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Sickness, or sickness behavior, is a state of altered physiology and behavior generated by the brain-immune axis during infection, which is generally assumed to contribute to host defense. Here, we examine this assumption by framing sickness as organismal-scale immunity and explore predicted parallels with immunity at the cellular and tissue scales.
Schizophrenia (SCZ) is frequently accompanied by peripheral immune dysregulation, yet robust and reproducible blood-based molecular markers remain limited. We sought a compact long non-coding RNA (lncRNA) signal in peripheral blood leukocytes (PBL) and examined how it aligns with immune-linked transcriptional programs and cellular compartments, using bulk RNA sequencing (RNA-seq), targeted validation, and a healthy-donor peripheral blood mononuclear cell (PBMC) single-cell reference for localization. PBL from 50 first-episode or unmedicated SCZ patients and 50 matched controls underwent RNA-seq. We performed reference-guided transcript annotation and generated lncRNA and mRNA count matrices. Differential expression was assessed with edgeR (TMM normalization). Candidate lncRNAs were prioritized using sample-level lncRNA-mRNA co-variation, followed by qRT-PCR validation in an independent cohort and evaluation with a two-feature logistic regression model using repeated 10-fold cross-validation. Pathway-scale analyses and weighted gene co-expression network analysis (WGCNA) summarized coordinated programs. Single-cell data from healthy donors were used for expression localization only, not case-control testing. We observed a small set of dysregulated lncRNAs alongside broader mRNA changes. Two candidates at the CCR3 and IL1RAP loci (TCONS_00134168/lncRNA-CCR3 and TCONS_00138311/lncRNA-IL1RAP) showed consistent case-control directionality and were supported by qRT-PCR. The two-lncRNA model showed strong internal discrimination (AUC = 0.933) but weaker, uncertain performance in a small external qRT-PCR set (AUC = 0.656). Enrichment analyses highlighted synapse-related annotations, RNA processing/translation, and immune signaling, with recurrent involvement of IL1RAP-linked IL-1 branches. WGCNA placed lncRNA-IL1RAP and IL1RAP within diagnosis-inversely associated co-expression programs, whereas lncRNA-CCR3 showed a more transcript-specific pattern. In the healthy-reference single-cell atlas, IL1B/IL1RAP/HSF1 signals were most prominent in the monocyte/macrophage compartment. Together, these findings support an exploratory two-lncRNA candidate marker concept, while underscoring the need for larger multi-center validation and targeted mechanistic follow-up without implying causality.
This study aimed to investigate the effect of different preferences of food-derived odors (common food flavors/spices) on the appetite, immune system, and CNS of mice through 15 days of olfactory exposure. According to the ranking of sniffing duration, beef essence was chosen as a pleasant odor, while garlic essence was chosen as an unpleasant odor. Results showed that food intake and body weight gradually increased in all groups, with the lowest values observed in the garlic odor group. Unpleasant garlic odor suppressed the mRNA transcription levels of agouti-related protein (AgRP) and neuropeptide Y (NPY) in the hypothalamic arcuate nucleus, along with elevated leptin levels, thereby inhibiting food intake and causing body weight loss. In addition, the serum TNF-α, IL-2, and IL-6 levels in the garlic odor group were significantly higher than those in the beef and control groups, which indicated that the immune system may be impaired by the exposure to unpleasant garlic odor. Furthermore, pleasant beef odors could promote the differentiation of hippocampal neurons and the levels of brain-derived neurotrophic factors and glial cell line-derived neurotrophic factor, which may have great potential in improving neurological disorders. Conclusively, unpleasant odors may suppress immune function or modulate the CNS by establishing an odor-CNS-immune pathway, while pleasant food odors affect only the CNS. The present study preliminarily provides novel insights that different preferences for food odors could affect the body weight, immune system, and CNS. It may serve as a reference for further research and development of aromatherapy as an adjuvant medicine and therapeutic method.
