Pub Date : 2025-12-01DOI: 10.1016/j.bbih.2025.101157
Ashley J. Douthitt , Aaron Bennett , Alexandra Koustova , Asim Abdelfattah , Darijana Horvat , Cédric G. Geoffroy
Spinal cord injury induces extensive neurological impairment and drives systemic and tissue-level inflammatory responses that accelerate secondary systemic damage. Emerging evidence suggests that gut microbiota-derived metabolites can influence post-injury inflammation, presenting a potential therapeutic approach. This study examines whether the tryptophan-derived metabolites indole and indole-3-propionic acid modulate inflammatory responses and improve outcomes following spinal cord injury. Female C57BL/6J mice received a severe thoracic-8 contusion-compression injury and were administered indole or indole-3-proprionic acid daily via oral gavage for the duration of the observation period. In an acute cohort, 7 days post-injury, neither treatment altered plasma inflammatory profiles relative to injury controls. However, both metabolites significantly reduced CD68+ macrophage presence within the injured spinal cord. In a chronic cohort, 42 days post-injury, metabolite treatment mitigated injury-induced body composition changes, improved locomotor recovery and reduced inflammatory pathologies within the liver and spinal cord. These findings identify gut-derived metabolites as a promising therapeutic strategy targeting the gut-spinal cord axis to attenuate systemic injury mechanisms and support recovery.
{"title":"Leveraging microbiota-metabolites to reduce inflammation and promote functional recovery following spinal cord injury in female mice","authors":"Ashley J. Douthitt , Aaron Bennett , Alexandra Koustova , Asim Abdelfattah , Darijana Horvat , Cédric G. Geoffroy","doi":"10.1016/j.bbih.2025.101157","DOIUrl":"10.1016/j.bbih.2025.101157","url":null,"abstract":"<div><div>Spinal cord injury induces extensive neurological impairment and drives systemic and tissue-level inflammatory responses that accelerate secondary systemic damage. Emerging evidence suggests that gut microbiota-derived metabolites can influence post-injury inflammation, presenting a potential therapeutic approach. This study examines whether the tryptophan-derived metabolites indole and indole-3-propionic acid modulate inflammatory responses and improve outcomes following spinal cord injury. Female C57BL/6J mice received a severe thoracic-8 contusion-compression injury and were administered indole or indole-3-proprionic acid daily via oral gavage for the duration of the observation period. In an acute cohort, 7 days post-injury, neither treatment altered plasma inflammatory profiles relative to injury controls. However, both metabolites significantly reduced CD68<sup>+</sup> macrophage presence within the injured spinal cord. In a chronic cohort, 42 days post-injury, metabolite treatment mitigated injury-induced body composition changes, improved locomotor recovery and reduced inflammatory pathologies within the liver and spinal cord. These findings identify gut-derived metabolites as a promising therapeutic strategy targeting the gut-spinal cord axis to attenuate systemic injury mechanisms and support recovery.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101157"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145684290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.bbih.2025.101141
Riccardo Bortoletto , Marco Garzitto , Marta Basaldella , Claudia Scipioni , Orietta Sepulcri , Martina Fabris , Francesco Curcio , Matteo Balestrieri , Marco Colizzi
Clinical high-risk (CHR) for psychosis state still lacks effective and safe treatments. Recent evidence supports the anti-neuroinflammatory properties of fatty acid palmitoylethanolamide (PEA) dietary supplementation across the psychosis spectrum. Sixteen subjects at CHR for psychosis with attenuated psychotic symptoms (APS) enrolled in a 12-week, open-label, nonrandomized, single-arm clinical trial of ultramicronized-PEA (um-PEA, 600 mg/day). Biobehavioral assessments were conducted at baseline, 4 weeks, and 12 weeks, particularly using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and quantifying changes in peripheral neuroimmune biomarkers. Linear mixed-effects models showed significant reductions in CAARMS total APS (Δ12-weeks = −3.8 units, −30.0 %) and Unusual Thought Content (UTC; Δ12-weeks = −2.0, −52.5 %). No treatment-emergent side effects were reported. In exploratory analyses including neuroimmune biomarkers as covariates and potential moderators, lower baseline Interleukin (IL)-1β was associated with greater improvement in UTC, while time-varying IL-10/IL-6 ratio, Interferon (IFN)-γ, and IL-6 were linked to changes in CAARMS total APS and UTC.
A reduction in APS was observed in subjects at CHR for psychosis receiving PEA supplementation, possibly through immune-inflammatory modulation, warranting further research into its therapeutic potential for this condition.
