Association Between Blood-Brain Barrier Disruption and Gut Microbiota Dysbiosis in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a chronic neurodegenerative disorder primarily characterized by motor dysfunction. It is the second most prevalent neurodegenerative disorder after Alzheimer’s disease. Its pathological manifestations include typical motor symptoms associated with Lewy bodies and loss of nigrostriatal dopaminergic neurons. Emerging evidence indicates that blood-brain barrier (BBB) dysfunction contributes to the onset and progression of PD. The BBB is essential for maintaining central nervous system (CNS) homeostasis by restricting the entry of circulating components and exogenous substances into the brain. In PD, disruption of BBB integrity facilitates the infiltration of circulating neurotoxins, macromolecules, and microorganisms, thereby triggering neuroinflammatory and immune responses. Furthermore, gut microbiota dysbiosis significantly impacts the integrity and function of the BBB via inflammatory mediators and metabolites, thus promoting PD progression. This study summarizes the associations between the BBB and gut microbiota with the onset and progression of PD and investigates the potential of enhancing BBB integrity and optimizing the gut microbiota as a theoretical foundation for developing novel therapeutic approaches for PD. Clinical trial number: not applicable.

Introduction

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder characterized by progressive motor impairment and a range of non-motor symptoms (Hopfner et al. 2024). It primarily affects the middle-aged and elderly population and is the second most common neurodegenerative disorder after Alzheimer’s disease (AD) (Marino et al. 2020; Ou et al. 2021). The pathological hallmarks of PD include progressive degeneration of nigrostriatal dopaminergic neurons and the accumulation of Lewy bodies (LBs), primarily composed of misfolded α-synuclein (α-syn), leading to dopamine deficiency and the classical motor symptoms of bradykinesia, tremor, and postural instability (Zhou et al. 2023). The blood-brain barrier (BBB) is a highly selective and dynamic interface formed by endothelial cells (ECs), pericytes, astrocytes, and the basement membrane, which separates the circulating blood from the central nervous system (CNS). It plays a critical role in maintaining CNS homeostasis by regulating the transport of nutrients and metabolites while preventing the entry of potentially harmful substances. The BBB’s primary function is to protect the brain from foreign substances while regulating the exchange of nutrients, drugs, and metabolites (Wu et al. 2023). Increasing evidence suggests that structural and functional disruption of the BBB is involved in PD pathogenesis, facilitating the infiltration of neurotoxic molecules and promoting neuroinflammation and neuronal damage (Chen et al. 2024). Furthermore, BBB dysfunction might be critically associated with PD pathogenesis. Recently, gut microbiota research has gained a lot of attention for its correlation with PD progression, and indicated that gut microbiota dysregulation is associated with CNS health (He et al. 2024). Thus, investigating the correlation between these two factors can enhance understanding of PD pathogenesis.

Gut microbiota dysbiosis is defined as the abnormal changes in the composition and function of the microbial community in the gut, which may significantly affect the host’s health (Hrncir 2022). In recent years, significant research has investigated the correlation between gut microbiota disruptions and various diseases, including stroke, major depressive disorder, perioperative neurocognitive disorders in elderly patients, and neurological disorders such as PD and AD (Mitrea et al. 2022). The gut microbiota regulates the host’s immune response and inflammatory processes via its metabolites, such as short-chain fatty acids (SCFAs), bile acids, and tryptophan metabolites (Wang et al. 2023). Furthermore, studies on the gut-brain axis have revealed that gut microbiota is crucially associated with CNS health. Gut microbiota dysbiosis can also promote the development of neurodegenerative diseases by affecting BBB integrity, neuroinflammation, and neurotransmitter homeostasis (Ashique et al. 2024). The PD patients have shown specific changes in gut microbiota, which correlate with the severity of motor symptoms (Sampson and Mazmanian 2015). Several animal studies on BBB dysfunction in PD have revealed that gut microbiota may play a potential modulating role in PD (Bhattarai et al. 2021). Therefore, a better understanding of the gut microbiota and its association with the host can identify interventions targeting gut dysbiosis, such as probiotics, prebiotics, and fecal microbial transplantation (FMT) for improving PD treatments (Loh et al. 2024).

The literature suggests a significant association between BBB disruption and gut microbiota dysbiosis. The gut microbiota dysbiosis may affect the BBB’s integrity through various mechanisms. Intestinal microbiota dysbiosis can promote abnormal activation and differentiation of immune cells, thus altering the balance of immune regulation. Furthermore, it can trigger an inflammatory response by releasing inflammatory factors, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and IL-1β, which can disrupt the BBB’s EC tight junctions (TJs), increasing their permeability (Aburto and Cryan 2024). Various studies have shown that gut microbiota metabolites can cross the BBB and subsequently affect CNS function (Dong et al. 2020a). For example, SCFAs reach the hippocampus and prefrontal cortex, regulate neuronal growth, differentiation, and neurotransmitter synthesis, and release (Huang et al. 2024). Moreover, they also affect spatial memory, mood, attention, and other behaviors, such as improving cognitive function and alleviating depression symptoms in aged mice (Gladen-Kolarsky et al. 2024). Lipopolysaccharides (LPS) can penetrate the BBB and activate microglia, inducing neuroinflammation or an immunological response that produces inflammatory mediators, impairing neuronal function and viability, which results in cognitive, motor, and fatigue-related behavioral impairments (Kalyan et al. 2022).

Taken together, BBB dysfunction and gut microbiota dysbiosis represent two interconnected factors in PD pathogenesis. This review aims to summarize current evidence on their roles and interactions, and to explore potential therapeutic strategies targeting BBB integrity and gut microbiota modulation in PD (Zhao et al. 2025).

Composition and Physiological Function of the BBB

The BBB is formed by the endothelium of the brain’s microvessels, whose structure and function are influenced by neighboring cells (Blanchette and Daneman 2015). The BBB is not an isolated physical structure; rather, a combination of various physiological characteristics intrinsic to ECs that limit vascular permeability (Profaci et al. 2020). The BBB’s endothelium is responsible for the delivery of oxygen and nutrients (e.g., glucose, amino acids, and other neurotransmitter precursors) to the brain and removing waste products (Pollak et al. 2018). Furthermore, BBB has been observed to modulate the maintenance and protection of neuronal function by tightly regulating the flow of ions, molecules, and cells between the blood and parenchyma (Profaci et al. 2020). In both the BBB and the choroid plexus, TJs between adjacent cells restrict the diffusion of polar solutes across the interstitial space (paracellular pathway), significantly reducing the infiltration of potentially harmful chemicals, neuroactive compounds, and infections (Pollak et al. 2018). The BBB primarily comprises components such as EC, pericytes, and astrocytes, each of which uniquely maintains BBB integrity. The EC in the CNS has several unique properties that precisely regulate the transport of substances through the BBB (Yamazaki and Kanekiyo 2017). These EC form TJs, which are highly specialized intercellular adhesion complexes (Daneman and Prat 2015). The TJs comprise transmembrane proteins, including claudin and occludin, that function as selective barriers, restricting paracellular permeability between the lumen and interstitial compartments of the ductus cavernosum and preserving intracerebral homeostasis (Huang et al. 2020). These transmembrane TJ proteins are connected to the actin cytoskeleton via Zonula Occludens-1 (ZO-1), a member of the membrane-associated guanylate kinase-like protein family (Fanning et al. 1998). Claudin is the primary structural component of the TJs (Günzel and Yu 2013), and claudin-5 is highly expressed in the brain EC (Morita et al. 1999). Claudin-5 deficiency has been found to cause BBB dysfunction in mice (Nitta et al. 2003). In the CNS, the expression of leukocyte adhesion molecules is significantly reduced compared to peripheral tissues (Daneman et al. 2010). This characteristic may inhibit the excessive infiltration of immune cells from the bloodstream into the brain parenchyma under homeostatic settings, thereby preserving immune privilege in the CNS (Muldoon et al. 2013). Astrocytes surround most microvessels and capillaries and interact with EC through their prominent end-feet in neurovascular units (NVU) (Oberheim et al. 2009). Furthermore, they maintain BBB integrity by inducing barrier properties and transporter protein polarization (Abbott et al. 2006). Pericytes are vascular wall cells that envelop the outside of microvessels (Yamazaki and Kanekiyo 2017) and have been demonstrated to modulate angiogenesis, extracellular matrix synthesis, and BBB integrity in both the developing and mature brain (Daneman et al. 2009). Moreover, basement membrane components regulate the cellular localization of occludin in EC, which in turn affects barrier stability (Savettieri et al. 2000). The composition and structure of the BBB under normal conditions and its pathological alterations in PD are illustrated in Fig. 1.

