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References 2025-02-05 06:47:26
Page Creation majorBlood-Brain Barrier page created by Karen Pendergrass
Did you know?
The blood-brain barrier is so selective that it prevents around 98% of small-molecule drugs from reaching the brain. However, certain bacteria and viruses, like Listeria monocytogenes and Neisseria meningitidis, have evolved mechanisms to bypass it, leading to severe brain infections.
Blood-Brain Barrier (BBB)
Researched by:
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Karen Pendergrass
ID
Karen Pendergrass
Karen Pendergrass is a microbiome researcher specializing in microbiome-targeted interventions (MBTIs). She systematically analyzes scientific literature to identify microbial patterns, develop hypotheses, and validate interventions. As the founder of the Microbiome Signatures Database, she bridges microbiome research with clinical practice. In 2012, based on her own investigative research, she became the first documented case of FMT for Celiac Disease—four years before the first published case study.
The BB is a crucial regulatory interface between the circulatory and central nervous systems, and its dysfunction has profound implications for neurodegeneration, inflammation, and systemic disease. Increasing evidence supports the role of the gut microbiome in BB modulation, highlighting microbiome-targeted therapies as a promising avenue for maintaining neurological health and preventing age-associated cognitive decline.
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Karen Pendergrass
Researched by:
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Karen Pendergrass
ID
Karen Pendergrass
Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.
Karen Pendergrass
Overview
The blood-brain barrier (BBB) is a highly specialized and dynamic compartment that regulates the uptake of molecules and solutes from the blood. It is established by brain endothelial cells and plays a crucial role in protecting the brain from exogenous components and xenobiotics. The BBB restricts immune cell entry into the central nervous system (CNS) and has an active role in neurovascular coupling, regulating cerebral blood flow to support neuronal activity. Damage to the BBB can lead to an influx of deleterious molecules into the CNS, accelerating leakage across the barrier. Thus, the BBB is a critical component of the brain’s defense system, and its disruption is a common aspect in various neurodegenerative and neurodevelopmental diseases. [1][2]
Structural Components of the BBB
The BBB is a highly specialized and dynamic compartment that regulates the uptake of molecules and solutes from the blood. It is composed of brain endothelial cells that form a tight monolayer, restricting the passage of substances into the brain. These endothelial cells are connected by tight junctions, such as ZO-1, which are essential for maintaining BBB integrity. Pericytes, contractile cells that surround the endothelial cells, contribute to the regulation of blood flow and permeability. Astrocytes, star-shaped glial cells, play a crucial role in maintaining the BBB by modulating endothelial cell activity and regulating the expression of tight junction proteins. [3][4]
Functional Components of the BBB
The blood-brain barrier regulates the trafficking of molecules and solutes from the blood into the brain, selectively restricting the entry of pathogens and toxins while permitting the passage of essential nutrients and hormones. It also plays a crucial role in neurovascular coupling by regulating cerebral blood flow to support neuronal activity. Additionally, the BBB contributes to the clearance of neurotoxic agents, including the removal of amyloid-β, which is implicated in Alzheimer’s disease. Beyond its protective functions, the BBB is actively involved in immune regulation by restricting the entry of immune cells into the brain and modulating immune activity within the central nervous system. [5][6]
Metal Ions and the Blood-Brain Barrier
Metal ions play a crucial role in maintaining the integrity of the blood-brain barrier (BBB). The BBB is a selective barrier that separates the brain from the bloodstream, and metal ions can affect its function and permeability. Excess metal ions, such as iron, can accumulate in the brain and disrupt the BBB, leading to increased permeability and the entry of toxic substances into the brain. This can contribute to neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, as well as stroke and epilepsy. The regulation of metal ion homeostasis is essential for maintaining the integrity of the BBB and preventing metal-induced neurotoxicity. [7][8]
The Microbiome and Blood-Brain Barrier Integrity
The gut microbiome also plays a crucial role in maintaining the integrity of the blood-brain barrier. Research has shown that the gut microbiome influences the BBB through various mechanisms, including the production of microbial metabolites that interact with the BBB. These metabolites can modulate the expression of genes involved in BBB function, such as LRP-1 and NRF2, and can also affect the permeability of the BBB. Dysbiosis of the gut microbiome has been linked to increased BBB permeability, which can lead to the entry of inflammatory molecules and toxins into the brain, contributing to neurodegenerative diseases. The gut microbiome’s influence on the BBB is a key aspect of the gut-brain axis, a bidirectional communication network between the gut and the brain. [9][10][11]
Microbial Metallomics of the Blood-Brain Barrier
