How Body Inflammation May Cause Blood-Brain Barrier Problems Linked to Brain Diseases

In healthy individuals, the BBB strictly regulates the transit of substances and cells between the periphery and the CNS. However, under peripheral inflammation, its function is compromised due to the activation of multiple inflammatory pathways that alter its structure and function [10]. Recent studies have demonstrated that gut dysbiosis can exacerbate peripheral inflammation and promote BBB alterations, suggesting a direct interconnection between these factors. Chronic inflammation, triggered by bacterial or viral infections or autoimmune processes, generates an environment rich in pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), which directly impact cerebral endothelial cells [11,12,13].

The increase in these inflammatory mediators activates intracellular pathways in endothelial cells, mainly those mediated by the transcription factor NF-κB [14]. The activation of NF-κB induces alterations in the expression of pivotal tight junction proteins, including claudin-5 and occludin. These alterations result in the degradation of these proteins and a subsequent reduction in barrier impermeability [15,16]. This structural breakdown facilitates the passage of plasma molecules and immune cells into the brain parenchyma, promoting a neuroinflammatory state [17].

Recent studies have identified a novel mechanism by which gut microbiota influences the integrity of the BBB. Specifically, the influence of microbial metabolites, such as short-chain fatty acids (SCFAs), on the regulation of peripheral inflammation has emerged as a significant factor in BBB dysfunction [18,19,20]. Pro-inflammatory bacterial byproducts, such as lipopolysaccharide (LPS), translocate across the intestinal barrier in cases of dysbiosis, thereby weakening its integrity. Conversely, SCFAs reinforce tight junctions and modulate immune responses within the intestinal tract, thus potentially enhancing the protective barrier function of the BBB. Recent studies have identified a correlation between gut dysbiosis and increased LPS production, which activates the Toll-like receptor 4 (TLR4), triggering systemic inflammatory responses that impair BBB integrity [21,22]. Additionally, certain bacterial metabolites, such as SCFAs, have demonstrated protective effects on the BBB by reinforcing tight junctions and modulating immune responses [23,24].

The gut–brain axis is a bidirectional communication network connecting the CNS with the gastrointestinal tract, integrating neuroendocrine, immunological, and metabolic signals [25]. A pivotal element of this interaction pertains to the gut microbiota, an ecosystem comprising microorganisms that exert influence on brain function by means of bioactive metabolites, cytokines, and neurotransmitters [12,26]. Recent research has identified a capacity for microbiota to modulate BBB function through the production of beneficial metabolites and the regulation of immune system activity and oxidative stress. Mounting evidence suggests that alterations in microbiota composition can affect the BBB, modifying its permeability and contributing to neuroinflammation and neurodegeneration [18,27].

The evidence associating peripheral inflammation with BBB dysfunction in various neurological pathologies provides a framework for understanding the mechanisms underlying neurodegeneration and underscores the importance of addressing peripheral inflammation as a pivotal therapeutic target. The identification of strategies to protect and restore BBB function offers a promising approach for the development of more effective neuroprotective therapies.

The primary objective of this review is to analyze the relationship between peripheral inflammation and BBB dysfunction, emphasizing the molecular mechanisms linking this dysfunction to neurodegenerative pathologies, and to evaluate emerging therapeutic implications for restoring BBB integrity and preventing associated neuronal damage.

In order to achieve the overarching objective, the following specific objectives were proposed: (i) examine the molecular and cellular mechanisms by which peripheral inflammation affects BBB structure and function, including tight junction dysregulation, increased permeability, and altered selective transport function; (ii) analyze evidence from studies in animal models and humans showing the relationship between chronic peripheral inflammation and neurodegenerative pathologies, highlighting diseases such as Alzheimer’s, Parkinson’s, and multiple sclerosis; (iii) review current and emerging therapeutic strategies aimed at reducing peripheral inflammation and protecting the BBB, such as anti-inflammatory interventions and the modulation of the gut microbiota; (iv) evaluate regional differences in the BBB, its susceptibility to dysfunction in various brain areas, and how this may explain the selective vulnerability of certain brain regions in neurodegenerative diseases; and (v) propose new directions for therapeutic research that integrate multidisciplinary approaches, such as the use of neuroprotective drugs targeting the BBB and personalized strategies for treatment delivery based on barrier heterogeneity.

