The blood-brain barrier

The blood-brain barrier (BBB) is a highly selective interface between the blood and the brain that plays an essential role in maintaining an optimal environment for central nervous system (CNS) function and homeostasis. Without the BBB, the CNS is at risk of invasion of toxins, pathogens, immune cells, or ion dysregulation, which would lead to neuronal dysfunction and degeneration [1]. BBB function emerges from an association of brain cells, including brain endothelial cells, mural cells (pericytes and vascular smooth muscle cells), astrocytes, neurons, microglia, and a basement membrane, which is referred to as the neurovascular unit (NVU) [2]. A healthy, functional BBB implies all these components are interacting correctly. Complex tight junctions between the brain endothelial cells seal the paracellular space forming a continuous barrier, while the astrocytes, pericytes, and basement membrane surround the endothelial cells [3]. The endothelial cells are coated in glycocalyx on the luminal side and surrounded in the basement membrane on the abluminal side [4]. The basement membrane is composed of both an inner vascular basement membrane, which is secreted by endothelial cells and pericytes and an outer parenchymal basement membrane, which is secreted by astrocytes [1]. Moreover, specific transporter proteins located on the endothelial cells regulate molecules entering and exiting the brain.

An intact BBB has very low paracellular permeability and high trans-endothelial electrical resistance (TEER). Importantly, brain endothelial cells present very low rates of vesicle trafficking, limiting the transcytosis transport further contributing to a functional BBB [5].

Although not the focus of this review, it is noteworthy to mention the existence of other blood-brain/cerebrospinal fluid barriers that are essential for brain homeostasis. The meninges (dura mater, arachnoid mater, and pia mater) comprise the outermost protection of the brain. Moreover, the brain ventricles contain highly vascularized structures, the choroid plexus, composed of fenestrated blood vessels and epithelia sealed by tight junctions. This choroid plexus epithelium comprises the so-called blood-cerebrospinal fluid barrier, which establishes a barrier between the blood and the cerebrospinal fluid barrier. These barriers have been extensively reviewed elsewhere [6,7,8].

This review will focus on recent findings describing how different pathological states compromise BBB integrity, discuss current potential therapeutic approaches that have been explored for improving BBB integrity and slowing neurodegenerative disease pathologies, and the recent findings in microbial mediated modulation of the BBB. Firstly, it is important to introduce the structure of the BBB to understand how each aspect of normal function can be altered or manipulated, affecting the integrity of the entire system. By putting everything into context by describing the BBB structure, emphasizing how the barrier alters in age and disease, and the current drugs explored to slow the negative outcomes of age and disease through acting directly on the BBB, the goal is to exploit the easily accessible and manipulable microbiota as a potential target to modulate the BBB.

BBB structure

Brain endothelial cells and tight junctions

The permeability of the BBB is one of the leading metrics used to assess BBB integrity and, it is a measure of the degree of both paracellular and transcellular transport [9]. Tight junction proteins between brain endothelial cells greatly restrict paracellular transport. Therefore, the expression and function of the tight junction proteins is often used as a metric of BBB integrity [10, 11]. Brain endothelial tight junction proteins include occludin, claudins (claudin-1, −3, −5, −12), and the membrane-associated guanylate kinase (MAGUK) protein family of zonula occludens (ZO1, ZO2, and ZO3) (Fig. 1) [12]. Another set of junction proteins, the adherens, are involved in the development, stabilization and organization of the intercellular junctions at the endothelium, and involve cadherins, catenins, PECAM-1, and the junctional adhesion molecules (JAMs) -A, -B, -C and endothelial cell-selective adhesion molecule (ESAM) [12, 13].

Fig. 1: Endothelial cell tight junctions and adherens junction proteins.
figure 1

The tight junction proteins include claudin-5, occludin, and zonula occludins (ZO-1,2,3). Claudin-5 and occludin are both transmembreane proteins while the zonula occludens are intracellular proteins. The adherens junctions include transcellular components, JAMs, ESAM, PECAM-1, and Ve-cadeherin. The cytoplasmic catenins form a complex with Ve-cadeherin. Actin cytoskeleton helps to anchor the junctional proteins in endothelial cells.