{"title":"Effects of palmitoylethanolamide in clinical high-risk for psychosis: A nonrandomized open-label trial","authors":"Riccardo Bortoletto , Marco Garzitto , Marta Basaldella , Claudia Scipioni , Orietta Sepulcri , Martina Fabris , Francesco Curcio , Matteo Balestrieri , Marco Colizzi","doi":"10.1016/j.bbih.2025.101141","DOIUrl":"10.1016/j.bbih.2025.101141","url":null,"abstract":"<div><div>Clinical high-risk (CHR) for psychosis state still lacks effective and safe treatments. Recent evidence supports the anti-neuroinflammatory properties of fatty acid palmitoylethanolamide (PEA) dietary supplementation across the psychosis spectrum. Sixteen subjects at CHR for psychosis with attenuated psychotic symptoms (APS) enrolled in a 12-week, open-label, nonrandomized, single-arm clinical trial of ultramicronized-PEA (um-PEA, 600 mg/day). Biobehavioral assessments were conducted at baseline, 4 weeks, and 12 weeks, particularly using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and quantifying changes in peripheral neuroimmune biomarkers. Linear mixed-effects models showed significant reductions in CAARMS total APS (Δ<sub>12-weeks</sub> = −3.8 units, −30.0 %) and Unusual Thought Content (UTC; Δ<sub>12-weeks</sub> = −2.0, −52.5 %). No treatment-emergent side effects were reported. In exploratory analyses including neuroimmune biomarkers as covariates and potential moderators, lower baseline Interleukin (IL)-1β was associated with greater improvement in UTC, while time-varying IL-10/IL-6 ratio, Interferon (IFN)-γ, and IL-6 were linked to changes in CAARMS total APS and UTC.</div><div>A reduction in APS was observed in subjects at CHR for psychosis receiving PEA supplementation, possibly through immune-inflammatory modulation, warranting further research into its therapeutic potential for this condition.</div></div><div><h3>Trial registration</h3><div>ClinicalTrials.gov Identifier NCT06037993.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101141"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145618110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.bbih.2025.101144
David M. Howard , Lachlan Gilchrist , Petroula Proitsi , Elisabeth R. Paul , Markus Heilig , Lars Östman , Robin Kämpe , J. Paul Hamilton
Immune and metabolic factors are important in the pathophysiology of major depressive disorder (MDD) but we know little about how these factors manifest in relation to the status of depressive illness—from genetic risk for MDD, to a depressive episode, to depression in remission. Using genetic, diagnostic, biometric, and blood-bioassay data from the UK Biobank, we examined measures of pro-inflammatory signaling (C-reactive protein) and metabolic dysfunction (metabolic syndrome symptomatology) in females (N = 37,806) and males (N = 17,946) as a function of polygenic load for MDD (high versus low) interacting with depression status (never depressed, currently depressed, or depression in remission). We examined socioeconomic status (SES) as an exploratory factor in this design. Groups were matched for several confounders using a propensity-matching algorithm (females: n = 6301 per group for N = 37,806; n = 2991 per group for N = 17,946). In females we found increased inflammation and metabolic dysfunction in the higher-versus-lower PRS quartile, in those below-versus-above the median SES, and in those suffering currently from depression relative to their remitted depressed and healthy counterparts. This association remained when considering only non-psychotropic-medicated persons. Nonetheless, we also saw in both male and female samples that measures of immunological and metabolic dysfunction increased with increasing anti-depressant medication load. We discuss these findings in terms of the epidemiological significance of immune and metabolic functioning in depression and their paradoxical relation with antidepressant treatment.
{"title":"Immune and metabolic disturbance as a function of genetic risk and phase of illness in major depression","authors":"David M. Howard , Lachlan Gilchrist , Petroula Proitsi , Elisabeth R. Paul , Markus Heilig , Lars Östman , Robin Kämpe , J. Paul Hamilton","doi":"10.1016/j.bbih.2025.101144","DOIUrl":"10.1016/j.bbih.2025.101144","url":null,"abstract":"<div><div>Immune and metabolic factors are important in the pathophysiology of major depressive disorder (MDD) but we know little about how these factors manifest in relation to the status of depressive illness—from genetic risk for MDD, to a depressive episode, to depression in remission. Using genetic, diagnostic, biometric, and blood-bioassay data from the UK Biobank, we examined measures of pro-inflammatory signaling (C-reactive protein) and metabolic dysfunction (metabolic syndrome symptomatology) in females (N = 37,806) and males (N = 17,946) as a function of polygenic load for MDD (high versus low) interacting with depression status (never depressed, currently depressed, or depression in remission). We examined socioeconomic status (SES) as an exploratory factor in this design. Groups were matched for several confounders using a propensity-matching algorithm (females: n = 6301 per group for N = 37,806; n = 2991 per group for N = 17,946). In females we found increased inflammation and metabolic dysfunction in the higher-versus-lower PRS quartile, in those below-versus-above the median SES, and in those suffering currently from depression relative to their remitted depressed and healthy counterparts. This association remained when considering only non-psychotropic-medicated persons. Nonetheless, we also saw in both male and female samples that measures of immunological and metabolic dysfunction increased with increasing anti-depressant medication load. We discuss these findings in terms of the epidemiological significance of immune and metabolic functioning in depression and their paradoxical relation with antidepressant treatment.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101144"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145618113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diverse neurological symptoms are experienced by long COVID and COVID-19 recovered individuals. However, the long-term effects of SARS-CoV-2 in the brain of both groups are underexplored. This study aimed to investigate changes in tissue microstructural and brain neurochemical levels in long COVID and recovered COVID-19 patients compared to healthy controls.
