Early-life gut microbiome maturity regulates blood-brain barrier and cognitive development
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ABSTRACT:
PROVIDER: PRJNA1232707 | ENA |
REPOSITORIES: ENA
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Project description:The gut microbiome is an emerging factor in the neurobiology of disease. Blood-brain barrier (BBB) integrity is essential for proper brain function. However, the role the initial microbiome plays in BBB and brain development is unclear. In this study, we colonized germ-free pregnant mice with human full-term- or preterm-infant-derived gut microbiota, thereby establishing these communities in the resulting offspring. We discovered that mice harboring a full-term-associated microbiome exhibited stronger memory and learning capabilities and dramatically decreased early-life BBB permeability when compared to those with a prematurity-associated microbiome. Whole-brain single-cell RNA sequencing revealed downregulation of synaptic signaling genes in BBB cell types of mice with the prematurity-associated microbiome, indicating that microbiome maturity influences BBB transcriptional programs that support cognitive development. Comprehensive metagenomics and metabolomics uncovered bacterial populations and genomic pathways corresponding with decreased levels of circulating long-chain acylcarnitines and lysophosphatidylcholines in mice with the full-term-associated microbiome. Our findings highlight the microbiome as a therapeutic target for improving long-term neurodevelopmental outcomes due to its effect on the early-life BBB.
2025-08-18 | GSE291278 | GEO
Project description: Not available
| S-EPMC12416178 | biostudies-literature
Project description:Chronic stress is a major risk factor for cognitive decline and blood-brain barrier (BBB) disruption, yet the underlying molecular mechanisms remain elusive. This study aimed to investigate the specific role of the metabolic intermediate homocysteine (Hcy) in chronic stress-induced BBB dysfunction and cognitive impairment. Methods: We utilized a rat model of chronic unpredictable mild stress (CUMS) and administered Vitamin B complex to lower Hcy levels in vivo. Regional Hcy accumulation, BBB permeability, and cognitive behaviors were assessed. In vitro, primary rat brain microvascular endothelial cells (BMECs) were exposed to Hcy to evaluate barrier-forming function, transcriptomic alterations, DNA methylation patterns, Cav1.2 expression, and reactive oxygen species (ROS) production. Results: CUMS selectively induced BBB hyperpermeability and significant Hcy accumulation predominantly within the rat hippocampus, which correlated intimately with cognitive deficits. Lowering Hcy levels via Vitamin B supplementation successfully restored hippocampal BBB integrity and alleviated cognitive impairment. In addition, elevated Hcy severely impaired the barrier function of BMECs. Mechanistically, Hcy reduced global DNA methylation in BMECs and specifically induced targeted DNA hypomethylation at the intro region of Cacna1c. This epigenetic shift caused the transcriptional derepression and overexpression of the Cav1.2 calcium channel. Upregulated Cav1.2 subsequently triggered a robust ROS burst, leading to tight junction degradation. Conclusions: Our findings unveil a novel metabolic-epigenetic axis where Hcy-driven Cacna1c hypomethylation directly disrupts BMEC function to dismantle the hippocampal BBB. Lowering Hcy or targeting this Hcy-Cav1.2 pathway establishes a promising therapeutic strategy for mitigating stress-related neurovascular damage and cognitive disorders.
2026-06-03 | GSE327052 | GEO
Project description:Chronic stress is a major risk factor for cognitive decline and blood-brain barrier (BBB) disruption, yet the underlying molecular mechanisms remain elusive. This study aimed to investigate the specific role of the metabolic intermediate homocysteine (Hcy) in chronic stress-induced BBB dysfunction and cognitive impairment. Methods: We utilized a rat model of chronic unpredictable mild stress (CUMS) and administered Vitamin B complex to lower Hcy levels in vivo. Regional Hcy accumulation, BBB permeability, and cognitive behaviors were assessed. In vitro, primary rat brain microvascular endothelial cells (BMECs) were exposed to Hcy to evaluate barrier-forming function, transcriptomic alterations, DNA methylation patterns, Cav1.2 expression, and reactive oxygen species (ROS) production. Results: CUMS selectively induced BBB hyperpermeability and significant Hcy accumulation predominantly within the rat hippocampus, which correlated intimately with cognitive deficits. Lowering Hcy levels via Vitamin B supplementation successfully restored hippocampal BBB integrity and alleviated cognitive impairment. In addition, elevated Hcy severely impaired the barrier function of BMECs. Mechanistically, Hcy reduced global DNA methylation in BMECs and specifically induced targeted DNA hypomethylation at the intro region of Cacna1c. This epigenetic shift caused the transcriptional derepression and overexpression of the Cav1.2 calcium channel. Upregulated Cav1.2 subsequently triggered a robust ROS burst, leading to tight junction degradation. Conclusions: Our findings unveil a novel metabolic-epigenetic axis where Hcy-driven Cacna1c hypomethylation directly disrupts BMEC function to dismantle the hippocampal BBB. Lowering Hcy or targeting this Hcy-Cav1.2 pathway establishes a promising therapeutic strategy for mitigating stress-related neurovascular damage and cognitive disorders.