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The claudins, specifically claudin-5, are considered the primary sealing component of the tight junctions [10, 11]. Claudin-5 and occludin are both transmembrane proteins, while ZO-1 is a peripheral membrane protein. Claudin-5 contributes to the reduced paracellular ion movement and helps narrow the paracellular cleft [11, 14, 15]. The functionality of claudin-5 may also rely on Rho-associated protein kinase signaling and phosphorylation of the claudin-5 [16]. Occludin is also present in the filaments of tight junctions and helps regulate adhesion properties between cells as well as interacting with the inner cellular scaffolding proteins and the actin cytoskeleton [11]. ZOs are peripherally associated proteins that interact with claudins, occludins, and JAMs to anchor the membrane proteins, tethering them to the actin cytoskeleton [10, 16].

BBB transporters

There are a limited number of solutes that can cross the BBB without the use of transporters. The only molecules that can passively diffuse across the BBB are gases such as oxygen and carbon dioxide, and small lipid-soluble molecules with a molecular weight under 400 Da or containing less than 8 hydrogen bonds (e.g., ethanol, antidepressants) [17]. Passive paracellular transport of water-soluble agents is very limited in the BBB due to the presence of the tight junctions. To accommodate all the other components necessary to keep brain homeostasis, the BBB is equipped with a range of different transporters to ensure that essential molecules can readily enter the brain. Beyond passive diffusion and transcellular transport, these transporters can be broken down into five additional categories: active efflux transport, carrier-mediated transport, receptor-mediated transport, absorptive-mediated transport, and ion transporters (Fig. 2).

Fig. 2: Transport mechanisms across the blood-brain barrier.
figure 2

A Passive diffusion across endothelial cells by a limited number of small molecules (blue). B Paracellular transport of limited water-soluble agents (pink) between endothelial cells, through tight junction proteins. C Active efflux transporters (yellow) mostly eliminate drugs and substanes from the brain include many ATP binding cassette (ABC) transporters (purple) which are P-glycoprotein (Pgp), multidrug resistance proteins (MRPs), and breast cancer resistance protein (BCRP). D Carrier-mediated transport can be in either direction depending on the transporter and can be clatherin-dependent endocytosis. Major transporters include the glucose carrier (GLUT1), the L-type amino acid transporter 1 and 2 (LAT1/2), cationic amino acid transporter 1 and 3 (CAT1/3), the monocarboxylic acid carrier (MCT1/8), the organic anion transporting polypeptide 1c1 (OATP1C1), the fatty acid transport protein 1 and 4 (FATP1/4), the sodium-independent concentrative nucleoside transporter-2 (CNT2), the organic anion transporter 3 (OAT3), organic anion transporter poypeptide 1a4 and 2b1 (OATP1A4 and OATP2B1), and the organic cation transporter 2 (OCTN2). E Receptor-mediated transport relies on the interaction between ligands (green) and receptors to transport larger molecules through the cells. These receptors include the transferrin receptor (TfR), insulin receptor (IR), leptin receptor (LEP-R), lipoprotein receptor 1 and 2 (LRP1/2), and the receptor for advanced glycation end products (RAGE). F Absorptive-mediated transport is caveolin-mediated endocytosis and relies on the interaction between the ligand (orange) and the glycocalyx on the endothelial cells. G Ion transporters (turquoise) regulate the ions between the barrier and includes sodium pumps, calcium transporters, and potassium channels.

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Active efflux transport (Fig. 2C) largely encompasses the ATP binding cassette (ABC) class of transporters. ABC transporters require energy in the form of ATP to transport molecules across the concentration gradient. These transporters largely prevent the accumulation of drugs, drug conjugates, nucleosides, and xenobiotics in the brain [12]. Examples of these transporters include P-glycoprotein (Pgp), multidrug resistant proteins (MRPs), and breast cancer resistant protein (BCRP). ABC transporters are largely known to actively prevent accumulation of drugs and other agents in the brain [12, 18, 19].

Carrier-mediated transporters (Fig. 2D) are highly selective and generally facilitates the transport of nutrients from the blood to the brain although they can be bi-directional depending on the concentration gradient [20, 21]. Many of these transporters also belong to the superfamily of solute carriers (SLC). Examples of some of the SLC transporters present on brain endothelial cells include organic anion transporting polypeptides (OATPS) and organic cation transporters (OCTS). Carrier-mediated transporters are responsible for transporting several molecules such as carbohydrates, amino acids, monocarboxylates, hormones, fatty acids, nucleotides, organic anions, and cations etc. Some examples of the carrier-mediated transporters include the glucose carrier 1 (GLUT1), the LAT1/2, cationic amino acid transporter 1 and 3 (CAT1/3), the monocarboxylic acid carrier 1 and 8 (MCT1/8), the fatty acid transport protein 1 and 4 (FATP1/4), the sodium-independent concentrative nucleoside transporter-2 (CNT2), the organic cation transporter 2 (OCTN2), the OAT3, and the organic anion transporting peptides (OATP1C1, OATP1A4, OATP2B1) [12].