Methods
We recruited 47 participants (long COVID = 19, COVID-recovered healthy controls = 12, and healthy controls without COVID-19 infection = 16) who underwent 3T MRI scans. We acquired T1 and T2 weighted images to assess myelin signal, diffusion weighted images to assess tissue microstructure, and magnetic resonance spectroscopy data to estimate brain neurochemical levels.
Findings
Our multimodal MRI study showed altered T1w/T2w signal between long COVID vs COVID-recovered-healthy controls, long COVID vs healthy controls, and COVID-recovered-healthy controls vs healthy controls. Furthermore, T1w/T2w signal intensity was significantly correlated with physical and cognitive function. Diffusion weighted imaging also showed altered tissue microstructure in these three group comparisons. However, brain neurochemicals were only significantly different between long COVID vs COVID-recovered-healthy controls.
Interpretation
This is one of the first studies to report different myelin signal and brain neurochemical changes between long COVID, COVID-recovered-healthy controls, and healthy controls without SARS-CoV-2 infection. These brain changes provide compelling evidence for the long-term effects of SARS-CoV-2 on brain function.
{"title":"Altered brain tissue microstructure and neurochemical profiles in long COVID and recovered COVID-19 individuals: A multimodal MRI study","authors":"Kiran Thapaliya, Sonya Marshall-Gradisnik, Maira Inderyas, Leighton Barnden","doi":"10.1016/j.bbih.2025.101142","DOIUrl":"10.1016/j.bbih.2025.101142","url":null,"abstract":"<div><h3>Background</h3><div>Diverse neurological symptoms are experienced by long COVID and COVID-19 recovered individuals. However, the long-term effects of SARS-CoV-2 in the brain of both groups are underexplored. This study aimed to investigate changes in tissue microstructural and brain neurochemical levels in long COVID and recovered COVID-19 patients compared to healthy controls.</div></div><div><h3>Methods</h3><div>We recruited 47 participants (long COVID = 19, COVID-recovered healthy controls = 12, and healthy controls without COVID-19 infection = 16) who underwent 3T MRI scans. We acquired T1 and T2 weighted images to assess myelin signal, diffusion weighted images to assess tissue microstructure, and magnetic resonance spectroscopy data to estimate brain neurochemical levels.</div></div><div><h3>Findings</h3><div>Our multimodal MRI study showed altered T1w/T2w signal between long COVID vs COVID-recovered-healthy controls, long COVID vs healthy controls, and COVID-recovered-healthy controls vs healthy controls. Furthermore, T1w/T2w signal intensity was significantly correlated with physical and cognitive function. Diffusion weighted imaging also showed altered tissue microstructure in these three group comparisons. However, brain neurochemicals were only significantly different between long COVID vs COVID-recovered-healthy controls.</div></div><div><h3>Interpretation</h3><div>This is one of the first studies to report different myelin signal and brain neurochemical changes between long COVID, COVID-recovered-healthy controls, and healthy controls without SARS-CoV-2 infection. These brain changes provide compelling evidence for the long-term effects of SARS-CoV-2 on brain function.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101142"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145618112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.bbih.2025.101152
May A. Beydoun , Jordan Weiss , Michael F. Gerogescu , Jason Ashe , Christian A. Maino Vieytes , Tianyi Huang , Hind A. Beydoun , Nicole Noren Hooten , Indira C. Turney , Michele K. Evans , Alan B. Zonderman
Socio-environmental and health-related variables were examined in relation to longitudinal change in select neuroimaging markers through metabolomics. Data from 2255 dementia-free UK Biobank participants were utilized. Statistical analyses involved descriptives, Principal Components Analysis (PCA) for metabolomic data reduction, mixed-effects linear regression models to assess longitudinal change (i.e. empirical Bayes estimators of slope), and Additive Bayesian Networks (ABN). Age was the primary consistent contributor to brain health decline over time, with specific metabolomic markers, mainly “free cholesterol in very large high-density lipoproteins (HDL)”, potentially offering protective effects against declines in microstructural integrity, through reduction of or slower pace of increase in mean Orientation Dispersion (ODmean). Air pollution, individual and household-level SES, sex and racial minority status correlated indirectly with brain health through intracranial volumes and time interval between assessments. These insights emphasize using a multifactorial approach to understanding brain aging for predictive models of neurodegeneration.