The brain’s vascularization is highly differentiated to meet the metabolic needs of distinct areas. Gray matter, which contains a high density of neuronal bodies, is richly vascularized, ensuring a constant supply of oxygen and nutrients required for neuronal function [54,55]. The BBB in gray matter is characterized by tightly regulated endothelial junctions, which provide an effective barrier against pathogens, toxins, and plasma macromolecules [56]. However, recent studies have indicated that gut microbiota can modulate these endothelial cells via microbial metabolites, thereby altering BBB permeability in a region-dependent manner [57,58]. Conversely, white matter, which is composed primarily of myelinated axonal fibers, has a lower density of blood vessels and a more diffuse vascular architecture, reflecting its comparatively lower metabolic demands [59,60]. This reduced vascularization renders the BBB in white matter more vulnerable to permeability changes under ischemic or inflammatory conditions. Recent findings indicate that systemic inflammation and microbiota dysbiosis can exacerbate white matter vulnerability by increasing endothelial stress, altering nutrient transport, and promoting immune cell infiltration [2]. These factors may explain the selective involvement of white matter in neuroinflammatory diseases such as multiple sclerosis.

In addition, regional disparities in BBB structure and function influence the propensity to neurodegeneration. In gray matter, the BBB’s heightened regulation is paramount for maintaining neuronal homeostasis and synaptic activity. Conversely, white matter endothelial junctions exhibit reduced restriction, potentially enabling the inadvertent passage of inflammatory molecules and immune cells, particularly during pathological states. This differential permeability may contribute to region-specific disease progression in neurodegenerative conditions [61,62].

The BBB’s heterogeneity contributes to the selective vulnerability of specific brain regions to neurodegenerative diseases, as evidenced by conditions such as Alzheimer’s and Parkinson’s disease. These conditions illustrate how BBB dysfunction influences disease progression by facilitating the entry of inflammatory mediators, toxins, and misfolded proteins [63,64]. In the field of neurodegenerative diseases, several hypotheses have been postulated to account for the selective vulnerability of particular brain regions. A prominent theory posits that metabolic demands and oxidative stress render specific areas more susceptible to neurodegeneration. Regions such as the hippocampus and substantia nigra, which exhibit high energy expenditure and extensive synaptic connectivity, are hypothesized to be particularly vulnerable to inflammatory and metabolic alterations [25,64].

Alzheimer’s disease, a prototypical example of neurodegeneration, is characterized by the accumulation of toxic proteins, such as β-amyloid, which predominantly aggregates in the entorhinal cortex and hippocampus, areas crucial for memory and learning [65]. The BBB in these regions, due to its high vascularization, is particularly exposed to inflammatory mediators and metabolic dysregulation arising from imbalances in the gut microbiota [66]. The dysfunction of BBB transport mechanisms and the destabilization of tight junctions facilitate the passage of β-amyloid from the peripheral circulation into the brain, accelerating plaque formation and exacerbating neurodegeneration [67]. Additionally, chronic peripheral inflammation in Alzheimer’s disease further compromises BBB function, allowing increased immune cell infiltration and exacerbating neuroinflammation in these key regions [68,69].

In Parkinson’s disease, the substantia nigra, which contains dopaminergic neurons responsible for motor control, exhibits heightened susceptibility to neurodegeneration [70]. Despite its relatively high vascularization, the BBB in the substantia nigra has been shown to have increased permeability, potentially facilitating the entry of inflammatory agents and reactive oxygen species (ROS) [71]. Recent evidence suggests that gut microbiota dysregulation may contribute to increased BBB permeability in the substantia nigra, promoting α-synuclein aggregation and neuronal damage [72]. This BBB dysfunction could permit the passage of neurotoxic proteins from the peripheral circulation, exacerbating dopaminergic neuron loss and accelerating the progression of Parkinsonian symptoms [73,74].

Neuroinflammatory diseases affecting white matter, such as multiple sclerosis, present a distinct pattern of BBB dysfunction, with the endothelial barrier in white matter being particularly susceptible to inflammatory processes, allowing immune cell infiltration, including T lymphocytes and monocytes [75]. This immune cell influx leads to myelin degradation, disrupting efficient neuronal signaling and resulting in neurological deficits [76]. Recent studies have indicated that gut microbiota-derived inflammatory signals may contribute to white matter BBB breakdown, thereby enhancing vulnerability to immune-mediated demyelination [77,78].

The present findings suggest that the selective vulnerability of specific brain regions to neurodegeneration may be influenced by a combination of intrinsic factors, such as metabolic demand and oxidative stress, and systemic inflammatory signals modulated by the gut microbiota. The hippocampus and substantia nigra, for instance, appear to be particularly susceptible to inflammatory insults, likely due to a combination of high vascularization, metabolic activity, and increased permeability of the BBB under inflammatory conditions. In this context, microbial-derived components such as lipopolysaccharides have been shown to exacerbate neuroinflammatory processes, while SCFAs have been demonstrated to exert a modulatory role in preserving BBB integrity. This observed regional heterogeneity in BBB susceptibility underscores the necessity to consider gut–brain interactions as a potential factor in explaining the distinct patterns of neurodegeneration observed across different disorders (Figure 2).

