Brain, Behavior, and Immunity最新文献

{"title":"D-lactate in immune regulation and neuroinflammation: beyond microbial fermentation","authors":"Rumi Murayama , Hiroyuki Nakamura , Kenji Hashimoto","doi":"10.1016/j.bbi.2025.106125","DOIUrl":"10.1016/j.bbi.2025.106125","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106125"},"PeriodicalIF":7.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cachexia in mice blunts improved cognitive flexibility induced by calorie restriction.","authors":"Kyna Conn, Laura K Milton, Alyssa Teoh, Priscila T Levi, Kelly L Walton, Zane B Andrews, Claire J Foldi, Sarah H Lockie","doi":"10.1016/j.bbi.2025.106123","DOIUrl":"10.1016/j.bbi.2025.106123","url":null,"abstract":"<p><p>Approximately 50-80 % of cancer patients suffer from cachexia, a metabolic syndrome involving inflammation, appetite loss, and muscle and fat wasting. Another common co-morbidity of cancer patients is cognitive impairment, and clinical evidence suggests the incidence of cachexia is linked to more severe cognitive symptoms. Given the difficulty of studying changes in cognitive function in human cancer patients, we set out to examine key aspects of cognitive performance in a mouse model of pancreatic cancer (pancreatic ductal adenocarcinoma; PDAC) cachexia, using an in-cage operant device (Feeding Experimental Device version 3; FED3) and a reversal learning task. Performance on the operant reversal task was compared to two control groups without cancer: ad libitum fed, sham injected with phosphate buffered saline (PBS), calorie restricted (CR) to 90-95 % of original body weight to control for reduced food intake and weight loss in cachexia mice. Our PDAC model recapitulated features of cachexia, including anorexia, weight loss, muscle wastage and inflammation. CR mice performed significantly better on the reversal task than both PDAC and PBS mice, achieving significantly more reversals and greater pellet retrieval. There was no difference between PBS and PDAC groups. These results suggest that the weight and appetite loss that occurs during cancer is processed by the brain differently to weight loss that occurs as a result of calorie restriction, with PDAC mice not experiencing an increase in motivational drive for food in line with their falling body weight. To mimic the malaise experienced by the PDAC group, we dosed CR mice with LiCl. Low dose (150 mM) LiCl did not affect responding, however, high dose (300 mM) LiCl significantly reduced both number of active pokes and pellet retrieval. This indicates a sickness-induced devaluation of reward, a factor that may impact poor performance of this task in the PDAC group. We additionally examined exploratory and anxiety-like behaviour in PBS and PDAC groups using a battery of maze-based tests. We saw no significant differences in performance between groups in the elevated plus maze, open field or light/dark box, suggesting no elevations in baseline anxiety-like symptoms in this cachexia model. These results occurred in the face of significantly elevated levels of the pro-cachexia factors GDF15, Activin A and Activin B, indicating that elevated levels of these TGF-β family peptides are not sufficient to produce behavioural changes in these tests. Our results provide evidence for a specific impact of sickness state on cognitive flexibility during pancreatic cancer.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":"106123"},"PeriodicalIF":7.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trajectories of depressive symptoms, metabolic syndrome, inflammation, and cardiometabolic diseases: A longitudinal Bayesian network approach.","authors":"Arja O Rydin, Yuri Milaneschi, Femke Lamers, Rick Quax, Noah van de Bunt, Angela Koloi, Bennard Doornbos, Brenda W J H Penninx","doi":"10.1016/j.bbi.2025.106120","DOIUrl":"10.1016/j.bbi.2025.106120","url":null,"abstract":"<p><strong>Introduction: </strong>Both cardiometabolic diseases (CMD) and depression carry high burden of disease and have a striking bi-directional comorbidity. Understanding mechanisms of this comorbidity is key in improving health outcomes. Through Bayesian network analysis and quantitative centrality assessments we disentangled longitudinal associational pathways connecting depressive symptoms with immuno-metabolic dysregulations and CMD.