Fig. 1.

The structure of the BBB under normal conditions and during PD pathogenesis. A The panel illustrates intact EC interconnected by TJ proteins (ZO-1, occludin, Claudin), surrounded by astrocyte end feet and pericytes within the basement membrane. The magnified view (right) highlights the triad maintaining BBB integrity: TJ complexes between EC, pericyte coverage, and astrocyte-vascular interactions. B The panel shows pathological features including pericyte loss, reduced TJ proteins, and activated ECs. The enlarged view (right) shows α-syn and amyloid-β plaque accumulation, neuronal degeneration with cell loss, activated microglia, reactive astrocytes, and inflammatory mediator leakage through damaged TJs

The BBB has multiple important physiological functions. It maintains ion homeostasis through specific ion channels and transporters, which modulate neuronal excitability, macrophage migration, and the maintenance of EC morphology. Furthermore, the selectivity and region-specificity of its transport system ensure the supply of nutrients to the brain (Kadry et al. 2020). The BBB plays a crucial role in maintaining separate central and peripheral neurotransmitter pools. It effectively restricts the passage of many peripheral neurotransmitters (e.g., serotonin, dopamine) into the brain, preventing interference with central synaptic signaling. Moreover, it utilizes specific sodium-dependent and other specialized transporters to tightly regulate the flux of neurotransmitter precursors and metabolites, thus protecting neurons from alterations in potentially deleterious bioactive substances (Kadry et al. 2020). It also inhibits the penetration of plasma macromolecules into the brain. Under physiological conditions, the choroid plexus filters plasma to produce CSF to control protein levels. The BBB prevents macromolecules from entering the brain through the normal pathway, which could promote significant damage (Wei et al. 2024). It has also been found that the BBB protects the brain from neurotoxins by regulating the entry of substances according to the needs of the CNS and by pumping harmful substances out of the CNS through efflux transporters at the BBB, protecting the CNS, which has a limited regenerative capacity (Obermeier et al. 2013).

Increased BBB Permeability in PD

Evidence of BBB Disruption in PD

Several studies have indicated that BBB disruption and increased permeability are the predominant characteristics in PD pathogenesis (Paul and Elabi 2022). Preclinical studies using neurotoxin-based models, such as MPTP-treated mice and 6-OHDA-treated rats, have consistently demonstrated increased BBB permeability in the striatum (Chen et al. 2008). Clinical evidence further supports BBB impairment in PD. Elevated blood-cerebrospinal fluid albumin ratios in patients indicate impaired barrier integrity (Pisani et al. 2012). Recently, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has revealed regional BBB leakage, particularly in posterior white matter regions (Al-Bachari et al. 2020). This leakage not only increases brain exposure to blood-borne neurotoxins but also facilitates neuroinflammation, creating a vicious cycle of injury.

Cellular Contributors to BBB Dysfunction in PD

The integrity of the BBB is maintained by the NVU, which consists of ECs, pericytes, astrocytes, and microglia. In PD, dysfunction of these cellular components collectively contributes to BBB function.

ECs form the physical barrier through TJ proteins such as claudin-5 and occludin. In PD, reduced expression and disorganization of these TJ proteins lead to increased paracellular permeability (Chen et al. 2024). Moreover, dysfunction of key transporters, including P-gp and LRP1, further compromises barrier integrity.

Microglia, as resident immune cells of the CNS, respond to injury such as trauma, ischemia, infection, or neurodegeneration (Mayer and Fischer 2024). In PD, activated microglia release pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and ROS, thus directly impairing TJ integrity (Liu and Quan 2018). Microglia adopting a pro-inflammatory phenotype exacerbate vascular leakage, while those with a protective phenotype may support BBB repair through anti-inflammatory mediators such as IL-10 and TGF-β1 (Choudhury et al. 2022). The balance between these functional states critically determines the net effect on the NVU.

In addition to ECs and microglia, other NVU components, including astrocytes and pericytes, also play essential roles in maintaining BBB integrity. Dysfunction of these cells further amplifies barrier disruption and contributes to PD progression.

Molecular Mechanisms Linking α-syn to BBB Disruption

α-syn, the principal component of LBs, plays a central role in PD pathology and directly contributes to BBB disruption. Extracellular α-syn can be transported bidirectionally across the BBB via low-density lipoprotein receptor-related protein-1 (LRP1) (Peng et al. 2022). In early PD, LRP1 expression is upregulated, potentially facilitating increased α-syn influx (Wilhelmus et al. 2011). Once within the brain parenchyma, pathological α-syn aggregates induce neuroinflammation, oxidative stress, and mitochondrial dysfunction, which in turn disrupt EC signaling and TJ stability (Calabresi et al. 2023). BBB disruption allows blood-derived α-syn and other neurotoxic molecules to enter the brain, amplifying pathology in a feed-forward loop (Sui et al. 2014).

In addition to α-syn-mediated effects, vascular endothelial growth factor (VEGF) is pathologically upregulated in PD and contributes to BBB dysfunction by promoting pathological angiogenesis and increasing vascular permeability (Lan et al. 2022). These vascular alterations further exacerbate neuronal injury, particularly in dopaminergic systems.

Genetic Factors Influencing the BBB and the Gut-Brain Axis in PD

Emerging genetic evidence links inherited risk factors to both barrier dysfunction and gut-brain axis dysregulation in PD. Genome-wide association studies (GWAS) have identified several PD risk loci, which are involved in BBB and gut homeostasis. Mutations in LRRK2, a common genetic cause of familial PD, are expressed in both intestinal epithelial cells and cerebrovascular ECs, where they may influence barrier integrity through inflammatory and autophagy pathways (Nguyen et al. 2025). Variants in GBA impair lysosomal function and disrupt α-syn clearance, affecting both the enteric nervous system and the NVU (Bougea 2025). Polymorphisms in genes involved in innate immunity (e.g., HLA-DRA) and lysosomal activity (e.g., TMEM175) further underscore the central role of neuroinflammation and cellular clearance mechanisms in BBB-gut axis dysregulation (Tansey et al. 2022).

