota axis in the maintenance of gut B-cell repertoire and protection from infection.
We investigated the influence of a Wnt5A-gut microbiota axis on gut B-cell repertoire and protection from infection, having previously demonstrated that Wnt5A in association with gut commensals helps shape gut T-cell repertoire. Accordingly, Wnt5A heterozygous mice, which express less than wild-type level of Wnt5A, and their isolated Peyer's patches (PPs) were studied in comparison with the wild-type counterparts. The percentages of IgM- and IgA-expressing B cells were quite similar in the PP of both sets of mice. However, the PP of the Wnt5A heterozygous mice harbored significantly higher than wild-type levels of microbiota-bound B cell-secreted IgA, indicating the prevalence of a microbial population therein, which is significantly altered from that of wild-type. Additionally, the percentage of PP IgG1-expressing B cells was appreciably depressed in the Wnt5A heterozygous mice in comparison to wild-type. Wnt5A heterozygous mice, furthermore, exhibited notably higher than the wild-type levels of morbidity and mortality following infection with Salmonella typhimurium, a common gut pathogen. Differences in morbidity/mortality correlated with considerable disparity between the PP-B-cell repertoires of the Salmonella-infected Wnt5A heterozygous and wild-type mice, in which the percentage of IgG1-expressing B1b cells in the PP of heterozygous mice remains significantly low as compared to wild-type. Overall, these results suggest that a gut Wnt5A-microbiota axis is intrinsically associated with the maintenance of gut B-cell repertoire and protection from infection.IMPORTANCEAlthough it is well accepted that B cells and microbiota are required for protection from infection and preservation of gut health, a lot remains unknown about how the optimum B-cell repertoire and microbiota are maintained in the gut. The importance of this study lies in the fact that it unveils a potential role of a growth factor termed Wnt5A in the safeguarding of the gut B-cell population and microbiota, thereby protecting the gut from the deleterious effect of infections by common pathogens. Documentation of the involvement of a Wnt5A-microbiota axis in the shaping of a protective gut B-cell repertoire, furthermore, opens up new avenues of investigations for understanding gut disorders related to microbial dysbiosis and B-cell homeostasis that, till date, are considered incurable.
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Chitosan lactate improves repeated closed head injury-generated motor and neurological dysfunctions in mice by impacting microbiota gut-brain axis.
The negative impact of repeated-mild traumatic brain injury (rmTBI) is profoundly seen in circadian-disrupted individuals. The unrelenting inflammation, glial activation, and gut dysbiosis are key neuropathological aberrations in the aftermath of rmTBI. In this study, we examined the impact of chitosan lactate (CL) on circadian disturbance (CD) + rmTBI-generated neurological dysfunctions and its prebiotic response on the gut-brain axis. Adult C57BL/6 mice were exposed to circadian disruption (CD) prior to rmTBI insults. The neurobehavioral changes were assessed by rotarod, open-field test (OFT), elevated zero maze (EZM), forced-swim test (FST), Y-maze, and novel object recognition test (NORT). The inflammatory, neuronal, and synaptic markers in the frontal cortex and hippocampus, and cecal gut microbiota phylum were examined using RT-PCR and western blotting. The goblet cells, tight junction proteins (occludin and zona occludens-1), and short-chain fatty acids (SCFAs) were analyzed using immunohistochemistry, alcian-blue PAS staining, and 1H-NMR methods. Mice exposed to CD + rmTBI (CDR) displayed robust neurological dysfunctions in rotarod, anxiety- and depressive-like behavior in EZM and FST, and cognition deficits in Y-maze and NORT. Administration of CL (1 and 3 mg/kg) mitigated the above neurobehavioral abnormalities. CL treatment also normalized the levels of inflammatory markers (NF-κB, IL-6, IL-18, and TNF-α), brain-derived neurotrophic factor, and neuronal/synaptic proteins (doublecortin, synaptophysin, and postsynaptic density protein-95). Increased goblet cells and tight junction proteins in the colon and SCFAs in the cecal samples indicated improved gut integrity following CL treatment. The results indicate that CL mitigated CDR-inflicted neurological abnormalities in mice by modulating neuroinflammation and gut-brain interactions.
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The psychobiotic revolution: comprehending the optimistic role of gut microbiota on gut-brain axis during neurological and Gastrointestinal (GI) disorders.