{"title":"Socio-environmental and health-related factors and their association with longitudinal change in brain neuroimaging markers through the plasma metabolome among UK adults: An additive Bayesian network analysis","authors":"May A. Beydoun , Jordan Weiss , Michael F. Gerogescu , Jason Ashe , Christian A. Maino Vieytes , Tianyi Huang , Hind A. Beydoun , Nicole Noren Hooten , Indira C. Turney , Michele K. Evans , Alan B. Zonderman","doi":"10.1016/j.bbih.2025.101152","DOIUrl":"10.1016/j.bbih.2025.101152","url":null,"abstract":"<div><div>Socio-environmental and health-related variables were examined in relation to longitudinal change in select neuroimaging markers through metabolomics. Data from 2255 dementia-free UK Biobank participants were utilized. Statistical analyses involved descriptives, Principal Components Analysis (PCA) for metabolomic data reduction, mixed-effects linear regression models to assess longitudinal change (i.e. empirical Bayes estimators of slope), and Additive Bayesian Networks (ABN). Age was the primary consistent contributor to brain health decline over time, with specific metabolomic markers, mainly “free cholesterol in very large high-density lipoproteins (HDL)”, potentially offering protective effects against declines in microstructural integrity, through reduction of or slower pace of increase in mean Orientation Dispersion (OD<sub>mean</sub>). Air pollution, individual and household-level SES, sex and racial minority status correlated indirectly with brain health through intracranial volumes and time interval between assessments. These insights emphasize using a multifactorial approach to understanding brain aging for predictive models of neurodegeneration.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101152"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.bbih.2025.101156
Wilson Vincent , Annesa Flentje , Benjamin S. Dominguez , Robert H. Paul , Savita Pahwa , Suresh Pallikkuth , Margaret Roach , Dietmar Fuchs , Samantha E. Dilworth , Torsten B. Neilands , Peter W. Hunt , Gowri Sunder , Cody Lentz , Sydney Telaak , Adam W. Carrico
Background
Microbial translocation, immune activation, inflammation, and dysregulated metabolism of neurotransmitter precursors are interacting pathophysiologic processes linked to neuropsychiatric comorbidities and faster HIV disease progression. We examined correlates of distinct phenotypes of gut-immune dysregulation in people living with HIV (PWH) who use methamphetamine.
Methods
Participants were 122 PWH who had biochemically confirmed recent methamphetamine use, including non-injection use. Peripheral plasma markers reflected: intestinal permeability, microbial translocation, immune activation, inflammation, and dysregulated metabolism of neurotransmitter precursors. Using latent profile analysis (i.e., clustering) of these markers, we identified gut-immune phenotypes and their clinical, demographic, and stigma-related correlates.
Results
Three immune profiles emerged: (1) low gut-immune dysregulation with lower microbial translocation, macrophage activation, inflammation, and tryptophan catabolism; (2) moderate gut-immune dysregulation with all markers within average range; and (3) high gut-immune dysregulation with higher microbial translocation, immune activation, inflammation, and tryptophan catabolism. In adjusted analyses, higher viral load (one log10 copy/ml; AOR = 1.97, 95 % CI = 1.02–3.82), injection of methamphetamine (AOR = 3.60, 95 % CI = 1.23–10.50), and internalized stigma (AOR = 1.78, 95 % CI = 1.01–3.15) were associated with having a moderate gut-immune dysregulation profile. Additionally, higher viral load (AOR = 2.98, 95 % CI = 1.53–5.24) and injecting methamphetamine (AOR = 5.45, 95 % CI = 1.34–17.78) were associated with having a high gut-immune dysregulation profile.
Conclusions
Distinct patterns of microbial translocation, immune activation, inflammation, and metabolism of amino acid precursors distinguished gut-immune phenotypes of PWH reporting injection methamphetamine use and greater internalized stigma. Interventions tailored to PWH who inject methamphetamine or struggle with internalized stigma could optimize HIV-related health outcomes.