Microbial Metallomics plays a critical role in understanding the relationship between microbial interactions, metal homeostasis, and the integrity of the blood-brain barrier. The BBB is vulnerable to disruptions caused by microbial and metal interactions, which can contribute to neuroinflammation, neurodegeneration, and cognitive dysfunction. Many neuroinvasive pathogens, such as Neisseria meningitidis and Escherichia coli K1, exploit iron acquisition mechanisms like siderophore-mediated scavenging to breach the BBB, leading to CNS infections and inflammation. Similarly, dysregulated zinc transport across the BBB is implicated in neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease, with gut microbiota capable of zinc sequestration altering its availability in the brain, further exacerbating pathology. Copper also plays a role in microbial neuroinvasion, as seen in Cryptococcus neoformans, an opportunistic fungal pathogen that utilizes copper resistance mechanisms to persist in the CNS, particularly in immunocompromised individuals. Additionally, chronic exposure to heavy metals such as lead and cadmium alters microbiome composition, promoting metal-resistant microbial strains that compromise BBB integrity, which has been linked to cognitive impairment and neurodevelopmental disorders. [12]
Microbiome-Targeted Strategies
Microbiome-targeted strategies for gut-brain barrier maintenance focus on modulating the microbiome to support integrity and reduce inflammation. Probiotics like Lactobacillus and Bifidobacterium promote balance, while prebiotics nourish beneficial bacteria. Synbiotics combine both to enhance microbial stability. Fecal Microbiota Transplantation (FMT) restores microbiome equilibrium in dysbiosis, and gut-directed psychobiotics, such as Bifidobacterium longum 1714, influence the gut-brain axis, alleviating anxiety and depression-like behaviors. [13] Chelation therapy offers a novel approach for oxidative stress and iron accumulation, with iron chelators like deferiprone showing promise in delaying neurodegeneration. [14] Together, these strategies provide potential therapeutic avenues for improving gut-brain barrier function and reducing neuroinflammation.
Research Feed
Microbiota–Gut–Brain Axis: Barrier Function and Lymphatic System in Neurological Health
December 16, 2024
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Brain Health •
Brain Health
Did you know?
The gut microbiome produces over 90% of the body’s serotonin, a key neurotransmitter that regulates mood, sleep, and cognition.
This review explores the microbiota–gut–brain axis, highlighting the role of gut microbiota in barrier integrity and lymphatic transport. It discusses microbial metabolites, vagus nerve signaling, and meningeal lymphatics as critical communication pathways, emphasizing their implications for gastrointestinal and neurological disorders.
What Was Reviewed?
This review explores the microbiota–gut–brain axis (MGBA), with a focus on the interplay between the gut microbiota, intestinal and blood-brain barrier integrity, and the lymphatic system. The authors examine how gut microbes influence barrier function through neural transmission, metabolite production, immune modulation, and gut hormone signaling. A significant aspect of the review is the role of lymphatic vessels as a previously underappreciated conduit between the gut and brain. The review also discusses the impact of microbiota dysbiosis on barrier dysfunction and its implications for both gastrointestinal and neurological diseases.
Who Was Reviewed?
The review synthesizes findings from various microbiome studies, including those investigating the microbiota's role in intestinal permeability, neuroinflammation, and neurological conditions. It integrates evidence from experimental models and human studies to highlight key mechanisms underlying MGBA communication.
Key Findings and Microbiome Associations
The review underscores that the gut microbiota exerts a profound influence on both the intestinal and blood-brain barriers, modulating permeability and contributing to systemic homeostasis. Several key points emerge:
Microbiota and Barrier Function: Gut microbes regulate intestinal and blood-brain barrier integrity through microbial metabolites such as short-chain fatty acids (SCFAs), neurotransmitter production, and immune modulation. Butyrate, for example, strengthens the blood-brain barrier by enhancing tight junction protein expression.
Lymphatic System as a Communication Pathway: The lymphatic network, particularly intestinal lacteals, serves as a conduit for microbiota-derived molecules and immune cells, linking gut health with central nervous system (CNS) function. Dysregulation of lymphatic transport mechanisms is implicated in neurological disorders.
Gut Microbiota Dysbiosis and Neurological Conditions: Altered microbiota composition contributes to neuroinflammatory and neurodegenerative diseases. Increased gut permeability and translocation of microbial products, such as lipopolysaccharides (LPS), trigger systemic inflammation, which can exacerbate conditions like Alzheimer's and Parkinson’s disease.
Vagus Nerve and Microbial Metabolites: The vagus nerve is a major conduit for gut-brain signaling. Microbial-derived neurotransmitters, including serotonin and dopamine precursors, influence neurological health. In animal models, vagotomy disrupts gut microbiota–mediated neurological effects, further supporting the role of direct neural communication.
Meningeal Lymphatics and CNS Immunity: The meningeal lymphatic system is increasingly recognized as an essential pathway for brain waste clearance and immune regulation. Dysfunction in these lymphatic vessels is linked to neuroinflammatory conditions such as multiple sclerosis and Alzheimer's disease.