The mammalian gut microbiota is a complex and dynamic "microbial organ" that interacts with its host. The gut microbiota contains a vast gene pool and metabolic capacity, producing key metabolites such as short-chain fatty acids (SCFAs), bile acids, vitamins, and other compounds. These metabolites regulate core physiological functions like energy metabolism, immune homeostasis, and neural behavior via the gut-brain axis (GBA), immune signaling networks, and other pathways. This review explores the bidirectional regulatory role of the gut microbiota. The gut microbiota influences the host's metabolism and immune functions through its metabolites and structural components, while the host's physiological state, internal environment, and lifestyle can alter the microbiota's composition and function, creating a complex feedback network. Furthermore, the main mechanisms of dysbiosis in diseases are also explored. Dysregulation of the gut microbiota can damage the intestinal mucosal barrier, induce chronic inflammation, disrupt metabolic and immune signaling, and contribute to diseases such as type 2 diabetes, non-alcoholic fatty liver disease, inflammatory bowel disease, rheumatoid arthritis, and neurodegenerative disorders. Microbiota-based interventions, such as probiotics, prebiotics, and fecal microbiota transplantation (FMT), can be promising in disease management, but their clinical applications face challenges, including individual genetic backgrounds, lifestyles, and environmental factors, as well as difficulties in achieving long-term colonization of specific strains. Future research needs to uncover precise causal mechanisms in host-microbe interactions, as well as develop individualized microbiota intervention strategies to provide new theoretical bases and practical tools for the prevention, diagnosis, and treatment of major diseases.
The human gut microbiome has emerged as a pivotal modulator of brain function and mental health, acting through intricate bidirectional communication along the gut-brain axis. Mounting evidence suggests that microbial communities influence neurodevelopment, neurotransmission, and behavior via pathways involving the vagus nerve, immune signaling, and microbiota-derived metabolites such as short-chain fatty acids and neurotransmitter precursors. This review critically examines the mechanistic underpinnings of microbiota-brain communication and evaluates current findings linking dysbiosis to psychiatric conditions, including depression, anxiety, schizophrenia, autism spectrum disorder, and bipolar disorder. In addition, it assesses the therapeutic potential of microbiome-targeted interventions-such as probiotics, fecal microbiota transplantation (FMT), and precision dietary modulation-in ameliorating neuropsychiatric symptoms. While the field holds considerable promise, limitations, including correlational study designs, small sample sizes, and a lack of standardized methodologies, underscore the need for rigorous, large-scale clinical trials. A deeper understanding of host-microbe interactions may catalyze a paradigm shift in psychiatric treatment, paving the way for novel, personalized microbiome-based therapeutics.
The PReDicT study showed that predictive algorithm-guided antidepressant treatment reduces anxiety and improves functioning in patients with depression. To estimate the costs, outcomes and cost-effectiveness of the PReDicT test compared with treatment as usual (TAU) for primary depression care in five European countries. Within-trial economic analysis was conducted over 24 weeks from the health/social care and societal perspectives alongside the PReDicT trial (NCT02790970) in France, Germany, The Netherlands, Spain, and the UK, according to Consolidated Health Economic Evaluation Reporting Standards guidelines. We calculated quality-adjusted life-years (QALYs) based on the EQ-5D-5L, capability-weighted life-years based on the Oxford Capabilities Questionnaire - Mental Health (OxCAP-MH) (Germany and UK only), and costs for 2018 (€). Multiple imputation for missing data, multivariable regression for cost and outcome differences, and bootstrapping and sensitivity analyses for uncertainty were conducted. There were significant outcome improvements (EQ-5D-5L PRedicT: +0.139; TAU: +0.140) and societal cost reductions (PRedicT: -€2589; TAU: -€2602) in both groups (N = 913) between the before and during trial periods. In the UK and Germany (n = 619), the PReDicT group showed significant additional capability well-being gains (OxCAP-MH: +2.127, p = 0.021). Cost-effectiveness probabilities ranged from 46 to 59% at trial level, but exceeded 80% in the UK. Results remained stable across different sensitivity analyses, with societal cost-effectiveness improved for those (self-)employed. We observed potentially meaningful health and economic benefits of closely monitored antidepressant treatment, as implemented in both treatment and control arms of the PReDicT trial. The PReDicT test itself had some added benefits in improved capabilities and productivity, however, with great uncertainty and country-level variations in cost-effectiveness.