Receptor-mediated transport (Fig. 2E) requires the binding of a ligand to a receptor on the plasma membrane and is responsible for the transport of proteins and peptides both into and out of the brain [22, 23]. Examples of some of the receptors involved in receptor-mediated transport include the transferrin receptor (TfR), insulin receptor (IR), leptin receptor (LEP-R), lipoprotein receptor 1 and 2 (LRP1/2), and the receptor for advanced glycation end products (RAGE). Both the TfR and IR have been widely utilized to transport CNS targeting drugs across the BBB via the trojan horse strategy [24]. Many of these receptors are clathrin-dependent endocytosed, one example being LRP1 which is responsible for the endocytosis of amyloid-beta and APOE 2 and 3 [12].

The other major form of endocytic pathway in brain endothelial cells is caveolae-dependent. In this case molecules are absorbed in the absence of receptors, but rather through charged interaction between the ligand and the glycocalyx of endothelial cells and can be referred to as absorptive-mediated transcytosis (Fig. 2F) [18]. Although controversial, albumin may transcytose through the BBB via caveolae-mediated vesicular trafficking, which although present, is greatly restricted in the BBB [18]. Another form of vesicular transport pinocytosis, which is responsible for the transport of fluids across cells, is largely lacking in the BBB [117].

In vitro cell models of the BBB offer many advantages such as the ability to test the effects of molecules on specific cell types in a high throughput manner, and to investigate several cellular mechanisms simultaneously and repetitively [120]. Cultured cells offer a way to dive deeper into the mechanism of action behind single entities quicker and more controlled than would be possible in animal or clinical models.

Drug therapy

Some drugs have been explored for their therapeutic effect, tightening the BBB primarily in cases of ischemic stroke, but several therapeutics have also showed promise in the context of the neurodegenerative diseases MS, ALS, and AD.

There are two waves of BBB disruption in ischemic stroke. The first wave of disruption is caused by a sudden loss of blood flow to the brain which can quickly lead to metabolic disturbances, inflammation, oxidative stress, and neuronal death, while the second wave occurs at the reperfusion of oxygenated blood into the affected area, putting oxidative stress on the system. For these reasons, several drugs have been explored for their protective effects in oxidative stress in vitro models and ischemic stroke mouse models (middle cerebral artery occlusion/reperfusion). One drug, 10-O-(N, N-dimethylaminoethyl) ginkgolide B methanesulfonate (XQ-1H) has previously been explored for its involvement in pharmacological activities including antagonizing platelet activating factor, suppressing oxidative stress and neutrophil infiltration [121,122,123]. XQ-1H protects against oxygen and glucose deprivation/reoxygenation in vitro with increased TEER, increased cell viability, increased tight junction protein expression, and decreased permeability [122]. XQ-1H alleviates BBB leakage in ischemic stroke model mice increasing the expression of claudin-5, occludin, ZO-1, and B-catenin [122]. XQ-1H also protects BBB integrity in rats and further protects against LPS induced inflammatory response in brain microvessel endothelial cells [121]. Anther drug, JLX001, the dihydrochloride of cyclovirobuxine D (CVB-D) also has protective effects over the BBB. In primary cultured microvascular endothelial cells and in rats, JLX001 protects against glucose deprivation and reoxygenation [124]. JLX001 increases the expression of the tight junction proteins, claudin-5 and occludin, through activating Wnt/B-catenin signaling pathway [124]. Exosomes harvested from bone marrow stromal cells obtained from type 2 diabetic rats have also been explored as a potential therapy following stroke. These exosomes improve neurological function as well as decrease BBB leakage by decreasing leakage in hemorrhage and increasing tight junction protein ZO-1 expression [125]. Another drug, activated protein C, reduces BBB breakdown and leakage in stroke model rodents and has anti-inflammatory effects, neuroprotective effects, and blocks hemorrhage after brain ischemia [126, 127]. Activated protein C which protects the BBB integrity also has therapeutic effects in MS, ALS, and AD [128,129,130]. This is a protease that has anticoagulant activity and inhibits BBB breakdown, neuronal damage, and inflammatory responses [131].