</p><p><strong>Methods: </strong>Data are from the Netherlands Study of Depression and Anxiety (NESDA), an ongoing longitudinal cohort study. Subjects (N = 1059, 68 % female, mean age 42.4 ± 12.5) had a lifetime depression diagnosis at baseline, and data at baseline, 2-, 6- and 9-year follow-up. Variables included depressive symptoms, metabolic syndrome components, inflammation, diabetes and atherosclerotic disease. Individual changes over time, determined using generalised mixed models, were fed into a Bayesian network model, resulting in a directed acyclic graph (DAG). For centrality evaluation, indegree and outdegree of variables (nodes) were assessed.</p><p><strong>Results: </strong>The DAG showed a path starting with the depressive symptom low energy, leading to appetite/weight alterations and hypersomnia, ultimately leading to the nodes of diabetes and markers related to dyslipidaemia and inflammation. Waist circumference was the node with highest centrality. This result remained robust in sensitivity analyses.</p><p><strong>Discussion: </strong>The findings traced a pathway linking specific energy-related depressive symptoms (e.g. low energy, appetite/weight oscillations and hypersomnia) to inflammation, dyslipidaemia and diabetes. Depressive symptoms and biological markers connected in this identified pathway may provide a valuable target to reduce cardiometabolic risk related to depression.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":"106120"},"PeriodicalIF":7.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic psychological stress-orchestrated glial-ILC3 circuit exacerbates intestinal inflammation and depression","authors":"Zhencui Zhang ,&nbsp;Shouyang Ren ,&nbsp;Xinyi Fan ,&nbsp;Huiying Chen ,&nbsp;Jiaheng Chen ,&nbsp;Xiaoqian Wang ,&nbsp;Han Zong ,&nbsp;Shengshuai Zhang ,&nbsp;Tianyi Zhao ,&nbsp;Yujie Sun ,&nbsp;Ruixin Pang ,&nbsp;Wengang Song ,&nbsp;Wen Zhang ,&nbsp;Ben Wang ,&nbsp;Zhengtao Chen ,&nbsp;Li Ge","doi":"10.1016/j.bbi.2025.106118","DOIUrl":"10.1016/j.bbi.2025.106118","url":null,"abstract":"<div><div>Chronic psychological stress can exacerbate intestinal inflammation both in patients with inflammatory bowel disease (IBD) and animal models of experimental colitis, but the underlying mechanism remains poorly understood. Here, we identified a chronic stress-orchestrated intestinal glia-Group 3 innate lymphoid cell (ILC3) circuit that impairs innate interleukin (IL)–22-mediated immune protection. We found that stress promoted the release of excessive amounts of glucocorticoid (GC) by the adrenal cortex through activation of the hypothalamic–pituitary–adrenal axis. Subsequently, chronically elevated level of GC dysregulated the phenotype and function of enteric glial cells (EGCs) through binding to the glucocorticoid receptor on EGCs, thereby weakening glial-derived neurotrophic factor production. These lead to the deficiency of innate IL-22 and impairment of gut defense. Simultaneously, we demonstrated that exacerbation of intestinal inflammation further unleashes the progression of neuroinflammation and anxiety/depression-like behaviors. Our work sheds light on a novel mechanism by which chronic psychological stress exacerbates intestinal inflammation, expanding the understanding of ILC3 biology and ILC3-mediated mucosal immunity. We proposed an innate IL-22-based therapeutic strategy for IBD patients with psychological comorbidities, and suggested stress management as a valuable component of IBD care in the context of bidirectional brain-gut communication.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106118"},"PeriodicalIF":7.6,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Social determinants of health, brain structure, and immune-metabolic mechanisms in depression: A multi-omic analysis from the UK Biobank","authors":"Huijie Xu ,&nbsp;Zheng Zhang ,&nbsp;Yanyue Ye ,&nbsp;Jing Gu ,&nbsp;Hui Chen ,&nbsp;Zhengqian Jiang ,&nbsp;Bohao Cheng ,&nbsp;Huajia Tang ,&nbsp;Sihong Li ,&nbsp;Zheng Chang ,&nbsp;Jiansong Zhou","doi":"10.1016/j.bbi.2025.106117","DOIUrl":"10.1016/j.bbi.2025.106117","url":null,"abstract":"<div><h3>Background</h3><div>Depression is a leading global health challenge, yet the role of Social Determinants of Health (SDH) in shaping depression risk − particularly through underlying biological mechanisms − remains insufficiently understood. This study leverages a multi-omics approach to explore how unfavorable social conditions influence depression through neural, and physiological pathways.