Implications of This Review
The findings emphasize the importance of maintaining gut microbiota balance to preserve barrier integrity and prevent systemic inflammation that may contribute to neurological diseases. This review suggests that therapeutic interventions targeting the microbiota—such as prebiotics, probiotics, fecal microbiota transplantation (FMT), and microbiota-modulating diets—could play a role in managing both gastrointestinal and neurodegenerative conditions. Additionally, interventions that enhance lymphatic function, such as VEGF-C-mediated lymphangiogenesis, have shown promise in mitigating neuroinflammatory disorders by regulating microbiota-host interactions.
FAQs
How does the Blood-Brain Barrier protect the brain?
How does the Blood-Brain Barrier protect the brain?
The Blood-Brain Barrier (BBB) is a highly selective, semi-permeable barrier that regulates the movement of substances between the bloodstream and the central nervous system. It is composed of tightly connected endothelial cells, astrocytes, and pericytes, which work together to prevent harmful pathogens, toxins, and large molecules from entering the brain while allowing essential nutrients like glucose and oxygen to pass through. The BBB also helps maintain brain homeostasis by regulating ion balance and protecting against neuroinflammation
What happens when the Blood-Brain Barrier becomes compromised?
What happens when the Blood-Brain Barrier becomes compromised?
When the BBB is disrupted, harmful substances such as toxins, inflammatory molecules, and pathogens can enter the brain, leading to neuroinflammation, oxidative stress, and neuronal damage. This has been implicated in various neurological conditions, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and stroke. Factors that can compromise BBB integrity include chronic inflammation, heavy metal exposure, infections, and metabolic disorders. Disruptions in metal homeostasis, particularly involving iron, zinc, and copper, can further exacerbate BBB dysfunction and contribute to neurodegeneration.
Can the Blood-Brain Barrier be repaired or strengthened?
Can the Blood-Brain Barrier be repaired or strengthened?
Yes, several strategies can help maintain or restore BBB integrity. These include anti-inflammatory interventions, microbiome-targeted therapies, and dietary modifications. Certain probiotics, prebiotics, and synbiotics have been shown to support gut-brain communication and reduce systemic inflammation, indirectly strengthening the BBB. Chelation therapies targeting heavy metal accumulation may also help mitigate oxidative damage and restore proper metal balance. Additionally, bioactive compounds such as polyphenols, omega-3 fatty acids, and lactoferrin have demonstrated protective effects on BBB function, reducing permeability and enhancing its resilience against neurotoxic insults. [15][16]
Update History
Microbial Metallomics
Microbial Metallomics is the study of how microorganisms interact with metal ions in biological systems, particularly within the human microbiome.
Fecal Microbiota Transplantation (FMT)
Fecal Microbiota Transplantation (FMT) involves transferring fecal bacteria from a healthy donor to a patient to restore microbiome balance.
References
- Blood-Brain Barrier Disruption and Its Involvement in Neurodevelopmental and Neurodegenerative Disorders.. Aragón-González A, Shaw PJ, Ferraiuolo L.. (Int J Mol Sci. 2022.)
- Blood-brain barrier dysfunction in multiple sclerosis: causes, consequences, and potential effects of therapies.. Zierfuss B, Larochelle C, Prat A.. (Lancet Neurol. 2024)
- Blood-Brain Barrier Disruption and Its Involvement in Neurodevelopmental and Neurodegenerative Disorders.. Aragón-González A, Shaw PJ, Ferraiuolo L.. (Int J Mol Sci. 2022.)
- Blood-brain barrier dysfunction in multiple sclerosis: causes, consequences, and potential effects of therapies.. Zierfuss B, Larochelle C, Prat A.. (Lancet Neurol. 2024)
- Blood-Brain Barrier Disruption and Its Involvement in Neurodevelopmental and Neurodegenerative Disorders.. Aragón-González A, Shaw PJ, Ferraiuolo L.. (Int J Mol Sci. 2022.)
- Blood-brain barrier dysfunction in multiple sclerosis: causes, consequences, and potential effects of therapies.. Zierfuss B, Larochelle C, Prat A.. (Lancet Neurol. 2024)
- The role of metal ions in stroke: Current evidence and future perspectives.. Wang S, Qin M, Fan X, Jiang C, Hou Q, Ye Z, Zhang X, Yang Y, Xiao J, Wallace K, Rastegar-Kashkooli Y, Peng Q, Jin D, Wang J, Wang M, Ding R, Tao J, Kim YT, Bhawal UK, Wang J, Chen X, Wang J.. (Ageing Res Rev. 2024.)