Summary: A Multifactorial Model of BBB Disruption in PD

The BBB disruption in PD is a multifaceted process involving structural breakdown of TJs, transporter dysfunction, and NVU dysregulation driven by chronic neuroinflammation and oxidative stress. Pathological changes in astrocytes, microglia, and pericytes converge to compromise endothelial integrity, while α-syn contributes to and is exacerbated by barrier failure. These coordinated alterations create a vicious cycle that promotes the entry of neurotoxic species, accelerates dopaminergic neuron loss, and propagates neuroinflammation. The BBB thus emerges as a dynamic interface whose dysfunction is both a cause and a consequence of PD pathology, offering multiple targets for therapeutic intervention (Olaoye et al. 2025).

Dysbiosis of Gut Microbiota in PD

The gut-brain axis enables bidirectional communication between the gastrointestinal tract and the CNS, playing a crucial role in maintaining physiological homeostasis (Post et al. 2023). The gut microbiota influences CNS function through neural, immune, and metabolic pathways, with microbial metabolites such as SCFAs and tryptophan derivatives acting as key mediators (Gao et al. 2020; O’Riordan et al. 2022). The gut microbiota can regulate the inflammatory response in the CNS and the progression of neurodegenerative diseases by modulating the activity and function of intestinal immune cells, which in turn affect the CNS (Quigley 2017). Gut-brain axis disruption caused by intestinal dysbiosis has been associated with various neurological disorders, including PD (Zheng et al. 2023). It has been observed that inflammation and α-syn misfolding and aberrant aggregation are key pathological mechanisms in PD.

Peripheral gut inflammation contributes to microglial activation and neuroinflammation. The gut microbiota has been linked with CNS function and can affect the CNS via the gut-brain axis (Mou et al. 2022). Furthermore, gut microbiota dysbiosis impairs intestinal barrier function, allowing inflammatory factors and immune cells to enter the systemic circulation, which then cross the BBB and activate microglia in the brain (Fung 2020). This activation stimulates a neuroinflammatory response, causing neuronal damage and dysfunction (Masanetz et al. 2022). Gut microbiota metabolites, such as SCFAs, also modulate intestinal barrier function and immune responses (Blaak et al. 2020). Several studies on mouse PD models have indicated that CD4⁺T cells are involved in neurodegenerative pathologies (Liu et al. 2021), and gut microbiota may stimulate inflammation by activating the CD4 + T cell response, which then induces the release of interferon-gamma (IFN-γ), IL-17, and other pro-inflammatory factors, thus activating macrophages and neutrophils (Ostanin et al. 2009). The inflammatory milieu induced by the immune response activated by T helper 1 (Th1) and T helper 17 (Th17) cells may aggravate the inflammatory environment, which exacerbates α-syn pathological aggregates accumulation in the enteric nervous system and promotes their spread to the CNS (Villumsen et al. 2019).

Gut microbiota dysbiosis can trigger a systemic inflammation by activating intestinal CD4⁺ T cells. Specific pathobionts or their metabolites can promote the differentiation of naïve T cells into pro-inflammatory Th1 and Th17 subsets. Activated Th1 cells release IFN-γ, while Th17 cells secrete IL-17 and IL-22. These cytokines can compromise the intestinal epithelial barrier, allowing bacterial products (e.g., LPS) to enter the circulation. Circulating inflammatory signals may subsequently impair BBB integrity and activate microglia, thereby promoting neuroinflammation. This Th1/Th17-driven inflammatory environment has been shown to promote the misfolding and aggregation of α-syn within the enteric nervous system, potentially facilitating its prion-like propagation to the CNS via the vagus nerve (Park and Ciofani 2025).

Gut microbiota dysbiosis may promote PD progression by modulating α-syn aggregation and propagation along the gut-brain axis (Metta et al. 2022). Microbial metabolites can influence α-syn aggregation and transmission (Duan et al. 2024). For instance, sodium butyrate has been reported to regulate α-syn levels in a context-dependent manner by activating the autophagy pathways (Duan et al. 2024). Furthermore, α-syn aggregation into toxic oligomers and LBs is a central pathological event in PD, leading to the dysfunction and loss of dopaminergic neurons in the substantia nigra. This neuronal depletion results in a severe striatal dopamine deficit, which underlies the cardinal motor symptoms of PD (bradykinesia, rigidity, tremor). Levodopa’s chronic pharmacological restoration of dopamine can reduce these symptoms, but it can also cause side effects such as levodopa-induced dyskinesia (LID) (Mahbub et al. 2024; Fujita et al. 2021). Alterations in BBB permeability may contribute to the development of LID. Increased BBB permeability can allow altering levodopa levels or other peripheral factors to enter the brain parenchyma, thereby exacerbating abnormal involuntary movements (Fujita et al. 2021). A study introduced PD patient-specific microbiota into the mouse gut and observed that these microorganisms influenced α-syn aggregation through metabolites, thus exacerbating the mice’s motor dysfunction (Sampson et al. 2016).

Recent clinical studies have demonstrated the associations between gut microbial dysbiosis and various manifestations and symptoms of PD, including disease onset, progression, and both motor and non-motor symptoms (Zhang et al. 2023). For example, reduced abundance of SCFA-producing bacteria has been linked to increased PD risk in patients with idiopathic rapid eye movement sleep behavior disorder (Nishiwaki et al. 2020). In terms of motor symptoms, reduced Lactobacillus abundance has been associated with impaired motor function, whereas increased Enterobacteriaceae is related to problems such as postural instability, difficulty walking, and motor stiffness (Barichella et al. 2019). An increase in Enterobacteriaceae, Clostridium, and Microbacterium spp. abundance in Warts helps differentiate the type of tremor in PD (Abusrair et al. 2022). Gut microbiota changes have also been linked with non-motor symptoms, e.g., reduction in Anaplasma fragilis is related to decreased motivation, whereas decreased Bifidobacterium has been associated with hallucinations or delusions (Jia et al. 2024). Current research on new-onset PD patients revealed that gastrointestinal symptoms triggered by intestinal dysbiosis can help predict changes in patients’ cognitive functioning (Jones et al. 2020). PD patients often suffer from concomitant gastrointestinal dysfunction, such as constipation and diarrhea, which have been associated with intestinal dysbiosis (Kim and Sung 2015; Chiang and Lin 2019). Previous research suggests that constipation is correlated with PD and that its severity may serve as a predictor of PD progression (Chen et al. 2015a). Moreover, in PD patients, the abundance of specific gut microbiota such as Prevotella, E. faecalis, and Trichosporonaceae is reduced, whereas that of Ruminalococcaceae and Kristensen spp. is increased, a significant difference from the healthy population (Grant et al. 2023). However, the clinical application of gut microbiota as a biomarker remains limited due to inter-individual variability and the influence of multiple confounding factors, including genetics, diet, and environmental exposures (Zhang et al. 2023).