微生物易位、免疫激活、炎症和神经递质前体代谢失调是与神经精神合并症和更快的HIV疾病进展相关的相互作用的病理生理过程。我们研究了使用甲基苯丙胺的HIV感染者（PWH）肠道免疫失调的不同表型的相关性。方法研究对象为122名生物化学证实近期使用甲基苯丙胺（包括非注射使用）的PWH。外周血浆标志物反映：肠道通透性、微生物易位、免疫激活、炎症和神经递质前体代谢失调。利用这些标记物的潜在特征分析（即聚类），我们确定了肠道免疫表型及其临床、人口统计学和耻感相关因素。结果出现了三种免疫特征：(1)低肠道免疫失调，微生物易位、巨噬细胞激活、炎症和色氨酸分解代谢降低；(2)中度肠道免疫失调，各项指标均在平均范围内；(3)肠道免疫高度失调，微生物易位、免疫激活、炎症和色氨酸分解代谢增加。在校正分析中，较高的病毒载量（1 log10拷贝/ml； AOR = 1.97, 95% CI = 1.02-3.82）、注射甲基苯丙胺（AOR = 3.60, 95% CI = 1.23-10.50）和内化病耻感（AOR = 1.78, 95% CI = 1.01-3.15）与中度肠道免疫失调相关。此外，较高的病毒载量（AOR = 2.98, 95% CI = 1.53-5.24）和注射甲基苯丙胺（AOR = 5.45, 95% CI = 1.34-17.78）与较高的肠道免疫失调相关。结论不同的微生物易位、免疫激活、炎症和氨基酸前体代谢模式区分了PWH报告注射甲基苯丙胺的肠道免疫表型和更大的内化耻感。针对注射甲基苯丙胺或与内在耻辱作斗争的PWH量身定制的干预措施可以优化与艾滋病毒相关的健康结果。
{"title":"Body talk: Correlates of gut-immune dysregulation phenotypes in people living with HIV who use methamphetamine","authors":"Wilson Vincent , Annesa Flentje , Benjamin S. Dominguez , Robert H. Paul , Savita Pahwa , Suresh Pallikkuth , Margaret Roach , Dietmar Fuchs , Samantha E. Dilworth , Torsten B. Neilands , Peter W. Hunt , Gowri Sunder , Cody Lentz , Sydney Telaak , Adam W. Carrico","doi":"10.1016/j.bbih.2025.101156","DOIUrl":"10.1016/j.bbih.2025.101156","url":null,"abstract":"<div><h3>Background</h3><div>Microbial translocation, immune activation, inflammation, and dysregulated metabolism of neurotransmitter precursors are interacting pathophysiologic processes linked to neuropsychiatric comorbidities and faster HIV disease progression. We examined correlates of distinct phenotypes of gut-immune dysregulation in people living with HIV (PWH) who use methamphetamine.</div></div><div><h3>Methods</h3><div>Participants were 122 PWH who had biochemically confirmed recent methamphetamine use, including non-injection use. Peripheral plasma markers reflected: intestinal permeability, microbial translocation, immune activation, inflammation, and dysregulated metabolism of neurotransmitter precursors. Using latent profile analysis (i.e., clustering) of these markers, we identified gut-immune phenotypes and their clinical, demographic, and stigma-related correlates.</div></div><div><h3>Results</h3><div>Three immune profiles emerged: (1) <em>low gut-immune dysregulation</em> with lower microbial translocation, macrophage activation, inflammation, and tryptophan catabolism; (2) <em>moderate gut-immune dysregulation</em> with all markers within average range; and (3) <em>high gut-immune dysregulation</em> with higher microbial translocation, immune activation, inflammation, and tryptophan catabolism. In adjusted analyses, higher viral load (one log10 copy/ml; <em>AOR</em> = 1.97, 95 % CI = 1.02–3.82), injection of methamphetamine (<em>AOR</em> = 3.60, 95 % CI = 1.23–10.50), and internalized stigma (<em>AOR</em> = 1.78, 95 % CI = 1.01–3.15) were associated with having a moderate gut-immune dysregulation profile. Additionally, higher viral load (<em>AOR</em> = 2.98, 95 % CI = 1.53–5.24) and injecting methamphetamine (<em>AOR</em> = 5.45, 95 % CI = 1.34–17.78) were associated with having a high gut-immune dysregulation profile.</div></div><div><h3>Conclusions</h3><div>Distinct patterns of microbial translocation, immune activation, inflammation, and metabolism of amino acid precursors distinguished gut-immune phenotypes of PWH reporting injection methamphetamine use and greater internalized stigma. Interventions tailored to PWH who inject methamphetamine or struggle with internalized stigma could optimize HIV-related health outcomes.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"51 ","pages":"Article 101156"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.bbih.2025.101148
Silvia Flaj Prados , Esperanza Herradón Pliego , Carlos Goicoechea Garcia , Eva Ma Sánchez-Robles , Lars Arendt-Nielsen , Cesar Fernández-de-las-Peñas , Visitación López-Miranda
Introduction
Many COVID-19 survivors suffer long-term multi-organ damage leading to some symptoms such as brain fog. Around 25 % of patients report persistent memory loss, concentration difficulties, or other cognitive impairments after a SARS-COV-2 infection. Animal models are crucial for studying the pathophysiology of post-acute COVID-19 sequelae (PASC).