The maternal microbiome is increasingly being recognized as a key determinant in various neonatal health outcomes, including offspring immunity, metabolism, brain function, and behavior. While the oral, vaginal, skin, and gut microbiota are significant contributors to the offspring's postnatal gut microbial seeding, the composition and diversity of the maternal gut microbiome during pregnancy seems to be critical in shaping neonatal health outcomes, even prior to birth. Growing evidence suggests that the balance among the microbial groups in the gut and their interactions with the host are crucial for health. Dysbiotic communities in pregnancy and early in life may lead to disease processes in offspring, though the specific processes by which maternal gut microbes affect offspring gut microbial development are unknown. Here, we summarize research examining gut microbial shifts during pregnancy, and their effects on the diversity and composition of the infant microbiome and on early health outcomes. We also discuss current theories for how the maternal gastrointestinal (GI) tract influences neonatal seeding, and how probiotics during the perinatal period may affect offspring health outcomes.
Background/Objectives: Umami peptides enhance flavor and contribute to appetite regulation (satiety) and metabolic health. By signaling to the orbitofrontal cortex, umami has been shown to improve cognitive function in Alzheimer's disease dementia. This taste boosts the immune system and induces saliva secretion. However, the molecular mechanisms linking umami peptides to systemic physiology remain poorly understood. This study provides the first integrated analysis of neurological, immunological, and endocrinological pathways activated by umami peptides. Methods: Novel umami peptides were identified using machine-learning and deep-learning analyses from a library of marine-derived bioactive peptides. T1R1-T1R3 heterodimer is the dominant receptor for umami taste transmission in humans, expressed on taste cells, intestinal cells, and hypothalamic tanycytes. Molecular docking confirmed the binding of novel ligands to the T1R1-T1R3 receptor complex. New candidates and experimentally validated umami peptides, identified by sensomics approaches from tauco, chicken soup, pufferfish, and dry-cured ham, were analyzed using gene ontology. Results: The functional enrichment analysis revealed crosstalk among key signaling processes, including glutamatergic and opioidergic pathways. In addition to the role of µ1 opioid receptor (OPRM1), hub gene intersections highlight cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and the anorexigenic pro-opiomelanocortin (POMC) neurons as potential regulators of the gut-brain axis in satiety signaling. Chemokine-encoding genes, melanin-concentrating hormone (MCH), oxytocin (OXT), and neurotensin (NTS) were other key target genes. Conclusions: The identified targets reveal the coordinated crosstalk between peripheral and central umami signaling that may contribute to the regulation of feeding behavior, satiety, cognition, memory, learning, and immune function. These network-based insights generate hypotheses and guide the design of nutritional and drug-like effectors for metabolic and cognitive health.
Major Depressive Disorder (MDD) is increasingly viewed through the lens of the neuroinflammatory hypothesis and gut-brain axis dysfunction. Short-Chain Fatty Acids (SCFAs), the primary metabolites produced by the gut microbiota, are vital signaling molecules that maintain intestinal barrier integrity, modulate peripheral immunity, and influence microglial function. While individual studies suggest altered SCFAs levels in MDD, a definitive, quantitative synthesis establishing a robust biomarker signature is currently lacking. This meta-analysis aimed to precisely characterize the signature of SCFAs (acetic, propionic, butyric, and isobutyric acid) in MDD patients compared to healthy controls. We systematically searched major databases across PubMed, Embase, and Web of Science databases for studies quantifying SCFAs levels up to September 15, 2025. Studies examining SCFAs levels in depressed patients and depressive-like murine models, as well as studies investigating SCFAs interventions for depressive-like behavior, were selected for synthesis. Risk of bias was evaluated using the Newcastle-Ottawa Scale. The effect sizes were synthesized using a random-effects model and presented as standardized mean differences. Eight human and 52 murine studies were included in the meta-analyses. Depressed patients showed significantly lower concentrations in blood (plasma and serum) of propionic (SMD = -0.60, p-value = 0.007), butyric (SMD = -0.50, p-value = 0.006), isobutyric (SMD = -0.72, p-value = 0.020), valeric (SMD = -0.43, p-value = 0.040) and isovaleric acids (SMD = -0.75, p-value = 0.002). Secondary analysis of MDD patients confirmed consistent reductions. High heterogeneity was observed. In murine models, SCFAs depletion was frequently observed, while supplementation improved depressive-like behaviors. MDD is characterized by a significant, quantifiable deficit in the circulating SCFAs metabolome, which provides strong empirical validation for the gut-brain axis hypothesis in depression. We advocate for the investigation of SCFAs as novel, measurable peripheral biomarkers and targeted therapeutic agents (e.g., butyrate supplementation) for precision nutritional psychiatry.