Beyond correlative findings, specific microbial signatures have been associated with distinct clinical features of PD, suggesting their potential as non-invasive biomarkers. These associations may reflect the metabolic heterogeneity of bacterial taxa. For example, butyrate-producing bacteria (e.g., Faecalibacterium and Roseburia) are thought to exert neuroprotective effects through anti-inflammatory and epigenetic mechanisms (Mirzaei et al. 2021), whereas LPS-producing Enterobacteriaceae may promote neuroinflammation and motor dysfunction (Sampson et al. 2016). Such functional differences suggest that microbial profiles may help distinguish clinical subtypes, including tremor-dominant and postural instability/gait difficulty phenotype (Wang et al. 2024). Furthermore, gut microbiota alterations have been detected in prodromal stages, specifically in individuals with idiopathic rapid eye movement sleep behavior disorder who subsequently develop PD, indicating potential for early risk prediction (Nishiwaki et al. 2020).

However, the clinical application of these microbial signatures remains challenging due to methodological variability, the need for validation in diverse cohorts, and the lack of established causal relationships. Despite these limitations, the gut microbiota may serve as an adjunctive tool for early diagnosis, patient stratification, and disease monitoring in PD. Further elucidation of the mechanisms linking microbial alterations to BBB dysfunction and neuroinflammation may provide deeper insight into PD pathogenesis.

The Association of BBB Dysfunction with Intestinal Dysbiosis

Alterations in gut microbiota composition can compromise intestinal barrier integrity and indirectly destabilize the BBB, forming a bidirectional interaction between dysbiosis and BBB dysfunction (Vincenzo et al. 2024). The underlying mechanisms involve impaired intestinal barrier function, immune dysregulation, and circadian rhythm disruption (Moreira Gobis et al. 2024). Dysbiosis may promote bacterial translocation and systemic inflammation (“leaky gut”) (Zheng et al. 2021), whereas probiotics (e.g., Lactobacillus plantarum) can enhance TJ protein expression (Chichlowski et al. 2020). Furthermore, pathogens (e.g., Clostridium difficile) can impair the integrity of ECs (Singh et al. 2019). Beneficial microbes and metabolites (e.g., butyrate) protect the intestinal barriers and BBB by modulating neurotransmitters, inhibiting microglial activation, and reducing inflammation (Vincenzo et al. 2024). Disruptions in circadian rhythm reduce the abundance of helpful bacteria (e.g., Lactobacillus) while promoting pathogens (e.g., Coccidioides), thus worsening barrier failure (Chodowiec et al. 2024). Healthy gut microbiota maintenance is essential for protecting BBB integrity and preventing associated neurological disorders. Understanding the complex relationships between microbial community structure, intestinal barrier function, and BBB stability is crucial for attaining valuable insights into neuroinflammatory disease pathogenesis and identifying potential therapeutic targets.

Inflammatory Response

Gut microbiota dysbiosis may induce intestinal inflammation, increasing intestinal permeability, which allows bacteria and their products (e.g., LPS, hydrogen sulfide [H₂S], and lipoteichoic acid [LTA]) to enter the circulation (Braniste et al. 2014). These microbial components can activate immune cells and promote the release of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, which may impair BBB integrity and exacerbate neuroinflammation (Al Bander et al. 2020; Garavaglia et al. 2024). Moreover, gut dysbiosis can lead to an increase in harmful products and a decrease in beneficial metabolites such as SCFAs (Braniste et al. 2014). SCFAs have anti-inflammatory effects and can maintain the integrity of the intestinal barrier and BBB by inhibiting histone deacetylase (HDAC) and activating G protein-coupled receptors (e.g., GPR41/43) (Sampson et al. 2016). Reduced SCFA levels have been linked to increased neuroinflammation and neuronal damage. Moreover, gut microbiota dysregulation damages the intestinal epithelium and activates the TLR4/TNF-α signaling pathway, which can cause several pro-inflammatory factors to cross the BBB and promote neuroinflammation (Tang et al. 2022). Similarly, the activation of the nuclear factor kappa B (NF-κB) signaling pathway stimulates the release of pro-inflammatory cytokines that can cross the BBB and induce neuroinflammation (Logsdon et al. 2018). For example, LPS produced by certain intestinal bacteria can activate the NF-κB signaling pathway, releasing pro-inflammatory cytokines such as TNF-α and IL-1β (Logsdon et al. 2018), which then exacerbate neuroinflammation and further promote PD progression by affecting the BBB integrity.

Effects of Metabolites

Microbiota produce various metabolites that can influence the BBB’s function and integrity (O’Riordan et al. 2022). These include SCFAs, tryptophan metabolites, bile acids, and other bioactive compounds generated through microbial fermentation and metabolism. Among these, SCFAs—primarily acetate, propionate, and butyrate—are key metabolites produced by colonic anaerobes through the fermentation of dietary fiber and resistant starch (Besten et al. 2013). SCFAs play important roles in regulating immune responses, metabolism, and host physiology. Mechanistically, they exert their effects through pathways such as G protein-coupled receptors and histone deacetylase (HDAC) inhibition, thereby influencing brain function via humoral and immune signaling (Yao et al. 2022). Moreover, SCFAs regulate the intestinal and systemic immune responses (e.g., butyric acid and propionic acid), TJ proteins (e.g., Claudin and propionic acid), and the immune response (e.g., Claudin and Occludin), which in turn affect BBB permeability and brain health (Braniste et al. 2014).

In addition to SCFAs, gut microbiota produce various bioactive molecules that can influence the brain, including neuroactive compounds such as gamma-aminobutyric acid (GABA), the neurotransmitter precursor tryptophan (for serotonin synthesis), secondary bile acids, and various metabolites derived from amino acid metabolism. Although most classical neurotransmitters do not readily cross the BBB, microbiota-derived molecules can either penetrate the BBB or act on peripheral targets (e.g., enteric nerves, vagus nerve) to relay signals to the CNS (Missiego-Beltrán and Beltrán-Velasco 2024). Once these substances cross the BBB, they act directly on nerve cell receptors to modulate the glial cells-induced inflammatory response (Missiego-Beltrán and Beltrán-Velasco 2024). Serotonin (5-HT) is primarily produced by intestinal enterochromaffin cells and plays important roles in neural development and synaptic function (Higa et al. 2022). Peripheral 5-HT does not cross the BBB; instead, central 5-HT synthesis depends on the transport of its precursor, tryptophan, into the brain (Barnes and Sharp 1999). Dysregulation of the serotonergic system has been implicated in PD progression. Reduced 5-HT levels may contribute to gastrointestinal dysfunction and non-motor symptoms, such as depression, and may be involved in gut-brain signaling pathways (Liu et al. 2015; Skaliter et al. 2021). Post-mortem research has revealed that in the brain of PD patients, 5-HT is more susceptible to neurodegeneration than the 5-HT in a healthy individual’s brain, which may explain the early non-motor symptoms (e.g., depression) and the subsequent motor fluctuations. Moreover, although peripheral 5-HT cannot cross the BBB, the indirect regulation of neuroinflammation via 5-HT1A/5-HT4 receptors remains an area of interest. The literature has revealed that 5-HT₄ receptor agonists can be employed to modify the function of the intestinal barrier and reduce LPS leakage. These agonists can suppress the activation of mast cells (Brodbelt et al. 2020). Studies have shown that in the MPTP-induced PD model mice, trimethylamine N-oxide (TMAO) has no significant effect on dopaminergic neurons, tyrosine hydroxylase (TH) protein content, or striatal DA levels. However, it markedly decreases 5-HT levels and exacerbates DA and 5-HT metabolism imbalance, thereby affecting neurotransmission (Quan et al. 2023).