2026-06-03 | GSE327662 | GEO
Project description:Increasing evidence indicates that high-fat diets (HFDs) are strongly associated with cognitive deficits. Tryptophan (Trp), an essential amino acid, has been implicated in regulating metabolic and neurological pathways, but its direct role in mitigating HFD-induced cognitive dysfunction has been insufficiently explored. We hypothesized that enhancing Trp availability could protect the brain from HFD-induced impairments by preserving blood-brain barrier (BBB) integrity and neuronal function. Mice fed HFD alone exhibited deficits in Morris Water Maze, Fear Conditioning, and Novel Object Recognition tests, accompanied by decreased expression of tight junction proteins claudin-1 and occludin. Trp supplementation restored these behavioral and molecular indices to levels comparable to the normal diet mice. Notably, we identified indole-3-propionic acid (IPA), a metabolite of Trp, as a key mediator underlying these protective effects. Administration of IPA replicated the cognitive improvements and BBB preservation seen with Trp supplementation. Transcriptomic analyses further revealed that both IPA and Trp supplementation converge on pathways regulating neuronal health and BBB function, including PPAR signaling, extracellular matrix organization, and adherens junction regulation. Mechanistically, IPA activates free fatty acid receptor 3 (FFAR3) in brain microvascular endothelial cells, thereby reducing paracellular permeability and restoring tight junction protein expression. Collectively, these results highlight the therapeutic promise of a Trp-rich diet in countering HFD-induced cognitive decline, with IPA-mediated FFAR3 activation as a pivotal mechanism underlying BBB preservation and neuronal protection. Our findings pave the way for novel, diet-based strategies to mitigate the growing burden of obesity-related neurocognitive disorders.
2026-01-01 | GSE288055 | GEO
Project description:The antagonistic pleiotropy theory of aging predicts genetic trade-offs between early-life and late-life fitness. However, empirical evidence for these trade-offs in vertebrates remains scarce, particularly in the context of ecologically relevant life histories. Here, we identify vestigial-like 3 (vgll3), a transcription cofactor previously linked with age at maturity in humans and Atlantic salmon through GWAS studies, as an antagonistically pleiotropic gene in turquoise killifish (Nothobranchius furzeri). By disrupting two conserved vgll3 isoforms, we show that reduction of vgll3, in an isoform- or dose-dependent manner, accelerated male growth and reproductive development. This indicates that vgll3 regulates male sexual maturity. However, early-life benefits come at a late-life cost, as older mutant males with a disrupted long isoform develop melanoma-like tumors, validated via transplantation into immunodeficient rag2 models, and exhibit increased age-related mortality rate. These findings highlight vgll3 as a key regulator of vertebrate life-history trade-offs, balancing early-life fitness with late-life disease risks.
2026-04-10 | GSE300596 | GEO
Project description:Background: Emerging evidence suggests that chronic stress compromises blood‒brain barrier (BBB) integrity by disrupting brain microvascular endothelial cells (BMECs), contributing to the development of cognitive impairments. Thus, targeting the BBB is expected to be a promising treatment strategy. The biological function of rutin has been investigated in neurological disorders; however, its regulatory role in stress-induced BBB damage and cognitive decline and the underlying mechanisms remain elusive. Methods: In a chronic unpredictable mild stress (CUMS) mouse model, a fluorescent dye assay and behavioral tests, including a novel object recognition test and Morris water maze, were performed to evaluate the protective effects of rutin on BBB integrity and cognition. The effects of rutin on BMEC function were also investigated in hCMEC/D3 cells (a human brain microvascular endothelial cell line) in vitro. Furthermore, the molecular mechanisms by which rutin restores BBB endothelium dysfunction were explored via RNA-seq, quantitative real-time PCR, western blotting, immunofluorescence and chromatin immunoprecipitation. Finally, biotinylated tumor necrosis factor-α (TNF-α) was employed to test the influence of rutin on the ability of circulating TNF-α to cross the BBB. Results: We identified that rutin attenuated BBB hyperpermeability and cognitive impairment caused by the 8-week CUMS procedure. Moreover, rutin promoted the proliferation, migration and angiogenesis ability of BMECs through positively regulating the expression of genes involved. Furthermore, rutin impeded histone deacetylase 1 (HDAC1) recruitment and stabilized H3K27ac to increase Claudin-5 protein levels. Ultimately, normalization of the hippocampal HDAC1‒Claudin-5 axis by rutin blocked the infiltration of circulating TNF-α into the brain parenchyma and alleviated neuroinflammation. Conclusions: This work establishes a protective role of rutin in regulating BMEC function and BBB integrity and reveals that rutin is a potential drug candidate for curing chronic stress-induced cognitive deficits.
2025-04-09 | GSE288810 | GEO
Project description:Electronic cigarette exposure disrupts blood-brain barrier integrity, promotes neuroinflammation, and leads to cognitive dysfunction
| PRJNA596914 | ENA
Project description:Vascular disruption has been implicated in COVID-19 pathogenesis, and may predispose to the neurological sequelae associated with the condition (known as Long COVID), yet it remains unclear how blood-brain barrier (BBB) function is affected in these conditions. Here, we show that BBB disruption is evident during acute infection and in Long COVID patients with cognitive impairment, commonly referred to as brain fog. Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), we show BBB disruption correlated with brain volume changes. Transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog. Accordingly, PBMCs showed increased adhesion to human brain endothelial cells in vitro, while exposure of endothelial cells to serum from Long COVID patients induced expression of inflammatory markers. Together, our data suggest that sustained systemic inflammation and persistent localised BBB dysfunction is a key feature of Long COVID-associated brain fog.
2024-02-22 | GSE251849 | GEO
Project description:Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment
| PRJNA1055552 | ENA