Neuroinflammation is a hallmark of various neurological and psychiatric disorders, including post-COVID-19 conditions caused by SARS-CoV-2 infection. The S1 subunit of the SARS-CoV-2 spike protein (S1 protein) can trigger neuroinflammation by activating microglia. However, the precise mechanism of S1 protein-induced microglial activation remains unclear. Our investigation revealed that the Kv1.3 channel plays a role in S1 protein-mediated neuroinflammation. We performed whole-cell patch clamp recording of microglia in CX3CR1GFP/+ mice, Iba1 immunohistochemistry analysis, and behavioral analysis. We found that the S1 protein increased Kv1.3 channel activity and microglial activation in the lateral septum, leading to behavioral changes. Chlorpromazine (CPZ), an antipsychotic linked to lower COVID-19 rates in clinical observations, blocked S1 protein-mediated increase in Kv1.3 channel current and microglia size. Mice injected with the S1 protein showed anxiety-like behavior, which CPZ alleviated. This study elucidates the molecular mechanism of S1 protein-mediated neuroinflammation and CPZ as a potential treatment for post-COVID symptoms. The COVID-19, caused by SARS-CoV-2, does not just affect the lungs; it can also harm the brain and mental health. The virus can trigger chronic neuroinflammation, which is linked to problems such as anxiety and depression. A protein from the virus called S1 activates immune cells in the brain, although the exact process is not fully understood. Our findings show that the S1 protein increases Kv1.3 channel activity and microglia activation in the lateral septum, leading to anxiety- and depression-like behaviors in mice, which the antipsychotic chlorpromazine can mitigate. Therefore, chlorpromazine may offer therapeutic benefits for post-COVID syndrome by inhibiting S1 protein–induced neuroinflammation.
Allergic asthma is the most common chronic health challenge for youth in the United States, and it occurs during a critical time in neurobiological development when stressors can have long-lasting effects on adult mental health and stress regulation. Prior research has shown that youth who experience asthma or social challenges are at increased risk for developing anxiety. To determine if chronic social changes during development exacerbate allergic asthma immune function, anxiety, and/or stress physiology, we used a mouse model to test the influences of youth allergen exposure and constantly changing social conditions ('social instability') on adult asthma- and anxiety-related behavior and physiology. During postnatal days 7-59, male and female BALB/cJ mice were repeatedly exposed to house dust mite extract (HDM) to cause airway inflammation and/or to repeat cycles of social isolation and reorganization to simulate social instability. In adulthood, we measured basal asthma- and inflammation-related cytokines in circulation and lung gene expression, baseline and reactive circulating corticosterone (CORT), anxiety-like behavior, and hypothalamic-pituitary-adrenal (HPA) axis/anxiety-related gene expression in prefrontal cortex (PFC) and hypothalamus. Social instability decreased adult basal circulating CORT and GR expression in PFC and increased circulating CORT reactivity and recovery. In allergen-exposed mice, social instability exacerbated circulating cytokine concentrations, lung gene expression, and female CORT responses to an acute stressor. But social instability negated female HDM-induced anxiety-like behavior and PFC FKBP5 gene expression. Results suggest that repeated social change (or repeated activation of the HPA) during adolescence decreases prefrontal sensitivity to glucocorticoids to produce adults that are resilient to anxiety in the context of allergic asthma.