Objective
To assess the presence of neuro-inflammatory and glial activation biomarkers in brain tissue after a SARS-CoV-2 infection in an animal model to better understand the pathophysiology of neurocognitive symptoms.
Methods
Twelve C57BL/6 female hACE2 mice infected with SARS-CoV-2 Omicron variant (BA.1.17 lineage) and eleven non-infected female mice were included. Different proteins evaluating the innate immune activation in neuro-inflammation (TLR4, MyD88, NF-κB signalling pathway), inflammatory state (interleukins IL-6, IL-18 and IL-1β), and glial neuro-inflammatory response (CD11d, Iba1, GFAP expression) were evaluated from cerebral tissue 28 days after infection.
Results
As compared to non-infected mice, significant higher (p = 0.014) post-COVID expression of IL-18 (suggesting an inflammatory state) and significant higher (p = 0.0473) post-COVID GFAP expression (indicating enhanced astrocytic glia activation in response to the infection) was observed in brain tissue. No significant differences in TLR4 (p = 0.512), MyD88 (p = 0.151), NF-κB p65 (p = 0.712), IL-6 (p = 0.962), IL-1β (p = 0.343), CD11d (p = 0.750), and Iba1 (p = 0.935) expressions were observed.
Conclusions
This study provides evidence on brain neuro-inflammation, highlighting glial activation and IL-18 overexpression after an acute SARS-CoV-2 infection. These findings improve current understanding of post-COVID neuroinflammation and could aid in the design of treatment strategies for persistent neurological sequelae, such as cognitive impairment and mental confusion.
{"title":"Glial activation and increase in cerebral pro-inflammatory cytokine expression in a female animal post-COVID model","authors":"Silvia Flaj Prados , Esperanza Herradón Pliego , Carlos Goicoechea Garcia , Eva Ma Sánchez-Robles , Lars Arendt-Nielsen , Cesar Fernández-de-las-Peñas , Visitación López-Miranda","doi":"10.1016/j.bbih.2025.101148","DOIUrl":"10.1016/j.bbih.2025.101148","url":null,"abstract":"<div><h3>Introduction</h3><div>Many COVID-19 survivors suffer long-term multi-organ damage leading to some symptoms such as brain fog. Around 25 % of patients report persistent memory loss, concentration difficulties, or other cognitive impairments after a SARS-COV-2 infection. Animal models are crucial for studying the pathophysiology of post-acute COVID-19 sequelae (PASC).</div></div><div><h3>Objective</h3><div>To assess the presence of neuro-inflammatory and glial activation biomarkers in brain tissue after a SARS-CoV-2 infection in an animal model to better understand the pathophysiology of neurocognitive symptoms.</div></div><div><h3>Methods</h3><div>Twelve C57BL/6 female hACE2 mice infected with SARS-CoV-2 Omicron variant (BA.1.17 lineage) and eleven non-infected female mice were included. Different proteins evaluating the innate immune activation in neuro-inflammation (TLR4, MyD88, NF-κB signalling pathway), inflammatory state (interleukins IL-6, IL-18 and IL-1β), and glial neuro-inflammatory response (CD11d, Iba1, GFAP expression) were evaluated from cerebral tissue 28 days after infection.</div></div><div><h3>Results</h3><div>As compared to non-infected mice, significant higher (p = 0.014) post-COVID expression of IL-18 (suggesting an inflammatory state) and significant higher (p = 0.0473) post-COVID GFAP expression (indicating enhanced astrocytic glia activation in response to the infection) was observed in brain tissue. No significant differences in TLR4 (p = 0.512), MyD88 (p = 0.151), NF-κB p65 (p = 0.712), IL-6 (p = 0.962), IL-1β (p = 0.343), CD11d (p = 0.750), and Iba1 (p = 0.935) expressions were observed.</div></div><div><h3>Conclusions</h3><div>This study provides evidence on brain neuro-inflammation, highlighting glial activation and IL-18 overexpression after an acute SARS-CoV-2 infection. These findings improve current understanding of post-COVID neuroinflammation and could aid in the design of treatment strategies for persistent neurological sequelae, such as cognitive impairment and mental confusion.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101148"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145684291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-07DOI: 10.1016/j.bbih.2025.101135
Kao Yamaoka , Yuri Ishii , Yuri Terasawa
Systemic inflammation affects psychological processes. Although the association between inflammation and psychophysiological state has been extensively investigated in patients with depression or inflammatory disease, how this relationship manifests in healthy individuals is not clearly known. Not all individuals exhibit distress in response to elevated inflammatory markers, suggesting the presence of psychological moderators. Elucidating the effect of elevated inflammatory markers on healthy adults would broaden the understanding of the relationship between inflammation and psychophysiological state. We investigated the moderating effect of individual factors, including emotion regulation, sleep quality, and interoceptive awareness, on the relationship between inflammatory markers and psychophysiological states in healthy adults. A total of 155 participants aged 30–59 years were assessed for inflammatory markers, individual factors, and subjective psychological and physical symptoms. Hierarchical regression and interaction models revealed that individuals with poor emotion regulation or low-quality sleep showed stronger associations between inflammatory markers and symptoms such as fatigue, somatic complaints, depression, and anxiety. Conversely, individuals with effective emotion regulation or high-quality sleep exhibited attenuated or even reversed associations, suggesting protective effects. Interoceptive awareness showed weaker and more context-dependent moderating effects. These results highlight the importance of psychological traits in modulating the effects of inflammation on mental and physical well-being in clinically healthy adults. Targeted interventions for enhancing emotion regulation and sleep quality may mitigate the psycho-physiological burden of inflammation and reduce the risk of future disease onset. The findings underscore the need for individualized psychoneuroimmunological models that incorporate trait-level moderators to explain variability in stress-related health outcomes.