MS is an autoimmune and inflammatory neurological disease of the CNS that damages the myelin sheath surrounding and protecting nerve cells [132]. The mechanisms of the BBB help regulate the immune responses of the brain and controls the exchange of immune cells between the blood and the brain. Activated protein C however has not been explored for it’s protection over BBB integrity in the context of MS, but rather for it’s anti coagulation effects, reducing disease severity in MS models [128]. The aspect of BBB protection from this molecule warrants investigation in the context of MS as another pathway in slowing disease progression. Additionally, patients with MS show a selective downregulation of the protein annexin A1 in the plasma and cerebral microvessel endothelia and annexin A1 knockout mice have increased BBB permeability [133]. The anti-inflammatory protein, recombinant annexin A1, therefore makes for a great candidate therapeutic. This anti-inflammatory protein also decreases BBB permeability and restores integrity in endothelial cells through cytoskeleton interactions in cultured brain endothelial cells [133].

Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disorder effecting nerve cells in the brain and spinal cord causing loss of muscle control [134]. One of the genetic factors to have a link to ALS is sporadic mutations in the antioxidant enzyme Cu/Zn superoxidase dismutase 1 (SOD1) [135]. Activated protein C downregulates SOD1 in SOD1 mutant mice, reduces blood-spinal cord barrier permeability, and slows disease progression [130]. Another aspect of slowing disease progression of ALS could be through protection of the BBB, but this warrants further investigation.

AD is a neurodegenerative disorder with two main pathological hallmarks of amyloid-beta plaque buildup and formation of neurofibrillary tangles [102]. As summarized above, there is a breakdown of the BBB in AD along with an increase in oxidative stress and inflammatory disfunction [112]. Previous therapeutics that target the amyloid cascade pathway have failed to alleviate AD pathology and restore cognition and memory, therefor new approaches are needed to slow or prevent AD. Since BBB breakdown and vascular dysfunction are a hallmark of AD, therapeutics targeting the BBB are of great potential [136]. Similar to the protease discussed in the context of stroke, MS, and ALS, the cell-signaling analog of activate protein C, 3K3A-activated protein C, in addition to improving cerebrovascular integrity also diminished neuroinflammatory responses and slows the generation of amyloid-beta plaque buildup in AD model mice [129]. This emphasizes the diverse effect of activated protein C on slowing disease progression in neurodegenerative disorders and improving BBB integrity in several disease models. Other potential therapeutics include specific inhibitors and genetic manipulation of cyclophilin A (CypA) which can ameliorate the vascular and neuronal dysfunction found in AD model mice through inhibition of the CypA — nuclear factor kappa B (NF-κB) — matrix metalloproteinases-9 pathway [137, 138]. NF-κB is a family of transcription factors involved in regulation of the inflammation and matrix metalloproteinases are activated under oxidative stress. AD patients have increased glutamate and one of the ways the BBB is disrupted in AD patients is with reduced GLUT1 expression, but the GLUT1 stimulator ceftriaxone has been shown to improve hippocampal memory and synaptic plasticity impairment in AD model mice [138, 139]. Another potential therapeutic, Minocycline is a microglial inhibitor which reduces BBB dysfunction by preventing production of glutamate, matrix metalloproteinases, and the proinflammatory cytokine, IL-1β, and increasing the levels of cells responsible for the remyelination of neurons which would be relevant in treating AD [138, 140,141,142]. By reducing the production of these, glutamate levels lower, the consequences of oxidative stress are reduced, and pro inflammatory cytokines are reduced, reducing the effects of inflammation and oxidative stress in progressing the disease and disruption of the BBB. Another drug explored as an AD therapeutic is Axitinib, which is a small molecule tyrosine kinase inhibitor that targets vascular endothelial grown factor receptors and is used as an anticancer drug. Axitinib decreases the disruption of tight junction proteins and reduces permeability of the BBB in AD disease mice while also increasing spatial awareness, exploration, associative memory, working memory and lowered amyloid-beta, indicating the potential for this drug to slow disease pathology [136]. The drugs that act on BBB integrity in the context of neurodegenerative disease warrant further investigation to understand the impact of restoring BBB integrity and protecting against breakdown.