PD reduces intestinal barrier function, which has a profound effect on the organism. Impaired intestinal barrier function facilitates the transport of LPS into the bloodstream, thus stimulating a systemic immunological response. Once LPS penetrates the BBB, it activates microglia, releasing pro-inflammatory cytokines that exacerbate neuroinflammation and promote the progression of PD (Roboon et al. 2021). The metabolite isoamylamine (IAA) produced by gut bacteria promotes the death of neuronal microglia, leading to cognitive decline (Teng et al. 2022). The gut microbiota affects early gastrointestinal symptoms of PD by interacting with neurons and the brain-gut axis. The brain-gut axis is primarily modulated via immunological, neuroendocrine, and neurological pathways (Cryan et al. 2019). Peptidoglycan is a gut microbial cell wall component that influences immune homeostasis in the gut, and its overexpression has been associated with the pathophysiology by influencing the immune response (Zheng et al. 2021). Tryptophan metabolites, such as indole derivatives and kynurenine acid metabolites, have important effects on the Parkinsonian cerebral-gut axis, and the KYN/TRT ratio is increased in serum and CSF of PD patients, which may be related to altered tryptophan metabolic pathways (O’Mahony et al. 2015). Bacterial amyloid-producing proteins, such as Fap and Curli, induce abnormal α-syn folding and accumulation, which is related to the pathology of PD (Sampson et al. 2020). These findings highlighted the potential role of gut microbial metabolites in PD development and provided new perspectives and strategies for its treatment.

Microbial Molecular Patterns and Virulence Factors

In addition to metabolites, gut microorganisms directly influence host physiology through their structural components and secreted virulence factors. Pathogen-associated molecular patterns (PAMPs), such as LPS from Gram-negative bacteria (e.g., Enterobacteriaceae), lipoteichoic acid (LTA) from Gram-positive bacteria (e.g., certain Clostridium spp.), and peptidoglycan (common to most bacteria), are potent inflammation inducers. These PAMPs are recognized by host pattern recognition receptors (PRRs) like Toll-like receptors (TLRs) on immune and epithelial cells. Their binding triggers downstream signaling cascades (e.g., NF-κB, MAPK), which result in the production of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), thus disrupting both the intestinal barrier and the BBB (Lin et al. 2025). Furthermore, some bacteria implicated in PD dysbiosis have specific virulence mechanisms. For instance, curli fibers produced by Escherichia coli are functional amyloids that can cross-seed and accelerate the aggregation of human α-syn, directly associating a specific bacterial product with PD pathology (Sampson et al. 2020). Integrating the taxonomic changes observed in various clinical studies (e.g., increases in Enterobacteriaceae, Clostridium) with the known biochemical properties of these taxa provides a mechanistic bridge between ‘who is there’ and ‘what they are doing’ in PD pathogenesis.

To systematically integrate the taxonomic alterations observed in clinical PD studies with their potential biochemical mechanisms, this review summarizes key dysbiotic taxa, their characteristic microbial components or metabolites, and the associated pathways implicated in neuroinflammation and BBB disruption in Table 1.

Table 1.

Integration of gut microbiota alterations in PD with their biochemical features and proposed mechanisms impacting neuroinflammation and BBB

Microbial Taxon/Group	Key Biochemical Components/Metabolites	Proposed Mechanisms in Neuroinflammation & BBB Disruption	References
Enterobacteriaceae (e.g., Escherichia coli)	Lipopolysaccharide (LPS); Curli fibers (functional amyloids)	• LPS activates TLR4/NF-κB signaling in immune and ECs, inducing pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) that disrupt TJs in both gut and BBB. • Curli fibers act as PAMPs and can cross-seed nucleation of human α-syn, promoting its aggregation and potentially propagating pathology.	Lin et al. (2025)
Clostridium spp. (certain pathobionts)	Lipoteichoic acid (LTA); various toxins (e.g., botulinum, tetanus neurotoxins)	• LTA activates TLR2-mediated pro-inflammatory responses. • Specific toxins may directly damage intestinal epithelium or enter the systemic circulation, contributing to increased permeability and systemic inflammation.	Long et al. (2009), Connell et al. (2022)
Prevotella	Short-chain fatty acids (e.g., propionate); mucus-degrading polysaccharides	• Reduced SCFA production diminishes anti-inflammatory signaling (e.g., via GPR41/43), impairs colonocyte energy metabolism, and weakens intestinal barrier integrity, potentially creating a pro-inflammatory milieu.	Donohoe et al. (2012), Brown et al. (2003)
Faecalibacterium prausnitzii	Butyrate: anti-inflammatory microbial products	• Loss of butyrate, a primary energy source for colonocytes, leads to epithelial hypoxia, TJ dysfunction, and reduced HDAC inhibition, collectively elevating gut permeability and inflammatory tone.	Chang et al. (2014)
Lactobacillus spp.	Lactic acid; SCFAs; bactericidal bacteriocins	• Depletion reduces competitive exclusion of pathogens, lowers beneficial SCFA levels, and diminishes local anti-inflammatory and barrier-strengthening effects.	Nicholson et al. (2012)
Bifidobacterium spp.	Acetate; tryptophan metabolites	• Depletion reduces acetate-mediated intestinal barrier support and anti-inflammatory immunomodulation (e.g., Treg induction). Altered tryptophan metabolism may shift the kynurenine pathway, influencing CNS inflammation.	O’Mahony et al. (2015 )

This comprehensive analysis not only indicates the taxonomic changes but also correlates distinct microbial signatures with specific biochemical processes that can promote intestinal barrier impairment, systemic inflammation, and subsequently, BBB disruption in PD.

Neuroendocrine Pathways

Recent studies suggest a bidirectional communication between the neuroendocrine system and gut microbiota (Farzi et al. 2018). The hypothalamic-pituitary-adrenal (HPA) axis is a central neuroendocrine regulatory system that modulates stress responses and the immune system (Foster et al. 2017). Recently, it was observed that gut microbiota dysbiosis can activate the HPA axis (Foster et al. 2017). Furthermore, HPA axis dysfunction can disrupt BBB integrity, thus promoting PD development (Marino and Souza 2020). During cellular injury or pathogen exposure, adrenal glands release glucocorticoids (e.g., cortisol), which bind to glucocorticoid receptors via the HPA axis (Burford et al. 2017). In PD patients, the HPA axis hyperactivity is characterized by elevated cortisol levels, which correlate with impaired glucocorticoid receptor signaling in immune cells (Ibrahimagic et al. 2016). This dysregulation may exacerbate neuroinflammation by compromising BBB permeability. During this process, adrenocorticotropic hormone serves a key mediator of the HPA axis and modulates cerebral vascular tone and BBB permeability (Herman et al. 2016). Dysfunctional adrenocorticotropic hormone signaling facilitates infiltration of cytotoxic molecules (e.g., pro-inflammatory cytokines, ROS) into the brain parenchyma, increasing the vulnerability of dopaminergic neurons in the substantia nigra (Lang et al. 2022). Moreover, chronic glucocorticoid exposure can disrupt TJ proteins (e.g., occludin, claudin-5) and upregulate matrix metalloproteinases (MMPs) (Lang et al. 2022), reducing BBB permeability and increasing α-syn aggregation; a hallmark of PD pathology.