{"title":"Moderating effects of individual factors on the relationship between inflammation and psychophysiological states in healthy adults","authors":"Kao Yamaoka , Yuri Ishii , Yuri Terasawa","doi":"10.1016/j.bbih.2025.101135","DOIUrl":"10.1016/j.bbih.2025.101135","url":null,"abstract":"<div><div>Systemic inflammation affects psychological processes. Although the association between inflammation and psychophysiological state has been extensively investigated in patients with depression or inflammatory disease, how this relationship manifests in healthy individuals is not clearly known. Not all individuals exhibit distress in response to elevated inflammatory markers, suggesting the presence of psychological moderators. Elucidating the effect of elevated inflammatory markers on healthy adults would broaden the understanding of the relationship between inflammation and psychophysiological state. We investigated the moderating effect of individual factors, including emotion regulation, sleep quality, and interoceptive awareness, on the relationship between inflammatory markers and psychophysiological states in healthy adults. A total of 155 participants aged 30–59 years were assessed for inflammatory markers, individual factors, and subjective psychological and physical symptoms. Hierarchical regression and interaction models revealed that individuals with poor emotion regulation or low-quality sleep showed stronger associations between inflammatory markers and symptoms such as fatigue, somatic complaints, depression, and anxiety. Conversely, individuals with effective emotion regulation or high-quality sleep exhibited attenuated or even reversed associations, suggesting protective effects. Interoceptive awareness showed weaker and more context-dependent moderating effects. These results highlight the importance of psychological traits in modulating the effects of inflammation on mental and physical well-being in clinically healthy adults. Targeted interventions for enhancing emotion regulation and sleep quality may mitigate the psycho-physiological burden of inflammation and reduce the risk of future disease onset. The findings underscore the need for individualized psychoneuroimmunological models that incorporate trait-level moderators to explain variability in stress-related health outcomes.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101135"},"PeriodicalIF":3.5,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145571557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sleep is a fundamental physiological state essential for immune function, metabolic regulation, and recovery from illness. During infection, sleep patterns are altered in a stereotyped fashion-characterized by increased non-rapid eye movement (NREM) sleep and reduced rapid eye movement (REM) sleep. These sleep changes are not incidental consequences of illness but reflect an evolutionarily conserved neuroimmune adaptation driven by proinflammatory cytokines. In particular, interleukin 1b (IL-1b) and tumor necrosis factor-a (TNFa) modulate sleep by acting directly on central nervous system circuits, including the serotonergic system and homeostatic sleep regulation. In this review, we synthesize current knowledge on how IL-1b and TNFa interact with sleep-regulating networks to alter behavioral state transitions during immune challenge. We also explore the broader clinical relevance of cytokine-driven sleep changes across infectious, psychiatric, and neurodegenerative disorders, and highlight emerging therapeutic opportunities targeting neuroimmune pathways to restore sleep homeostasis. Understanding these interactions is essential for advancing mechanistic insight into sleep regulation and for improving clinical management of inflammation-related sleep disturbances.