Postpartum depression (PPD) is a psychological disorder affecting approximately 10-15% of women following childbirth, with significant implications for maternal and infant well-being. While hormonal fluctuations and psychosocial factors have long been considered primary contributors, recent reports demonstrated that gut microbiome is implicated in modulating maternal mood and behavior. The bidirectional communication between the gut and brain, mediated by microbiota-gut-brain axis, along with genetic and epigenetic modifications, has gained increasing attention as a potential mechanistic pathway in PPD. However, the precise genetic and epigenetic underpinnings of this interaction remain to be elucidated. This review aims to explore the genetic and epigenetic landscape of postpartum depression, with a significant focus pertinent to gut microbiota role in shaping neurobiological outcomes. By integrating recent findings from genomic, epigenomic, and microbiome research, we seek to elucidate novel mechanistic insights and potential therapeutic avenues. A comprehensive literature search was conducted using public databases, including PubMed, Google Scholar, and NCBI, to identify relevant studies on PPD, gut microbiota, genetics, and epigenetics. Gut microbiota and neuroimmune modulation: peripartum changes in gut microbiota composition have been linked to immune dysregulation, inflammation, and neurotransmitter imbalances, all of which are implicated in PPD pathophysiology. Genetics and epigenetics of PPD: Genome-wide association studies (GWAS) revealed a profound genetic risk loci associated with PPD. Additionally, DNA methylation, histone modifications, and non-coding RNAs have profound functional implications in gene expression regulation, influencing PPD susceptibility. Epigenetic influence of the gut microbiome: The gut microbiome affects epigenetic modifications, such as DNA methylation and histone acetylation, which may lead to fetal programming and maternal mental health disorders. Choline metabolism and maternal mental health: Choline, an essential nutrient involved in epigenetic regulation, influences gut microbiota composition and brain function. Dysregulation in choline metabolism is associated with higher risk of PPD. Clinical and therapeutic implications: Understanding the genetic and epigenetic mechanisms underlying PPD offers new avenues for personalized therapeutic interventions, including probiotic and prebiotic strategies, microbiome-based treatments, and targeted epigenetic therapies. The interplay between genetics, epigenetics, and gut microbiota represents a novel and promising area of research in understanding postpartum depression. The microbiota-gut-brain axis serves as a crucial mediator in this relationship, influencing neuroimmune regulation, neurotransmitter synthesis, and epigenetic modifications. Future studies should focus on integrating multi-omics approaches to unravel the molecular complexity of PPD and develop targeted interventions aimed at restoring microbiome and epigenetic homeostasis.
Sodium arsenite (NaAsO₂) contamination in food and water poses a significant threat to human health, with its reproductive toxicity requiring further investigation. Selenium (Se), an essential trace element, has been shown to combat oxidative damage, enhance immunity, and mitigate the toxicity of heavy metals. This study examined the ameliorative effect of organic selenomethionine (Se-Met) against AsIII-induced reproductive toxicity in zebrafish. Zebrafish were exposed to 300 μg/L AsIII and fed a diet supplemented with Se-Met (1 μg/g) either prophylactically or therapeutically. Behavioral analysis revealed that AsIII exposure disrupted courtship behavior and reduced spawning, whereas Se-Met treatment partially restored normal spawning activity. Histological examination showed decreased sperm counts in AsIII-exposed males, which were ameliorated restored by Se-Met. At the molecular level, AsIII exposure down regulated Cyp11a, Cyp17a and Cyp19a1b in gonads, as well as Fshβ and Cyp19a1a in the brain, while Se-Met supplementation partially reversed these effects. In addition, CYP17A1 protein expression in spermatogonia was markedly reduced by AsIII but showed a clear recovery tendency following Se-Met treatment. In conclusion, low-dose Se-Met supplementation partially alleviates AsIII-induced reproductive toxicity in zebrafish, supporting its potential role as a partially ameliorative agent against sodium arsenite exposure.
Meningitis remains the leading infectious cause of neurological disabilities globally, disproportionately affecting children younger than 5 years and populations in the African meningitis belt. Whereas previous global estimates focused on ten pathogen categories, this study presents the most comprehensive analysis to date, assessing the meningitis burden attributable to 17 causative pathogens based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 framework. GBD is a systematic, scientific effort aimed at quantifying the comparative magnitude of health loss caused by diseases, injuries, and risk factors across age groups, sexes, and geographical locations over time. We estimated meningitis mortality using the Cause of Death Ensemble model (CODEm) and morbidity using DisMod-MR 2.1, incorporating data from vital registration, verbal autopsy, surveillance, hospital data, and systematic reviews. Aetiology-specific estimates were generated with pathogen-linked case-fatality ratios and splined binomial regression models. Risk factor attribution was based on established risk-outcome pairs and population attributable fractions. In 2023, there were 259 000 (95% uncertainty interval 202 000-335 000) global deaths and 2·54 million (2·20-2·93) incident cases of meningitis. Children younger than 5 years accounted for more than a third of deaths (86 600 [53 300-149 000]). Streptococcus pneumoniae, Neisseria meningitidis, non-polio enteroviruses, and other viruses were the leading causes of death, while non-polio enteroviruses caused the most cases. The four WHO-defined preventable meningitis pathogens of interest (S pneumoniae, N meningitidis, Haemophilus influenzae, and Group B streptococcus) contributed to 98 700 deaths (77 000-127 000) and 594 000 cases (514 000-686 000). Low birthweight, short gestation, and household air pollution were the top risk factors for meningitis-related mortality. Although mortality and incidence have declined significantly since 1990, progress is insufficient to meet WHO 2030 targets. Despite marked progress in reducing bacterial meningitis via global vaccination campaigns, a substantial meningitis burden persists, attributable both to common pathogens such as S pneumoniae and N meningitidis and to emerging non-bacterial pathogens such as Candida spp and drug-resistant fungi. Achieving WHO goals will require sustained investment in surveillance, vaccination, maternal screening, and health-system strengthening, especially in high-burden settings. Gates Foundation, Wellcome Trust, and UK Department of Health and Social Care.