Peripheral inflammation has been demonstrated to induce neurodegeneration, a process that is associated with the sustained activation of microglia, the resident immune cells of the CNS. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β, which are elevated in chronic systemic inflammation, have been shown to promote microglial activation and shift them toward a pro-inflammatory phenotype [82,83]. This sustained activation of microglia has been shown to lead to the increased production of ROS and nitric oxide, which in turn causes oxidative stress, synaptic dysfunction, and neuronal apoptosis [84]. Furthermore, systemic inflammation has been demonstrated to impair the function of the BBB, thereby allowing the entry of peripheral immune cells and inflammatory mediators into the CNS, which in turn exacerbates neuroinflammation and neuronal injury [85].

In Alzheimer’s disease, chronic inflammation and BBB dysfunction have been implicated in the accumulation of β-amyloid (Aβ) plaques. Systemic inflammation weakens Aβ clearance mechanisms, leading to its accumulation in vulnerable brain regions, such as the hippocampus [62,86]. Furthermore, the entry of peripheral inflammatory mediators through a compromised BBB exacerbates tau pathology, contributing to neuronal loss and cognitive decline [87]. Recent studies have indicated that gut microbiota alterations may modulate Aβ pathology by influencing peripheral immune responses and inflammatory signaling. For instance, recent research has shown that changes in gut microbial composition can alter systemic cytokine levels, impacting Aβ deposition and clearance mechanisms in the brain [88,89]. This observation suggests the potential involvement of a gut–brain axis in the pathogenesis of Alzheimer’s disease, whereby gut dysbiosis contributes to systemic inflammation, affecting blood–brain barrier (BBB) permeability and accelerating neurodegenerative changes [90].

Parkinson’s disease exacerbates α-synuclein aggregation, a hallmark of PD pathology. Unlike in Alzheimer’s disease, where β-amyloid accumulation is influenced by BBB dysfunction, in PD, systemic inflammation particularly impacts dopaminergic neurons by increasing oxidative stress and disrupting mitochondrial function. Increased BBB permeability in the substantia nigra has been associated with enhanced immune cell infiltration, oxidative damage, and dopaminergic neuron loss [91,92]. Furthermore, gut microbiota alterations in PD patients have been linked to increased levels of pro-inflammatory cytokines and LPS, which may further compromise BBB integrity and promote α-synuclein misfolding and aggregation [93]. This highlights the role of systemic inflammation and microbial metabolites in driving neurodegenerative mechanisms beyond the CNS.

Peripheral inflammation has been demonstrated to exacerbate protein aggregation, in addition to altering brain metabolism and neurotransmission. Pro-inflammatory cytokines have been shown to interfere with synaptic plasticity by impairing glutamate homeostasis and reducing neurotrophic support, leading to cognitive dysfunction and motor deficits [94]. Furthermore, metabolic disruptions induced by systemic inflammation, such as impaired glucose metabolism and mitochondrial dysfunction, have been observed in both Alzheimer’s disease and Parkinson’s disease, further exacerbating neuronal vulnerability [95,96].

Current therapeutic strategies for neurodegenerative diseases principally concentrate on the management of symptoms rather than on the underlying mechanisms that drive disease progression. There are significant unmet needs in the effective modulation of neuroinflammation and BBB dysfunction, particularly in the context of systemic inflammatory responses [97]. Emerging evidence suggests that targeting systemic inflammation and modulating gut microbiota composition may offer therapeutic potential in neurodegenerative diseases. Interventions such as anti-inflammatory treatments, probiotic supplementation, and dietary modifications aimed at restoring gut microbial balance have shown promise in mitigating neuroinflammation and preserving BBB function [98]. These strategies, still in early stages, may provide novel approaches to slow disease progression and protect neuronal integrity by addressing inflammation at its systemic origin.

Chronic peripheral inflammation is widely regarded as a pivotal element in the pathophysiology of BBB dysfunction. This condition, characterized by the influx of inflammatory mediators and immune cells into the brain, has been implicated in the exacerbation of neuroinflammation and neuronal damage. Thus, anti-inflammatory interventions have emerged as a promising therapeutic approach, offering a potential means to safeguard the BBB and mitigate neurodegeneration.

A particularly salient strategy in this regard involves the use of cytokine inhibitors, which have demonstrated considerable potential with regard to neurodegenerative diseases. A growing body of research has indicated that the inhibition of pro-inflammatory cytokines can result in a reduction in the permeability of the BBB and a concomitant protection against neuronal damage [99,100]. TNF-α inhibitors, such as etanercept and adalimumab, which are already employed in the treatment of autoimmune diseases like rheumatoid arthritis, are being evaluated in clinical trials for the treatment of multiple sclerosis and Alzheimer’s [101,102]. Similarly, corticosteroids and other immunosuppressive medications have demonstrated the capacity to decrease systemic inflammation and, in certain instances, alleviate the consequences of BBB dysfunction [103].