{"title":"IL-1b and TNF-a-driven sleep alterations: Neuroimmune mechanisms and behavioral implications","authors":"Nathan Zhang , Kyungsoo Park , Shinjae Chung , Yeong Shin Yim","doi":"10.1016/j.bbih.2025.101139","DOIUrl":"10.1016/j.bbih.2025.101139","url":null,"abstract":"<div><div>Sleep is a fundamental physiological state essential for immune function, metabolic regulation, and recovery from illness. During infection, sleep patterns are altered in a stereotyped fashion-characterized by increased non-rapid eye movement (NREM) sleep and reduced rapid eye movement (REM) sleep. These sleep changes are not incidental consequences of illness but reflect an evolutionarily conserved neuroimmune adaptation driven by proinflammatory cytokines. In particular, interleukin 1b (IL-1b) and tumor necrosis factor-a (TNFa) modulate sleep by acting directly on central nervous system circuits, including the serotonergic system and homeostatic sleep regulation. In this review, we synthesize current knowledge on how IL-1b and TNFa interact with sleep-regulating networks to alter behavioral state transitions during immune challenge. We also explore the broader clinical relevance of cytokine-driven sleep changes across infectious, psychiatric, and neurodegenerative disorders, and highlight emerging therapeutic opportunities targeting neuroimmune pathways to restore sleep homeostasis. Understanding these interactions is essential for advancing mechanistic insight into sleep regulation and for improving clinical management of inflammation-related sleep disturbances.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101139"},"PeriodicalIF":3.5,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145521108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-05DOI: 10.1016/j.bbih.2025.101138
Isabel Garcia , Fatmanur Kilic , Chris-Ann Bryan , Jose Castro-Vildosola , Sai Anusha Jonnalagadda , Akhila Kasturi , Jacqueline Tilly , Jordyn Smith , Sofia Valentin , Sergio Moncayo , Tamara Hala , Eric Klein , Brian F. Corbett
Psychological stress causes gut dysbiosis, which is associated with adverse effects on physical and mental health in humans and mice. Identifying taxa of gut bacteria changed by stress, and whether stress differentially alters their relative abundance in males and females, has important implications for stress-related disorders. We modeled individual differences in resilience or susceptibility using the chronic social defeat stress (CSDS) paradigm. Here, C57BL/6 mice are exposed to a novel retired breeder CD-1 aggressor for 10 min per day for 10 days. In this paradigm, resilient and susceptible subpopulations can be identified using the social interaction paradigm following CSDS. Fecal samples were collected immediately following Day 1 and Day 10 of CSDS. 16S ribosomal RNA sequencing was used to identify the relative abundance of 200 bacteria species. We analyzed group differences in phyla, genera, and species in resilient, susceptible, and non-stressed control male and female C57/BL/6 intruders along with CD-1 aggressors. Stress reduced microbiome diversity and caused gut dysbiosis in all groups, including aggressors. These changes were not observed in non-stressed mice. CSDS altered the relative abundance of every gut bacteria phylum. CSDS reduced genera in the Firmicutes phylum whereas sex altered fewer genera. The relative abundance of an uncultured Ruminococcus species on Day 1 predicted social avoidance following CSDS, with a stronger correlation in stressed females compared to males. Together, our findings demonstrate that CSDS changes gut microbiome composition in male and female mice.
{"title":"Social stress changes gut microbiome composition in male, female, and aggressor mice","authors":"Isabel Garcia , Fatmanur Kilic , Chris-Ann Bryan , Jose Castro-Vildosola , Sai Anusha Jonnalagadda , Akhila Kasturi , Jacqueline Tilly , Jordyn Smith , Sofia Valentin , Sergio Moncayo , Tamara Hala , Eric Klein , Brian F. Corbett","doi":"10.1016/j.bbih.2025.101138","DOIUrl":"10.1016/j.bbih.2025.101138","url":null,"abstract":"<div><div>Psychological stress causes gut dysbiosis, which is associated with adverse effects on physical and mental health in humans and mice. Identifying taxa of gut bacteria changed by stress, and whether stress differentially alters their relative abundance in males and females, has important implications for stress-related disorders. We modeled individual differences in resilience or susceptibility using the chronic social defeat stress (CSDS) paradigm. Here, C57BL/6 mice are exposed to a novel retired breeder CD-1 aggressor for 10 min per day for 10 days. In this paradigm, resilient and susceptible subpopulations can be identified using the social interaction paradigm following CSDS. Fecal samples were collected immediately following Day 1 and Day 10 of CSDS. 16S ribosomal RNA sequencing was used to identify the relative abundance of 200 bacteria species. We analyzed group differences in phyla, genera, and species in resilient, susceptible, and non-stressed control male and female C57/BL/6 intruders along with CD-1 aggressors. Stress reduced microbiome diversity and caused gut dysbiosis in all groups, including aggressors. These changes were not observed in non-stressed mice. CSDS altered the relative abundance of every gut bacteria phylum. CSDS reduced genera in the Firmicutes phylum whereas sex altered fewer genera. The relative abundance of an uncultured <em>Ruminococcus</em> species on Day 1 predicted social avoidance following CSDS, with a stronger correlation in stressed females compared to males. Together, our findings demonstrate that CSDS changes gut microbiome composition in male and female mice.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"50 ","pages":"Article 101138"},"PeriodicalIF":3.5,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145520733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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