</div></div><div><h3>Methods</h3><div>Drawing on data from 257,698 participants in the UK Biobank. Cox proportional hazards regression models were used to examine the relationship between SDH, polygenic risk scores (PRS), and depression. Correlation analyses were conducted to explore associations between SDH, biomarkers, brain structure, and depression. Two-sample mendelian randomization (MR) was applied to investigate causal relationships, while structural equation modeling (SEM) was used to examine interactions among SDH, depression, brain structure, PRS, and immune-metabolic biomarkers.</div></div><div><h3>Results</h3><div>Depression was significantly associated with SDH. Multivariable Cox regression showed that unfavorable SDH increased depression risk (HR = 1.916), and higher PRS was also linked to increased risk (HR = 1.288). The combination of unfavorable SDH and high PRS yielded the highest depression risk (HR = 2.578). MR analysis further emphasized the causal relationship between unfavorable SDH and depression. SDH was also linked to brain structural changes and metabolic markers, with smaller brain volumes in regions like the hippocampus and insula in the unfavorable SDH group, along with associations with biomarkers such as triglycerides and C-reactive protein. SEM analysis revealed that SDH influenced depression through immune-metabolic and brain structural pathways.</div></div><div><h3>Conclusions</h3><div>These findings underscore the multifaceted nature of depression, highlighting how social disadvantage becomes biologically embedded through genetic and physiological mechanisms. Addressing key modifiable components of SDH may represent a powerful strategy for targeted prevention, especially in genetically at-risk populations.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106117"},"PeriodicalIF":7.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of characteristic microbes and metabolites in confined environments population","authors":"Xiangru Feng ,&nbsp;Jiaqian Zhong ,&nbsp;Jiaming Wang ,&nbsp;Xiaoxuan Lu ,&nbsp;Yijia Chen ,&nbsp;Yanying Yao ,&nbsp;Xiaoguo Ji ,&nbsp;Mengyao Zhao ,&nbsp;Jiayang Jin ,&nbsp;Juan Li ,&nbsp;Liming Zhao","doi":"10.1016/j.bbi.2025.106114","DOIUrl":"10.1016/j.bbi.2025.106114","url":null,"abstract":"<div><div>Chronic stress in confined environments can disrupt the microbiota-gut-brain axis. However, the characteristic microbial and metabolic alterations in socially and radically basic activity-restricted people in confined environments (SRBARC) remain unclear. This study integrated assessments of emotional states, gut microbiota, and metabolomic profiles to investigate their<!--> <!-->interrelationships in SRBARC, aiming to identify characteristic microbes and metabolites. The results suggested that the SRBARC tend to exhibit depressive/anxiety-like behaviors, accompanied by hypothalamic–pituitary–adrenal (HPA) axis activation, suppressed testosterone, and elevated pro-inflammatory cytokines. Full-length 16S rDNA sequencing analysis indicated lower Shannon and Chao1 indices in the gut microbiota of the SRBARC. Random forest analysis combined with dual-cohort verification suggested that <em>Blautia massiliensis</em>, <em>Blautia wexlerae</em>, <em>Coprococcus comes</em>, <em>Faecalibacterium prausnitzii</em>, and <em>Lachnospiraceae bacterium</em> may serve as characteristic microbes with diagnostic value (discovery cohort AUC = 0.836, validation cohort AUC = 0.840). Metabolomic analysis of feces, serum and urine revealed alterations in amino acid metabolism and disruptions in tetrahydrobiopterin (BH4) synthesis in the SRBARC, which affected serotonin (5-HT) and dopamine (DA) pathways. Four metabolites, including 5-methoxytryptophol, were identified as potentially metabolites associated with emotional states. These characteristic microorganisms and metabolic features were associated with neuroinflammation and immunity, and their interactions may play a key role in regulating emotional states in SRBARC. In summary, this study suggested a potential interplay among gut microbiota, neurotransmitter metabolism, and emotional states in the SRBARC, identifying potential key microbial signatures and metabolites that may provide a theoretical foundation for developing gut microbiota-based intervention strategies.