Microbial metabolites

In contrast to drug therapy, recently, gut-derived microbial metabolites have been explored for their potential in modulating the BBB. Interestingly, changes in the gut microbiota have been associated with changes in the brain and pathologies of conditions such as the neurodegenerative disorders [143]. This connection between the gut microbiota and the brain is referred to as the gut-brain axis, a field which has attracted increasing levels of interest over the past two decades. Some of the major influencers of the gut microbiota composition, and therefore brain and behavior, are diet, exercise, environment, age, drugs and medications, and infections [143]. Furthermore, components of the foods we ingest are metabolized by the microbes residing in our guts producing metabolites important for our health [144]. There are many categories of distinct microbial metabolites including short chain fatty acids (SCFAs), bile acids, neurotransmitters, and other bioactive molecules of microbial origin produced in the gut which influence brain signaling. Very few have been explored for direct interactions with the BBB thus many opportunities still exist to explore the physiological effects of these metabolites [145, 146].

SCFAs have previously been implicated in processes such as gastrointestinal function, blood-pressure regulation, circadian rhythm, and immune function, and more recently explored for the effects on BBB physiology [143]. Specifically, one SCFA, propionate, has protective effects on the integrity of the BBB and protection of tight junction proteins [146]. It is not yet fully understood the mechanisms underlying BBB protection, but studies indicate it may be through a CD14-depenent mechanism, suppressing expression of LRP1, and protection from oxidative stress [146]. Earlier indications that the gut microbiota plays a role in affecting BBB integrity have been shown through the use of LPS from gram negative bacteria. The effects of LPS on BBB integrity have been largely covered in a previous section, since LPS is a major model of systemic inflammation.

The relationship between BBB integrity and the gut microbiota is evident in germ free mice models which lack a microbiota and have increased BBB permeability and altered tight junction protein expression effects, which continue from in utero into adulthood [147]. Additionally, rhesus monkeys with altered microbiomes from oral treatment of the antibiotic, amoxicillin-clavulanic acid, have increased BBB permeability to albumin [148]. The antibiotic treatment decreased the relative abundance of Firmicutes, a SCFA producing phylum of bacteria in the gut, which correlates with a decrease in SCFA concentrations and an increase in BBB permeability [148]. Other research has also identified that abundance of Firmicutes plays a role in altering BBB function and found that the ratio of Firmicutes/Bacteroidetes increased in aging mice as well as the alpha diversity (the mean species diversity), while the BBB function became impaired [96]. The aged mice also had compromised learning and memory behaviors and increased anxiety, which suggests that the gut microbiome and the BBB are linked to the deleterious changes in aging brains [96]. In another study mice treated with low-dose penicillin in early life, however, have increased mRNA and protein expression of tight junction proteins in the hippocampus [149]. Antibiotic treatment in mice (which reduced the abundance of Bacteroidetes) also reduced the expression of tight junction protein mRNA expression in the hippocampus, but increased expression in the amygdala [150]. There is not yet a proposed mechanism for how antibiotic treatment affects tight junction expression in specific regions of the brain in these studies, but it could be through changes in metabolite composition or cytokine involvement. It is important to note the regions of the brain that are more susceptible to the changes in BBB integrity as regions like the hippocampus and amygdala are heavily affected in neurodegenerative disease as they are vital for long-term memory and processing emotions and behavior. The differences in these studies may be explained by the different effects the antibiotics have on the gut microbiota composition, species of the models, and timing of the antibiotic treatments. These findings further highlight the modulating effects the gut microbiota composition and specific metabolites like SCFAs, have on the integrity of the BBB.

The SCFA, butyrate, has exhibited protective effects against both PD and stroke. In a mouse model of PD, sodium butyrate increased occludin and ZO-1 protein expression as well as attenuated behavioral impairment and neuronal damage induced by the PD model [151]. Direct injection of sodium butyrate decreased BBB permeability in ischemic stroke model mice and reduced the loss of sensory motor function induced by stroke [152]. Another microbial-derived metabolite, Urolithin A, a coumarin, is found in plasma of healthy adults and derived from ellagitannins found in pomegranates, walnuts, and berries and has both protective effects on BBB integrity pre stroke and therapeutic effects post stroke [153]. Urolithin A treatment has increased hippocampus neurogenesis, decreased reactive gliosis, and reduced inflammation in the middle cerebral artery occlusion mouse model of stroke [153]. The metabolite has also been explored for treatments during healthy aging, AD, and MS [154].