The literature shows that gut dysbiosis can affect neuroendocrine hormone secretion, such as ceruloplasmin, which can influence BBB integrity (Farzi et al. 2018). Furthermore, certain molecules produced by gut microbiota, such as SCFAs, 5-HT, and GABA, can directly or indirectly affect the BBB via the vagus nerve (Parker et al. 2020). The vagus nerve serves as a primary pathway linking the gut to the brain and modulates CNS function by relaying signals generated by the gut microbiota (Gwak and Chang 2021). Moreover, vagal activation can affect neuroinflammation and BBB integrity (Kwon et al. 2024). For example, the activated vagus nerve can inhibit inflammatory factors, thus reducing neuroinflammation (Kwon et al. 2024). In addition to the above pathways, gut microbiota dysbiosis can stimulate certain metabolites produced by gut microbiota, such as propionic acid, which can protect the BBB integrity via the NRF2 signaling pathway (Hoyles et al. 2018). Propionic acid can inhibit pathways associated with non-specific microbial infections, inhibit LRP-1 expression via a CD14-dependent mechanism, and protect the BBB from oxidative stress damage through the NRF2 signaling pathway (Hoyles et al. 2018). The vagus nerve has a dual role in PD: it is implicated in the gut-to-brain propagation of α-syn pathology based on the Braak hypothesis, and also mediates the cholinergic anti-inflammatory pathway that can suppress neuroinflammation. This paradox is resolved by modern “brain-first” and “body-first” subtype models, which propose different origins of the disease. Furthermore, irrespective of the original location, neuroinflammation serves as a primary driver of development. The vagus nerve acts as both a possible pathway for disease and a promising target for neuromodulation, with its overall impact influenced by a balance between pathological damage and compensatory anti-inflammatory mechanisms (Ling et al. 2025).

Role of Circulating microRNAs and Angiogenesis

In addition to cytokines and metabolites, circulating microRNAs (miRNAs), as key epigenetic regulators, participate in the crosstalk between BBB dysfunction and gut microbiota dysbiosis. Altered peripheral miRNA profiles, including miR-7, miR-153, and miR-223, have been reported in patients with PD. These miRNAs can cross the compromised BBB or be delivered via exosomes to regulate the expression of TJ proteins (e.g., claudin-5, occludin) in brain ECs, thus influencing BBB permeability (Ayyanar and Vijayan 2025). Gut microbiota dysbiosis can modulate the expression of miRNAs in the host intestine and systemic circulation. These alterations may further affect cerebrovascular integrity and angiogenesis. For instance, certain gut microbiota-derived metabolites can regulate the expression of pro‑angiogenic signals such as VEGF. Aberrant angiogenesis and compromised BBB together form a vicious cycle that exacerbates neuroinflammation (Xue et al. 2025). Therefore, investigating the regulatory network of miRNAs within the gut–cerebrovascular axis may provide new targets for biomarker discovery and therapeutic intervention in PD.

Oxidative Stress and Autophagy

Gut microbiota dysbiosis may induce intestinal and systemic oxidative stress, generating increased ROS levels (Mostafavi Abdolmaleky and Zhou 2024). Excessive ROS can cause mitochondrial dysfunction, which in turn compromises blood–brain barrier (BBB) integrity and increases its permeability (Zhao et al. 2022). As a result, circulating neurotoxic substances may more readily enter the brain and contribute to dopaminergic neuronal damage and PD progression (Bucher et al. 2024). Recent studies indicate that gut dysbiosis-mediated mitochondrial dysfunction in CNS cells elevates oxidative stress, leading to neuronal inflammation (Chidambaram et al. 2021). This inflammatory response affects the gut and propagates to the brain via the circulation, where it promotes protein misfolding and aggregation, as well as axonal damage and neuronal demyelination (Chidambaram et al. 2021).

Dysbiosis also affects autophagy, a key process in maintaining intestinal barrier homeostasis. Impaired autophagy can disrupt epithelial integrity and increase intestinal permeability, allowing microbial products and microbe-associated molecular patterns (MAMPs) to enter the circulation and trigger systemic and central inflammatory responses (Alsegiani and Shah 2022). Furthermore, defective autophagy may impair intracellular bacterial clearance and contribute to persistent dysbiosis (Larabi et al. 2020). Autophagy dysfunction is also linked to mitochondrial damage and ROS accumulation, which can activate the NLRP3 inflammasome and promote the production of pro-inflammatory mediators, further aggravating neuroinflammation and BBB dysfunction (Atilano et al. 2023).

Figure 2 indicates a schematic of the communication between gut microbiota dysbiosis, oxidative stress, and BBB disruption along the gut-brain axis.

Fig. 2.

Communication between BBB disruption and gut microbiota dysbiosis in brain-gut axis pathophysiology. A Transition from healthy microbiota (balanced microbial diversity) to dysbiosis (pathobiont dominance) causes intestinal epithelial structural imbalance. Key features include an intact mucus layer progressing to a leaky gut (compromised TJs). B Systemic effects of dysbiosis: Reduced microbial fermentation of dietary fiber decreases SCFAs (acetate, butyrate/ATP) production. Circulating LPS and indoxyl acetate (IAA) promote oxidative stress (ROS), which drives endothelial dysfunction and BBB disruption. C Neurovascular impairment promotes BBB disruption (disrupted TJs, perivascular inflammation). Compensatory vagus nerve cholinergic signaling suppresses inflammation, while probiotics restore gut-mucosal homeostasis

Association of BBB Destruction in PD Patients with Intestinal Dysbiosis

Several recent studies have demonstrated that gut microbiota can influence brain function via the BBB. However, the specific mechanisms by which the gut-brain axis regulates BBB permeability in PD remain incompletely understood. Although numerous studies have reported associations between BBB disruption and gut microbiota dysbiosis in PD, most evidence is derived from correlational analyses, and definitive causal relationships have yet to be established (Loh et al. 2024).

Metabolite TMAO influences stroke and vascular cognitive impairment by modulating brain function via cholesterol metabolism, foam cell formation, thrombosis, and oxidative stress (Tu and Xia 2024). Furthermore, TMAO may stimulate BBB disruption by affecting oxidative stress, microglial activation, and neuronal apoptosis, promoting mental, cognitive, and behavioral disorders (Ge et al. 2023). Studies that analyzed the acute MPTP-induced PD mouse model revealed that elevated TMAO levels may exert potentially detrimental effects (Quan et al. 2023), which could be related to its impact on α-syn conformation and aggregation (Uversky et al. 2001). Therefore, it has been hypothesized that TMAO produced during intestinal dysbiosis can modulate PD development and progression, as well as other neurodegenerative diseases, by influencing BBB integrity and permeability.