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106114"},"PeriodicalIF":7.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiota mediates prenatal METH exposure-induced anxiety- and depression-like behaviors by modulating the Wnt signaling pathway","authors":"Jia-Hao Li ,&nbsp;Jia-Li Liu ,&nbsp;Xiu-Wen Li ,&nbsp;Jian-Zheng Yang ,&nbsp;Yi Liu ,&nbsp;Hui Wang ,&nbsp;Li-Jian Chen ,&nbsp;Kai-Kai Zhang ,&nbsp;Xiao-Li Xie ,&nbsp;Qi Wang","doi":"10.1016/j.bbi.2025.106112","DOIUrl":"10.1016/j.bbi.2025.106112","url":null,"abstract":"<div><div>Prenatal methamphetamine (METH) exposure poses a significant threat to offspring health, including anxiety and depression-like behaviors. This study investigated the neurotoxicity of prenatal METH exposure in offspring and explored the underlying mechanisms involving the gut microbiota. Our results revealed that prenatal METH exposure induced anxiety- and depression-like behaviors in offspring, accompanied by increased hippocampal inflammation and decreased hippocampal neurogenesis. Importantly, offspring exposed to prenatal METH exhibited gut microbiota dysbiosis, characterized by a reduced abundance of beneficial bacteria and an increased abundance of pro-inflammatory bacteria. To assess the involvement of the gut microbiota, we conducted cross-fostering and inulin supplementation experiments. Cross-fostering with control dams partially reversed METH-induced behavioral deficits, suggesting a role for maternal microbiota transmission. Inulin supplementation, both during pregnancy and in offspring, effectively remodeled the gut microbiota composition and alleviated anxiety and depression-like behaviors. This effect was associated with reduced hippocampal inflammation and increased hippocampal neurogenesis, potentially mediated by activation of the canonical Wnt signaling pathway. This study provides evidence for the critical role of the gut microbiota in mediating the neurodevelopmental consequences of prenatal METH exposure, and highlights the potential of inulin supplementation as a promising therapeutic strategy.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106112"},"PeriodicalIF":7.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential associations between relationship stressors and natural killer cell gene expression by race/ethnicity and sex among older U.S. adults","authors":"Mariana Rodrigues ,&nbsp;Jemar R. Bather ,&nbsp;Adolfo G. Cuevas","doi":"10.1016/j.bbi.2025.106116","DOIUrl":"10.1016/j.bbi.2025.106116","url":null,"abstract":"<div><div>Close interpersonal relationships can shape health, in part, through immune-related biological pathways. While chronic relational stress has been linked to inflammation and immune dysregulation, little is known about how such stressors relate to transcriptional markers of innate immune activity. As such, we investigated whether multiple forms of relationship stress were associated with altered expression of two genes related to natural killer cell function, <em>FCGR3A</em> and <em>NCAM1,</em> and whether these associations varied by sex or race/ethnicity. Data were drawn from the Midlife in the United States study, a population-based sample of midlife adults (n = 1,215) who provided whole-transcriptome RNA sequencing data and completed validated relationship stress measures. Covariate-adjusted linear mixed effects models, which included random intercepts for study site, quantified the associations of each stress domain z-score with log2(<em>FCGR3A</em>) and log2(<em>NCAM1</em>), and tested for moderation by sex and race/ethnicity. While males maintained relatively stable expression across stress domains, females showed significant positive associations between <em>FCGR3A</em> expression and both marital risk and spouse/partner strain. For participants in the non-Hispanic Other group, higher friend and cumulative strain was significantly associated with elevated <em>FCGR3A</em> expression. This group also exhibited significant <em>NCAM1</em> upregulation in response to family, friend, and cumulative strain. In contrast, Hispanic participants showed a non-significant trend toward <em>NCAM1</em> downregulation under relationship strain, but not significant changes in <em>FCGR3A</em>. These findings suggest that relationship stress may be differentially biologically embedded through changes in innate immune gene expression across demographic groups, highlighting the importance of social context in shaping transcriptional markers of immune function. Further research is needed to clarify whether these patterns confer adaptive immune readiness or contribute to long-term immune dysregulation.