- Iatrogenic Iron Promotes Neurodegeneration and Activates Self-Protection of Neural Cells against Exogenous Iron Attacks.. Xia M, Liang S, Li S, Ji M, Chen B, Zhang M, Dong C, Chen B, Gong W, Wen G, Zhan X, Zhang D, Li X, Zhou Y, Guan D, Verkhratsky A, Li B.. (Function (Oxf). 2021)
- Impact of gut-brain interaction in emerging neurological disorders.. Lin MS, Wang YC, Chen WJ, Kung WM.. (World J Clin Cases. 2023)
- Microbiota-gut-brain axis: interplay between microbiota, barrier function and lymphatic system.. Zhuang M, Zhang X, Cai J.. (Gut Microbes. 2024)
- Mechanistic Effect of Heavy Metals in Neurological Disorder and Brain Cancer.. Agnihotri, S.K., Kesari, K.K.. (Kesari, K. (eds) Networking of Mutagens in Environmental Toxicology. Environmental Science and Engineering(). Springer, Cham. 2019.)
- Microbial Metallomics.. P. Basu. (Metallomics. 2013.)
- Gut Microbiome and Modulation of CNS Function.. Osadchiy V, Martin CR, Mayer EA.. (Compr Physiol. 2019)
- Molecular targets and therapeutic interventions for iron induced neurodegeneration.. Siddhi Bagwe-Parab, Ginpreet Kaur,. (Brain Research Bulletin. 2020.)
- Molecular targets and therapeutic interventions for iron induced neurodegeneration.. Siddhi Bagwe-Parab, Ginpreet Kaur,. (Brain Research Bulletin. 2020.)
- Gut Microbiome and Modulation of CNS Function.. Osadchiy V, Martin CR, Mayer EA.. (Compr Physiol. 2019)
Aragón-González A, Shaw PJ, Ferraiuolo L.
Blood-Brain Barrier Disruption and Its Involvement in Neurodevelopmental and Neurodegenerative Disorders.Int J Mol Sci. 2022.
Zierfuss B, Larochelle C, Prat A.
Blood-brain barrier dysfunction in multiple sclerosis: causes, consequences, and potential effects of therapies.Lancet Neurol. 2024
Aragón-González A, Shaw PJ, Ferraiuolo L.
Blood-Brain Barrier Disruption and Its Involvement in Neurodevelopmental and Neurodegenerative Disorders.Int J Mol Sci. 2022.
Zierfuss B, Larochelle C, Prat A.
Blood-brain barrier dysfunction in multiple sclerosis: causes, consequences, and potential effects of therapies.Lancet Neurol. 2024
Aragón-González A, Shaw PJ, Ferraiuolo L.
Blood-Brain Barrier Disruption and Its Involvement in Neurodevelopmental and Neurodegenerative Disorders.Int J Mol Sci. 2022.
Zierfuss B, Larochelle C, Prat A.
Blood-brain barrier dysfunction in multiple sclerosis: causes, consequences, and potential effects of therapies.Lancet Neurol. 2024
Wang S, Qin M, Fan X, Jiang C, Hou Q, Ye Z, Zhang X, Yang Y, Xiao J, Wallace K, Rastegar-Kashkooli Y, Peng Q, Jin D, Wang J, Wang M, Ding R, Tao J, Kim YT, Bhawal UK, Wang J, Chen X, Wang J.
The role of metal ions in stroke: Current evidence and future perspectives.Ageing Res Rev. 2024.
Xia M, Liang S, Li S, Ji M, Chen B, Zhang M, Dong C, Chen B, Gong W, Wen G, Zhan X, Zhang D, Li X, Zhou Y, Guan D, Verkhratsky A, Li B.
Iatrogenic Iron Promotes Neurodegeneration and Activates Self-Protection of Neural Cells against Exogenous Iron Attacks.Function (Oxf). 2021
Lin MS, Wang YC, Chen WJ, Kung WM.
Impact of gut-brain interaction in emerging neurological disorders.World J Clin Cases. 2023
Zhuang M, Zhang X, Cai J.
Microbiota-gut-brain axis: interplay between microbiota, barrier function and lymphatic system.Gut Microbes. 2024
Read ReviewAgnihotri, S.K., Kesari, K.K.
Mechanistic Effect of Heavy Metals in Neurological Disorder and Brain Cancer.Kesari, K. (eds) Networking of Mutagens in Environmental Toxicology. Environmental Science and Engineering(). Springer, Cham. 2019.
Siddhi Bagwe-Parab, Ginpreet Kaur,
Molecular targets and therapeutic interventions for iron induced neurodegeneration.Brain Research Bulletin. 2020.
Siddhi Bagwe-Parab, Ginpreet Kaur,
Molecular targets and therapeutic interventions for iron induced neurodegeneration.Brain Research Bulletin. 2020.