Chronic stress can trigger major depressive disorder through peripheral immune factors. Enhanced circulating levels of complement component 3 (C3), a key innate immunity molecule that is predominantly produced by the liver, have been observed in depressed patients. However, the role of liver-derived C3 in the regulation of behavior under chronic stress remains ambiguous. Here, we found that liver-derived C3 critically contributes to stress susceptibility and blood-brain barrier (BBB) impairment in the nucleus accumbens (NAc) by inhibiting endothelial cell claudin-5, a pivotal tight junction protein for BBB integrity. In three mouse models of depression, hepatic C3 expression was notably increased in mice, with no comparable changes in other peripheral organs. Genetic ablation of C3 ameliorated chronic social defeat stress (CSDS)-induced increases in NAc BBB permeability and depressive-like behavior, and this amelioration was reversed upon re-expression of hepatic C3. Consistently, knockdown of hepatic C3 similarly improved these deleterious effects induced by CSDS. Furthermore, overexpression of hepatic C3 was sufficient to induce depressive-like behavior following subthreshold social stress. Hepatic C3 manipulation bidirectionally regulated expression of claudin-5 in NAc endothelial cells. Mechanistically, the liver-derived C3 suppressed claudin-5 expression in brain endothelial cells and increased stress susceptibility in mice through the C3a receptor-CCAAT/enhancer-binding protein-α signaling pathway in the NAc. Moreover, corticosterone upregulated hepatic C3 release by activation of nuclear factor-κB (NF-κB). Taken together, these results demonstrate that liver-derived C3 promotes susceptibility to depression by increasing BBB permeability under chronic stress, and propose targeting hepatic C3 as a promising therapeutic strategy for depression.
Social threat can potentiate inflammation and increase the risk of inflammation-related diseases. Identifying individuals with heightened neural sensitivity to social threat could guide targeted prevention and treatment protocols. The cAMP response element-binding protein (CREB) transcription factor is a key mediator of neural influences on immune cell gene expression, and we hypothesize that individual differences in basal CREB activity could serve as a blood biomarker of individual differences in neural sensitivity to social threat. We utilized pre-intervention data from a randomized-controlled trial (n = 44; 67% female; average age = 19.4 ± 1.8; NCT05304052) that included functional neuroimaging and peripheral blood collection. CREB gene regulation was assessed by TELiS promoter-based bioinformatics, and central nervous system (CNS) social threat sensitivity was assessed by fMRI-measured changes in activity in the anterior insula (AI), dorsal anterior cingulate cortex (dACC), and amygdala in response to a standardized social-evaluative stress task (modified Montreal Imaging Stress Task; MIST). In unadjusted regression analysis, greater baseline CREB activity correlated with greater reactivity in the AI (b = 0.54, p < 0.001), dACC (b = 0.46, p = 0.004), and amygdala (b = 0.33, p = 0.015). In adjusted analyses, controlling for standard covariates (e.g., sex, age, baseline depressive and anxiety symptoms), the associations were significant for AI and dACC (p < 0.05), and marginally significant for the amygdala (p = 0.08). Ancillary analyses suggest that variations in leukocyte subset abundance may drive these associations. Findings suggest basal CREB activity in blood may serve as a biomarker for CNS reactivity to social threats. Larger studies are needed to replicate these findings and determine their implications for social behavior, health, and responses to social interventions.