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106116"},"PeriodicalIF":7.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Micro-encapsulation differentially impacts probiotic effects on brain structure and function in an elderly population – A randomised placebo-controlled trial","authors":"Julia Rode ,&nbsp;Ashley N. Hutchinson ,&nbsp;Myrto S. Chatzopoulou ,&nbsp;Sinéad B. Bleiel ,&nbsp;Rediet Fikru Gebresenbet ,&nbsp;Linda Andersson ,&nbsp;Jonas Persson ,&nbsp;Romain Daillère ,&nbsp;Benoît Beitz ,&nbsp;Bouthaina Ben Abdallah ,&nbsp;Lina Tingö ,&nbsp;Cecilia Bergh ,&nbsp;Robert J. Brummer","doi":"10.1016/j.bbi.2025.106113","DOIUrl":"10.1016/j.bbi.2025.106113","url":null,"abstract":"<div><div>Increasing evidence suggests that modulations of the gut-brain axis with probiotics impact healthy ageing. This double-blinded, randomised, placebo-controlled study compared effects of micro-encapsulated and non-encapsulated <em>Lacticaseibacillus rhamnosus</em> HN001 in 87 community-dwelling elderly (60–80 years). Resting state functional connectivity differed significantly in regions involved in visual processing and perception between the two probiotic groups (p &lt; 0.0001). Brain morphometry was not altered. Significant time*group effects (p &lt; 0.05) were observed for processing speed, non-significant effects were observed for short-term memory and anxiety symptoms, while other cognitive domains, depression, perceived stress, and sleep quality were unaffected. Distribution of available and stored peripheral serotonin was significantly affected (p &lt; 0.05), while levels of γ-aminobutyric acid and glutamate in striatum and circulating brain-derived neurotrophic factor did not show significant time*group effects. Micro-encapsulated probiotics target the gut differently, which impacts the effects on brain health assessed by (functional) magnetic resonance imaging in older adults.</div><div>The trial is registered at <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> under ID: NCT05801042.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106113"},"PeriodicalIF":7.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Purinergic and extracellular vesicle signaling in alcohol-induced blood–brain barrier breakdown and neuroimmune activation","authors":"Namdev S. Togre ,&nbsp;Priyanka S. Bhoj ,&nbsp;Naveen Mekala,&nbsp;Rebecca Hancock,&nbsp;Jayshil Trivedi,&nbsp;Yuri Persidsky","doi":"10.1016/j.bbi.2025.106115","DOIUrl":"10.1016/j.bbi.2025.106115","url":null,"abstract":"<div><div>Chronic alcohol consumption is a major risk factor for neuroinflammation and cognitive decline, yet the molecular underpinnings connecting peripheral alcohol-induced injury to central nervous system (CNS) dysfunction remain poorly defined. Emerging evidence implicates purinergic P2X7 receptor (P2X7R) signaling and extracellular vesicles (EVs) as key mediators in peripheral–central communication. Ethanol exposure promotes oxidative stress, mitochondrial dysfunction, and blood–brain barrier (BBB) disruption, leading to sustained microglial activation and neuronal injury. Concurrently, alcohol-induced damage in the gut, liver, and lung, triggers systemic inflammation and EV release. These EVs, enriched in proinflammatory cytokines, miRNAs, mitochondrial DNA, and other DAMPs, can cross the compromised BBB and engage innate immune receptors, such as TLR4 and P2X7R, on glial cells, amplifying neuroimmune responses.</div><div>In this review, we integrated recent findings on EV biogenesis, P2X7R signaling, and neurovascular dysfunction in the context of alcohol use disorder. We proposed a mechanistic model in which ethanol-triggered P2X7R activation drives EV release, turning these vesicles into inflammatory couriers that carry peripheral injury signals to the brain. We emphasize EV cargo as promising biomarkers of alcohol-related neurodegeneration and explore emerging therapies that target EV pathways or P2X7R to curb alcohol-induced CNS damage.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106115"},"PeriodicalIF":7.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}