Several studies have revealed a bidirectional modulation between the gut microbiota and the CNS, called the “gut-brain axis” (Loh et al. 2024) (Table 2). Gut microbiota is essentially involved in the modulation of BBB integrity in patients with neurodegenerative diseases such as PD (Jain et al. 2023). It has been observed that in PD patients, altered gut microbiota reduces midbrain dopaminergic neurons (TH⁺ cells), motor dysfunction, and Th17 homeostatic cells in the ileocecal region, increasing intestinal inflammation and barrier disruption (Munoz-Pinto et al. 2024). This cascade increases pro-inflammatory cytokine levels and reduces the number of CD4⁺ immune cells. These pro-inflammatory factors can enter the CNS through the broken BBB and exacerbate the inflammatory response in the midbrain region, resulting in increased leakage of IgG-positive microvessels and elevated levels of IL-17 (Munoz-Pinto et al. 2024).

Table 2.

Experimental studies on gut microbiota and PD model

Experimental Model	Intervention/Manipulation	Mechanistic Insights	References
MPTP-induced PD mice	FMT from PD patients	Gut dysbiosis promotes α-syn pathology via TLR4/NF-κB activation and microglial priming.	Sun et al. (2018)
6-OHDA rat model	Probiotic Lactobacillus rhamnosus E9	Probiotics modulate intestinal barrier integrity via upregulating occludin and ZO-1 expression.	Xie and Prasad (2020)
α-syn overexpressing mice	Oral gavage with Curli-producing E. coli	Bacterial amyloids cross-seed α-syn misfolding via molecular mimicry.	Sampson et al. (2025)
In vitro BBB model	Treatment with LPS + TMAO	LPS/TMAO activates ROS-NLRP3 inflammasome axis in brain ECs.	Helms et al. (2016)
Germ-free (GF) mice	Colonization with PD patient microbiota	Gut microbiota is necessary for α-syn-induced neuroinflammation and neurodegeneration.	Zhang et al. (2022a)
MPTP mice + PM treatment	Polymannuronic acid (PM) supplementation	PM suppresses TLR4/TNF-α signaling in both gut and brain.	Missiego-Beltrán et al. (2024)
SH-SY5Y neuronal cells	Co-culture with PD microbiota metabolites	Gut-derived metabolites (e.g., TMAO) impair mitochondrial Complex I activity.	Ioghen et al. (2024)
A53T α-syn transgenic mice	Butyrate dietary supplementation	Butyrate activates HDAC inhibition-mediated autophagy-lysosomal pathway.	Chen et al. (2015b)

Important experimental studies demonstrating the efficacy of microbiota-targeted interventions in PD models, highlighting the development of therapeutic strategies

Potential Strategies to Enhance BBB Integrity in PD

Enhancing BBB integrity has emerged as a promising therapeutic strategy for the prevention and treatment of PD. BBB dysfunction is closely associated with neuroinflammation and involves complex cellular and molecular mechanisms. The integrity of the BBB is regulated by the neurovascular unit, including ECs, pericytes, astrocytes, microglia, and oligodendrocytes, which interact through multiple signaling pathways to maintain barrier function (Takata et al. 2021). Targeting these cellular interactions and signaling networks may provide novel opportunities for preserving BBB stability and mitigating PD progression (see Table 2).

Astrocytes

Astrocytes play an important role in the maintenance of the BBB (Schiera et al. 2024). Astrocytes are intracranial pressure receptors that detect the amount of blood perfusion in the brain. Furthermore, they act as components of the NVU and secrete paracrine factors, which primarily modulate the ECs (Marina et al. 2020), and alter the BBB permeability regulator proteins (Komarova et al. 2017), thus affecting the BBB properties (Manu et al. 2023). Paracrine factors secreted by astrocytes include insulin-like growth factor (IGF-1) (Bake et al. 2016), sonic hedgehog (SHh) (Wang et al. 2014), ANG-1 (Prat et al. 2001), and retinoic acid (RA) (Mizee et al. 2014), etc., which support BBB integrity. Recent studies have found that astrocytes specifically expressing Dmp1 regulate BBB integrity via mitochondrial translocation, a process critical for preventing BBB disruption (Andjelkovic et al. 2023). The astrocyte-derived factors that promote BBB permeability include VEGF (Argaw et al. 2012), NO (Manu et al. 2023), endothelin (D’Orléans-Juste et al. 2019), and glutamate (Sharp et al. 2003). Therefore, PD can be treated by enhancing the BBB integrity by inducing astrocytes to express paracrine factors while inhibiting the production of related derived factors.

Microglia

Microglia are not directly related to the BBB; however, they can interact with cerebrovascular ECs (Bisht et al. 2021). In the adult CNS, capillary-associated microglia (CAM) interact with microvasculature (Bisht et al. 2021). Furthermore, microglia can provide the structural framework for the nascent CNS vasculature (Hikage et al. 2021) and enhance brain function through synaptic pruning (Paolicelli et al. 2011). In the pathological state, activated microglia release ROS, such as superoxide anion, and other mediators, such as MMP and inflammatory cytokines and chemokines (TNF-α, IL-1α, IL-1β, macrophage inflammatory protein-1α (MIP-1α)/CCL3, CCL2, and CXCL10), which activate ECs and disrupt BBB integrity (Bernardo-Castro et al. 2020). The polarization status of microglia significantly influences BBB integrity (Ronaldson and Davis 2020), with cells adopting a protective phenotype contributing to barrier maintenance, whereas those acquiring a pro-inflammatory phenotype may promote BBB dysfunction (Takata et al. 2021). Recent studies have validated that treatment with the novel compound Florbenzylidenehydrazine (FLZ) improves microbiota dysbiosis and protects the PD model by restoring BBB structure and inhibiting substantia nigra astrocyte and microglial activation (Zhao et al. 2021).

Pericytes

Pericytes can take up, divide, and degrade α-syn aggregates (Dieriks et al. 2022; Stevenson and Dieriks 2023). Studies have shown that in PD patients, lysosomal levels in pericytes are higher than those in healthy controls. The degradation capacity of pericytes in PD patients is reduced, suggesting that the increase in lysosomes compensates for the impaired lysosomal function (Dieriks et al. 2022; Stevenson et al. 2022). Pericytes degrade α-syn aggregates to reduce α-syn-induced neurotoxicity, thus alleviating PD (Stevenson and Dieriks 2023). Moreover, induced pluripotent stem cell (iPSC)-derived pericyte transplantation has been found to promote BBB regeneration and repair, therefore improving BBB integrity (Kim et al. 2024). In a mouse stroke model, iPSC-derived pericyte transplantation improved neurologic function and reestablished BBB integrity (Sun et al. 2020).

PD Prevention and Treatment Through Modulation of Gut Microbiota

Therapeutic strategies targeting the gut microbiota aim to restore microbial composition and function toward a healthy state. Increasing evidence linking gut microbiota dysbiosis to PD has prompted the development of microbiota-based interventions.Approaches such as probiotics, prebiotics, synbiotics, and fecal microbiota transplantation (FMT) have shown potential in alleviating gastrointestinal symptoms and, in some cases, improving motor function (Anand et al. 2022) (Fig. 3).

Fig. 3.