Arsenic (As) is a major public health threat, with more than 200 million people at risk of consuming drinking water that exceeds World Health Organization safety guidelines. Given that inorganic arsenic (iAs) is linked to various neuropsychiatric and neurodegenerative disorders, a better understanding of its mechanisms of toxicity is warranted. Current evidence suggests that microglia are central to the pathophysiology of As-induced effects in the central nervous system. Microglia are resident immune cells in the brain that play a crucial role in surveillance, clearance of pathogens, and wound healing. They undergo distinct stages of development throughout life, and their behavior is known to be disrupted by environmental insults such as iAs. To characterize the mechanisms by which iAs alters microglial function, we examined the impact of subtoxic exposure to trivalent inorganic arsenic (As(III)) on microglial activity, both in the presence and absence of immune challenges, using a spontaneously immortalized murine cell line derived from the neonatal cerebral cortex (SIM-A9). Results indicate that iAs causes early activation of SIM-A9 cells through upregulation of toll-like receptor 4-mediated NF-κB signaling, followed by the slower onset of anti-inflammatory effects mediated through increased Nuclear Factor Erythroid 2-related Factor 2 (Nrf2) activity. This later attenuation of responses to inflammatory stimuli suggests that iAs exposure may impair neonatal microglial function and sensitize individuals to secondary challenges relevant to a range of neurological functions and disorders.
Adolescence is a key stage marked by rapid physical growth, brain maturation, and psychosocial transitions. This period is characterized by enhanced neuroplasticity, particularly in brain regions responsible for executive function and impulse control. Nutrition, genetics, and environmental conditions interact in shaping physical and cognitive outcomes, underscoring the complexity of adolescent development. Adequate intake of macro- and micronutrients is essential to support hormonal changes and growth, while deficiencies can compromise cognition, immunity, and long-term health. Genetic predispositions contribute to variability in growth and metabolism, yet environmental factors mediate these effects. Simultaneously, adolescents face psychosocial stressors, including peer influence, identity formation, and academic demands, which may trigger emotional dysregulation, anxiety, or depression. Additional challenges, such as social media exposure and substance use, further complicate developmental outcomes. Recognizing the convergence of biological, behavioral, and environmental influences is critical to developing strategies that foster resilience, address vulnerabilities, and promote sustained well-being throughout adolescence.
The intestinal microbiome plays a fundamental role in canine health and well-being, regulating functions, including digestion, immunity, metabolism, and behavior. Dysbiosis refers to the disruption of the balanced composition of resident commensal communities, and gut bacteria can influence behavior via neurological, metabolic, endocrine, and immune-mediated pathways. Growing evidence supports the existence of a bidirectional communication between the gut and the central nervous system, known as the gut-brain axis, through which intestinal microorganisms may influence behavior via neurological, metabolic, endocrine, and immune-mediated pathways. Despite the expanding interest in this field, the contribution of intestinal dysbiosis to the development and severity of behavioral and neurological disorders in companion dogs remains poorly understood. This review aims to critically analyze the literature from 2011 to 18 September 2025 concerning the association between dysbiosis, the gut-brain axis, and both gastrointestinal and non-gastrointestinal illnesses in dogs. To our knowledge, this review represents the first application of Text Mining (TM) in this domain: TM facilitates the identification and analysis of valuable information from extensive datasets, converting unstructured content into structured data, thereby enabling quantitative analysis. We used the following search terms on three bibliographic databases (PubMed, Scopus, and Web of Science): "dysbiosis" AND "canine" OR "dog" AND "gut-brain axis" AND "behavior". Of the 1176 records retrieved, 35 studies were checked following the PRISMA guidelines, and they met the predefined inclusion criteria in the final analysis.
Body-brain neuroimmune signaling is important for maintaining homeostasis and behavior. Dysregulation of these interoceptive communication pathways leads to compromised physical and mental health often associated with psychiatric disorders. Specialized interoceptive nodes considered as "gateways" to the brain offer an interface for communication with the periphery to aid in homeostatic maintenance and behavioral regulation. In this regard, sensory circumventricular organs (CVOs) with their strategic locations, fenestrated vasculature, and efferent neuronal projections, provide a unique opportunity for sensing and translating homeostatic and immune perturbations into adaptive behaviors. Despite their well-recognized role in homeostatic maintenance, mechanisms by which sensory CVOs detect and translate homeostatic and immune fluctuations into behavioral responses are not well understood. In this review, we attempt to discuss sensory CVO associated neuroimmune signaling and cell circuit mechanisms that regulate behaviors relevant to mental health.