Methylamines are another subset of microbial-derived metabolites that are produced by the microbial metabolism of choline and L-carnitine. Recently, methylamine trimethylamine N-oxide (TMAO) has been explored for its protective effects on BBB function both in vitro and in vivo [155]. The precursor to TMAO, trimethylamine, on the other hand impairs BBB function, emphasizing the need to better understand the relationships between microbial-derived metabolites, host processing of these metabolites and BBB physiology [155]. More recently, another microbial product, p-cresol, a glucuronide, has been found to decrease permeability of the BBB in vitro and has protective effects over LPS induced BBB disruption in mice [156]. The direct effects p-cresol has on BBB physiology may be through functional antagonism of the TLR4 complex, a receptor complex activated by LPS [156]. It is intriguing that SCFAs, coumarins, methylamines, and glucuronides have direct effects on BBB integrity. This emphasizes the profound role a diverse subset of microbial-dependent metabolites have on barrier function; therefore more metabolites must be explored for direct influence on BBB physiology.

Not all components of the gut microbiome, however, are protective over the BBB as seen with LPS and evident with deoxycholic or chenodeoxycholic acid. Deoxycholic or chenodeoxycholic acid are bile acids that can directly interact with the BBB, increasing the permeability and disrupting the tight junction proteins [157]. These bile acids are regulated by the microbiome and concentrations can alter with alteration in the gut microbiota composition. Chenodeoxycholic acid is a primary bile acid synthesized in the liver from cholesterol, which is then stored in the gallbladder before being excreted in the small intestine. Deoxycholic acid, on the other hand, is a secondary bile acid, which means it is formed when primary bile acids undergo microbial mediated transformations [158]. The balance between these beneficial and harmful metabolites depends heavily on the gut microbiota composition, and an altered composition compared to a healthy one can lead to more harm than good. Reducing the interactions between the harmful components of the microbiota and the BBB and increasing the interaction of the beneficial/protective components may help to alleviate some of the detrimental characteristics of a compromised BBB.

The interaction between the gut microbes and their metabolites is suggested to introduce a fourth facet of communication to the gut-brain axis [146]. The previously identified and accepted pathways of communication include the nervous system via the vagus nerve, the immune system, and enteroendocrine signaling pathways [159]. The additional pathway would be the direct modulatory effects microbes and metabolites have on the BBB itself, influencing the integrity of the brain’s primary defense mechanism and therefore impacting brain health. This interaction, however, may not be its own individual communication pathway, but rather the BBB is an interface of communication between the gut microbiota, blood, and the brain. The gut microbiota may be interacting with the other pathways such as inflammation, or endocrine which then interact with and affect the integrity of the BBB, but either way it is now apparent that the gut microbiota is a modulator of BBB integrity. In summary, there are several factors that can influence gut microbiota composition which impacts the microbial-derived metabolites that enter circulation, and these metabolites in circulation or lack of metabolites directly interact and influence BBB physiology (Fig. 5). Further understanding of the cellular mechanisms through which microbial metabolites affect BBB physiology would potentially allow microbial-derived metabolites to be exploited for therapeutic protection against BBB breakdown in the context of inflammation, oxidative stress, and age-related diseases.

Fig. 5: Proposed summary of the relationship between the gut microbiome and the blood-brain barrier.
figure 5

A (i) Factors such as the environment, age, circadian rhythm, medication/drugs, exercise, infection, diet and stress can affect the composition and landscape of the gut microbiota. (ii) the gut microbiota and colonized bacteria produce metabolites. These metabolites produced alter with regards to relative concentrations and molecules with changes in microbiota. (iii) gut-derived microbial metabolites cross the gut lumen whether as direct molecules or in derived forms and enter circulation. (iv) once in circulation, the microbial-derived metabolites can interact with the BBB. B In the absence of a gut microbiota (germ-free animals) or where there are compositional alterations in the gut microbiota, microbial metabolites are not produced or are differentially produced that can enter systemic circulation and the lack or increase in microbial-derived metabolites is associated with BBB dysfunction.

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Concluding remarks and future perspectives

The BBB function and structure are vital to maintain brain heath and proper function. The disruption of any of the functions of the BBB potentially leads to BBB breakdown or loss of integrity putting brain homeostasis at risk. Deterioration of BBB form and function is a feature part of healthy aging, but it is worsened in many neurodegenerative disorders and is a hallmark of cognitive decline. As the aging population increases, it becomes even more vital to understand the potential mechanisms of future therapies for maintaining and increasing BBB integrity. Emerging research in the gut-brain axis and the protection or disruption by gut microbial-derived metabolites have on BBB integrity are only beginning to be explored. As we begin to better understand the role of the gut-derived metabolites on the system, it will be interesting to incorporate and exploit these interactions for the purpose of therapeutics to either restore or protect against BBB breakdown.