Therapeutic strategies for PD treatment targeting BBB repair and gut microbiota. A Astrocyte-derived paracrine factors (RA, SHh, IGF-1, ANG-1) enhance endothelial integrity. Pericyte transplantation stabilizes cerebral capillaries through structural integration (cross-sectional view). B Probiotics (Bifidobacteria, Lactic acid bacteria) exert anti-inflammatory effects. FMT involves processing donor stool, formulating it into medicaments, and delivering it via oral/gastric/enema routes. Mediterranean diet components (dietary fiber, fish-derived omega-3, whole grains, olive oil polyphenols) regulate microbial metabolite production

Microbiological Treatment

Microbiota-based therapies represent a promising approach for PD management. Probiotic interventions have shown potential in modulating inflammation and improving both gastrointestinal and neurological symptoms. For example, Lactobacillus acidophilus NCFM and Bifidobacterium lactis HN019 have been reported to reduce inflammation and ameliorate motor and non-motor symptoms in PD models (Divyashri et al. 2022). Current clinical evidence has indicated that prebiotics can modulate the immune system, promote intestinal motility, and relieve constipation, as well as provide benefits in other aspects of gastrointestinal health, suggesting their potential value in clinical applications (Alfonsetti et al. 2022). Other microbiota-targeted compounds, such as polymannuronic acid, have been shown to attenuate neuroinflammation and enhance intestinal barrier and BBB integrity in experimental PD models (Dong et al. 2020b). Similarly, specific probiotic strains, including Lactobacillus rhamnosus E9, have demonstrated beneficial effects on motor function and intestinal barrier integrity through modulation of gut microbiota (Aktas et al. 2024). Collectively, these findings support the therapeutic potential of microbiota-based interventions in PD, although further clinical validation is required.

Fecal Microbiota Transplantation

FMT has emerged as a promising strategy for modulating gut microbiota in PD. By restoring microbial composition, FMT promotes the production of beneficial metabolites, such as short-chain fatty acids and branched-chain amino acids (BCAAs), which may exert neuroprotective effects (Chu et al. 2023). Furthermore, FMT modifies the gut’s microbial makeup to improve dysbiosis in individuals with PD, possibly reducing systemic and neuroinflammation while providing neuroprotective advantages (Yang et al. 2023). Moreover, it significantly improves gut microbial metabolic disorders and reduces intestinal inflammation and barrier disruption in a mouse PD model by introducing the gut microbiota of a healthy donor into the patient (Zhao et al. 2021).

FMT attenuates BBB disruption, reduces microglia and astrocyte activation in the substantia nigra striata region, and inhibits neuroinflammatory responses (Hu et al. 2023). At the molecular level, it inhibits the TLR4/TNF-α signaling pathway in the gut and brain, thus delaying neurodegenerative processes (Zhao et al. 2021). Furthermore, it has a protective effect on dopaminergic neurons and increases DA and 5-HT levels in the striatum, which is crucial for improving PD symptoms and quality of life in these patients (Zhang et al. 2022b). Recently, a clinical trial validated the efficacy of FMT in treating PD, which demonstrated its effectiveness in ameliorating motor symptoms and constipation in PD patients, marking the first randomized, double-blind, placebo-controlled study of FMT (Kragsnaes et al. 2021). However, further studies are required to determine the specific microbial components responsible for these effects and to establish its long-term safety and efficacy.

Diet Quality

Epidemiological evidence suggests that dietary patterns influence the risk of neurodegenerative diseases, including PD. Recent studies have highlighted associations between higher diet quality and a reduced risk of PD (Kwon et al. 2024).In contrast, suboptimal dietary patterns commonly observed in PD patients are characterized by low fiber intake and increased consumption of added sugars (Kwon et al. 2024).

Among dietary patterns, the Mediterranean diet and the Mediterranean–DASH Intervention for Neurodegenerative Delay (MIND) diet have attracted considerable attention. The Mediterranean diet, which is rich in fruits, vegetables, fish, and olive oil, has been associated with a lower risk of PD, potentially due to its anti-inflammatory and antioxidant properties (Su et al. 2025; Strikwerda et al. 2021). Similarly, the MIND diet, which emphasizes green leafy vegetables, berries, nuts, fish, and olive oil, has been linked to reduced PD risk. Higher adherence to the MIND diet has been associated with a decreased risk of PD, with studies reporting an approximate 13% risk reduction per unit increase in diet score (Knight et al. 2022). This further suggests that the risk of PD can be effectively reduced by optimizing the diet.

The gut microbiota composition in PD patients significantly differs from that of healthy controls. A healthy diet can improve intestinal microecology by regulating gut microbiota composition; increasing the abundance of beneficial bacteria, and decreasing harmful bacteria, improving the gut microbiota (Kwon et al. 2024). Furthermore, a healthy diet can reduce inflammatory factors and systemic inflammation, delaying PD progression (Kwon et al. 2024). Higher dietary fiber intake is associated with increased anti-inflammatory bacteria, whereas increased added sugar intake enhances pro-inflammatory bacteria (Kwon et al. 2024). A diet that improves gut health may reduce gastrointestinal symptoms, improve quality of life, and even slow disease progression in PD patients.

Conclusions

This review summarizes the association of the BBB and gut microbiota with the onset and progression of PD. Recent studies highlight BBB dysfunction as a critical factor in PD pathogenesis. As a protective barrier for the brain, the BBB prevents harmful molecules from entering the CNS; however, its integrity is impaired in PD patients. This disruption allows neurotoxins and macromolecular proteins from circulating blood to penetrate the brain, thus stimulating inflammatory and immune responses that exacerbate PD. Furthermore, gut microbiota dysbiosis significantly impacts BBB integrity and function. Altered gut microbiota may mediate BBB dysfunction through inflammatory mediators and metabolites, accelerating PD development. Modulating gut microbiota and restoring BBB integrity thus represent novel therapeutic strategies for PD. In summary, both the BBB and gut microbiota are crucially involved in PD progression. Enhancing BBB integrity and correcting microbial dysbiosis could provide new avenues for PD prevention and treatment. Future research should elucidate the mechanisms underlying these interactions to develop effective therapies that delay disease progression and improve patients’ quality of life.

Future research should prioritize translating these mechanistic insights into clinical applications using advanced models (e.g., human brain organoids, gnotobiotic animals) to identify the most therapeutically tractable signals within the BBB-gut axis, such as specific microbial metabolites, miRNAs, or pro-angiogenic factors like VEGF. The integration of gut microbiota characterization, neuroimaging of BBB integrity, and individual genetic information is crucial for formulating personalized intervention strategies, transcending a uniform approach to PD therapy.

It is important to acknowledge the limitations inherent in this field. Most information supporting the BBB-gut axis in PD is derived from preclinical models, necessitating meticulous validation for applicability to human pathology. Establishing definitive causal associations and temporal sequences in humans requires extensive longitudinal cohort research and well-designed interventional trials. The considerable inter-individual heterogeneity in the gut microbiota, shaped by diet, medication, and environment, is significantly challenging for the development of standardized biomarkers or therapies, highlighting the necessity for classification and individualization.

Author Contributions

Li Liu, Li Rong Jiang, Yang Yu, Wei Dong conceived and designed the project. Wanyu Yao, li Liu, Jiaxin Wang, Shanshan Chen, Chaofan Zhang drafted the manuscript. Ruiyi liao, Yiwei Wang, Kunling Ou designed the figure. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.

Funding

This study was supported by funding from the Open Fund of Key Laboratory of Medical Electrophysiology (Grants KeyME-2025-07) and the Luzhou Science and Technology Department Applied Basic Research program (2024JYJ011, 2025JYJ089).

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

All the authors declare that they have no conflicts of interest.