The microbiota-gut-brain axis is a complex central nexus, intricately communicating with human health, affecting neurophysiological and cognitive processes. In this review article, the therapeutic potential of psychobiotics is comprehensively examined as a relatively new category of probiotics that have been shown to have beneficial effects on mental health, particularly in the context of the increasing prevalence of neurological and gastrointestinal pathologies in developing economies particularly Pakistan. This current discussion examines the pathways through which psychobiotics are postulated to influence their beneficial effect such as their role in biosynthesis of neuroactive substances, the regulation of the hypothalamic-pituitary-adrenal (HPA) axis, and inflammatory response. Some specific strains of bacteria including Lactobacillus plantarum PS128, Lactobacillus helveticus NS8, Bifidobacterium longum 1714, Lactobacillus rhamnosus (JB-1), and Bifidobacterium infantis (35624) play an important role in overcoming anxiety and mood disorders. The neuroactive chemicals (gamma-aminobutyric acid (GABA), dopamine, norepinephrine, acetylcholine, and serotonin) are extracted from gut microbes and have the ability to alter the brain activity. Other metabolites and intermediate substances, such as Brain-Derived Neurotrophic Factor (BDNF) and short-chain fatty acids (SCFAs), maintain the integrity of the intestinal barrier and control the immune system and inflammatory response. The psychobiotic food pyramid aims to protect gut and mental health while psychobiotic supplements are been known to alleviate chronic stress and anxiety. They are used to treat different types of mental conditions, such as neurodegenerative, neurodevelopmental, psychiatric, and GI disorders as well. Mental health disorders (with depression having the highest percentage) are increasing in various countries including Pakistan every day, with women being affected more than men. The review incorporates existing evidence based on both preclinical and clinical studies and clarifies the nexus of critical importance between the disorder of gut microbiota and the pathogenesis of mental health disorders that were aggravated in the course of the COVID-19 pandemic. Additional research is imperative in determining the long-term effectiveness and safety of psychobiotic interventions, particularly against a diverse population and different socioeconomic environments. This study therefore, contributes to highlighting the tremendous potential of psychobiotics as a cost-effective and innovative approach to supplementing traditional mental healthcare modalities.
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Gut-brain axis in the pathogenesis of sepsis-associated encephalopathy.
The gut-brain axis is a bidirectional communication network linking the gut and the brain, overseeing digestive functions, emotional responses, body immunity, brain development, and overall health. Substantial research highlights a connection between disruptions of the gut-brain axis and various psychiatric and neurological conditions, including depression and Alzheimer's disease. Given the impact of the gut-brain axis on behavior, cognition, and brain diseases, some studies have started to pay attention to the role of the axis in sepsis-associated encephalopathy (SAE), where cognitive impairment is the primary manifestation. SAE emerges as the primary and earliest form of organ dysfunction following sepsis, potentially leading to acute cognitive impairment and long-term cognitive decline in patients. Notably, the neuronal damage in SAE does not stem directly from the central nervous system (CNS) infection but rather from an infection occurring outside the brain. The gut-brain axis is posited as a pivotal factor in this process. This review will delve into the gut-brain axis, exploring four crucial pathways through which inflammatory signals are transmitted and elevate the incidence of SAE. These pathways encompass the vagus nerve pathway, the neuroendocrine pathway involving the hypothalamic-pituitary-adrenal (HPA) axis and serotonin (5-HT) regulation, the neuroimmune pathway, and the microbial regulation. These pathways can operate independently or collaboratively on the CNS to modulate brain activity. Understanding how the gut affects and regulates the CNS could offer the potential to identify novel targets for preventing and treating this condition, ultimately enhancing the prognosis for individuals with SAE.
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Assessing the joint effects of brain aging and gut microbiota on the risks of psychiatric disorders.
We aim to explore the potential interaction effects of brain aging and gut microbiota on the risks of sleep, anxiety and depression disorders. The genome-wide association study (GWAS) datasets of brain aging (N = 21,407) and gut microbiota (N = 3,890) were obtained from published studies. Individual level genotype and phenotype data of psychiatric traits (including sleep, anxiety and depression) were all from the UK Biobank (N = 107,947-374,505). We first calculated the polygenic risk scores (PRS) of 62 brain aging modes and 114 gut microbiota taxa as the instrumental variables, and then constructed linear and logistic regression analyses to systematically explore the potential interaction effects of brain aging and gut microbiota on psychiatric disorders. We observed the interaction effects of brain aging and gut microbiota on sleep, anxiety and depression disorders, such as Putamen/caudate T2* vs. Rhodospirillales (β = -0.012, P = 8.4 × 10-4) was negatively associated with chronotype, Fornix MD vs. Holdemanella (β = -0.007, P = 1.76 × 10-2) was negatively related to general anxiety disorder (GAD) scores, and White matter lesions vs. Acidaminococcaceae (β = 0.019, P = 1.29 × 10-3) was positively correlated with self-reported depression. Interestingly, Putamen volume vs. Intestinibacter was associated with all three psychiatric disorders, including chronotype (negative correlation), GAD scores (positive correlation) and self-reported depression (positive correlation). Our study results suggest the significant impacts of brain aging and gut microbiota on the development of sleep, anxiety and depression disorders, providing new clues for clarifying the pathogenesis of these disorders.
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Nutraceuticals in Psychiatric Disorders: A Systematic Review.
Correct nutrition and diet are directly correlated with mental health, functions of the immune system, and gut microbiota composition. Diets with a high content of some nutrients, such as fibers, phytochemicals, and short-chain fatty acids (omega-3 fatty acids), seem to have an anti-inflammatory and protective action on the nervous system. Among nutraceuticals, supplementation of probiotics and omega-3 fatty acids plays a role in improving symptoms of several mental disorders. In this review, we collect data on the efficacy of nutraceuticals in patients with schizophrenia, autism spectrum disorders, major depression, bipolar disorder, and personality disorders. This narrative review aims to provide an overview of recent evidence obtained on this topic, pointing out the direction for future research.