Another relevant strategy is the modulation of intracellular signaling pathways implicated in inflammation. In this line, the nuclear factor kappa B pathway, a major regulatory pathway, is involved in the expression of various cytokines and the destabilization of tight junctions in the BBB [104]. One potential therapeutic strategy to consider is the use of molecules that inhibit NF-κB signaling [105]. Curcumin is an example of a natural compound that possesses anti-inflammatory properties [106,107]. However, other compounds, including JAK-STAT inhibitors, are being examined for their potential to reduce inflammation and safeguard the BBB [108].

In recent years, the concept of the gut–brain connection has gained significant traction within the field of neurodegenerative diseases. The gut microbiota plays a pivotal role in regulating systemic inflammation and modulating the immune response. This regulatory function can directly influence the function of the BBB [109]. It has been demonstrated that gut dysbiosis can trigger systemic inflammation, which in turn can affect the BBB and contribute to neuroinflammation. Thus, the modulation of the gut microbiota through the administration of probiotics, prebiotics, and selective antibiotics has been postulated as a prospective therapeutic modality to enhance the function of the BBB and mitigate the risk of neurodegeneration.

Probiotics, such as Lactobacillus and Bifidobacterium, have been utilized to restore balance to the gut microbiota and reduce systemic inflammation [110]. Some studies have demonstrated that the administration of probiotics in animal models of Alzheimer’s and Parkinson’s can enhance the integrity of the BBB, reduce neuroinflammation, and mitigate the accumulation of toxic proteins, including β-amyloid and α-synuclein [111]. A similar mechanism may underlie the effects of prebiotics, which are known to stimulate the proliferation of beneficial bacteria [112,113].

A significant challenge in the treatment of neurodegenerative diseases is the difficulty in effectively delivering drugs to the brain due to the restrictive function of the BBB. However, the heterogeneity of the BBB in different brain regions presents an opportunity to develop more precise and specific therapeutic approaches.

BBB vascularization and permeability have been shown to vary significantly between different brain regions, with some areas being more vulnerable to BBB dysfunction than others. The hippocampus exhibits heightened vulnerability to toxic protein accumulation and BBB dysfunction in diseases such as Alzheimer’s [114]. Similarly, in Parkinson’s disease, the substantia nigra, due to its high vascular density and the presence of dopaminergic cells, demonstrates increased susceptibility to neuroinflammation and disruption of the BBB [115].

In this line, research endeavors have focused on the development of nanoparticles and lipid vectors. These particles can be engineered to selectively target areas of the brain exhibiting BBB dysfunction [116]. This approach facilitates the efficient transport of neuroprotective drugs, while concomitantly circumventing systemic side-effects [117]. Additionally, investigations are underway that explore the use of monoclonal antibodies [118]. These antibodies are designed to bind to particular receptors present on BBB endothelial cells [119]. The goal is to employ this mechanism as a strategy to enable the selective facilitation of drug penetration into the brain (Figure 3).

Insights into the regional heterogeneity of BBB dysfunction highlight the need for precision medicine approaches. By tailoring interventions based on an individual’s specific BBB permeability profile and inflammatory status, clinicians could optimize treatments, using region-specific drug delivery systems and personalized anti-inflammatory regimens to mitigate neurodegenerative damage.

Given the established link between gut dysbiosis and BBB integrity, dietary interventions and probiotic supplementation present practical approaches to support brain health. Targeting the gut–brain axis through microbiome modulation could reduce systemic inflammation and reinforce BBB function, offering a non-invasive strategy to complement pharmacological treatments.

This study’s findings underscore the importance of developing drugs capable of crossing the BBB without compromising its function. Novel therapeutic agents, including nanoparticle-based drug delivery systems and monoclonal antibodies targeting BBB transport mechanisms, hold promise for enhancing drug efficacy while minimizing systemic side-effects.

Modifiable lifestyle factors such as diet, physical activity, and stress management can play a crucial role in preserving BBB integrity. Public health initiatives aimed at promoting healthy lifestyle choices could contribute to the prevention of neuroinflammation-related BBB dysfunction, thereby reducing the incidence of neurodegenerative diseases.

The emerging evidence on the gut–brain–BBB axis and inflammation-driven neurodegeneration provides a foundation for updating clinical guidelines to incorporate BBB-protective strategies. Recommendations could include routine gut microbiota assessments, inflammation control strategies, and targeted therapeutic approaches for at-risk populations.

By translating these research findings into practical healthcare, professionals and policymakers can work towards developing comprehensive strategies to address BBB dysfunction and its role in neurodegenerative diseases, ultimately improving patient outcomes and quality of life.