Gut Permeability and Microbiota in Parkinson’s Disease: Mechanistic Insights and Experimental Therapeutic Strategies

As a prevalent neurodegenerative disorder, Parkinson's disease (PD) predominantly occurs in people over sixty years of age, with roughly one percent of this population affected. Throughout North American populations, the disorder appears in about 572 individuals per 100,000, although specific rates differ based on regional and demographic characteristics [1]. Emerging evidence indicates that PD involves a more complex pathophysiology than previously understood, which includes roles for intestinal permeability and the gut microbiome, moving beyond its traditional characterization as a disorder of motor symptoms caused by dopaminergic neuron loss. The association between intestinal disorders and PD has long been established. Growing clinical data support a bidirectional relationship between gastrointestinal (GI) inflammation and neurodegeneration, aligning with the concept of the 'gut–brain axis'. There are two main models of the origin of PD, the brain-first and body-first hypothesis, according to the supposed initiation of α-synuclein aggregation. Braak's hypothesis, as the representative body-first hypothesis observed α-syn aggregation in the stomach and lower esophagus of patients with PD but not in those without PD [2]. Supporting this, animal studies have shown that duodenal and pyloric injected α-syn preformed fibrils (PFF) can travel to the brain via the vagus nerve, leading to symptoms like PD, such as motor issues and cognitive decline. The spread of α-synucleinopathy from the gut to the brain can be severed by truncal vagotomy [3]. Vagotomy reduces but does not completely eliminate PD-like pathology, suggesting other contributing mechanisms or pathways. PD patients exhibit non-motor symptoms (e.g., constipation, depression, cognitive decline) that may arise from peripheral pathology (e.g., Enteric Nervous System dysfunction) or brain regions unaffected by vagal spread [4]. Increased intestinal permeability ("leaky gut") plays a critical role by allowing toxins and pathogens to enter the bloodstream, which may exacerbate neurodegenerative processes. A recent study supports the hypothesis that PD originates in the gut. Analysis of 9350 patients undergoing upper GI endoscopic biopsy revealed a 76% increased risk of PD associated with GI mucosal damage, including erosion, rupture, or ulceration. Notably, GI symptoms often precede motor symptoms and PD diagnosis by over a decade [5], with recent evidence linking upper GI mucosal damage to an increased long-term risk of PD, underscoring the gut's potential role in prodromal disease. Further recent reviews have expanded on this idea, emphasizing that the gut–brain axis and/or microbiota–gut–brain axis—including microbial metabolites, immune activation, and barrier impairment—may be key drivers of initiating and perpetuating neurodegenerative processes, including PD [6] (Figure 1) Paracellular leakage is a direct consequence of impaired tight junction function. Key players in this dysfunction include transmembrane proteins (e.g., claudins, occludins) and their cytoplasmic partners (e.g., ZO-1/ZO-2), whose disruption leads to intestinal hyperpermeability [7]. This condition is influenced by both genetic factors and environmental elements, which include diet and toxins [8,9]. Various factors contribute to increased intestinal permeability. An unhealthy diet, especially pro-inflammatory substances like refined carbohydrates, gluten, added sugars, can greatly elevate the risk of leaky gut [10]. Additionally, environmental factors that may influence gut health include external stressors such as additives, preservatives, heavy metals, and other chemicals and toxins, along with chronic stressors such as sleep disorders, smoking, and alcohol abuse [11,12].

A healthy intestinal barrier is essential for preventing systemic inflammation, which is linked to various health issues, including PD [13]. The importance of personalized therapy, particularly through gut microbiome engineering and stem cell transplantation, is increasingly being recognized as a promising strategy for establishing gut microbial homeostasis, restoring gut integrity, and enhancing neurological health. In parallel, induced pluripotent stem cell-based therapies (iPSCs) are gaining traction for their dual potential to replace lost dopaminergic neurons and model patient-specific disease mechanisms, offering another avenue for personalized intervention in PD [14,15]. Individualized interventions targeting the gut microbiome may alleviate inflammation and improve neurological outcomes. This review aims to synthesize current insights into the relationship between gut health, blood–brain barrier (BBB) permeability, and PD, highlighting how compromised barriers contribute to neurodegeneration and emphasizing the need for innovative, personalized treatment strategies to improve patient outcomes and quality of life (Figure 1).

The intestinal barrier is a complex and specialized structure made up of several key components that function synergistically to maintain gut homeostasis and provide protection against harmful substances (Figure 2). The epithelium serves as the crucial boundary separating the gut lumen from the body's internal milieu and is composed of a single sheet of varied columnar cell types, including enterocytes, goblet cells, and Paneth cells [7]. This diverse cellular composition is crucial for facilitating various gut functions, including nutrient absorption, digestive enzyme secretion, and immune responses [16]. Tight junctions form secure connections between these cells, critically controlling paracellular permeability. This regulation is essential as it permits the selective passage of certain molecules while simultaneously acting as a barrier against pathogens and toxins. These structures are composed of proteins such as occludin, claudins, and zonula occludens protein 1 (ZO-1), which can be modulated by various physiological and pathological stimuli [17]. Dysregulation of tight junctions—often triggered by pro-inflammatory cytokines (e.g., TNF-α, IL-6), gluten peptides, or elevated zonulin—leads to a state of increased intestinal permeability, commonly referred to as "leaky gut." This breach facilitates the translocation of microbial metabolites, lipopolysaccharides (LPS), and misfolded proteins (e.g., α-synuclein) into the systemic circulation, which in turn drives neuroinflammation and microbiota remodeling, thereby disturbing the gut–brain axis [18,19,20,21,22] (Figure 2). Such mechanisms underscore the intestinal barrier's pivotal role in both gastrointestinal and neurological health.

Covering the epithelial layer is a thick, stratified mucus layer that acts as the first line of defense against luminal contents. This mucus layer is primarily composed of mucins, which are high-molecular-weight glycoproteins secreted by specialized epithelial cells known as goblet cells (Figure 2). Mucins provide a viscous barrier that traps harmful substances and contributes to the lubrication of the intestinal surface, facilitating the passage of luminal contents [23]. Mucus composition varies regionally: the stomach and colon exhibit dense, continuous layers for mechanical protection, while the small intestine maintains a thinner layer to optimize nutrient absorption [24]. This mucus is enriched with antimicrobial peptides (AMPs, e.g., Paneth cell-derived α-defensins, lysozyme, Reg3 proteins) and secretory IgA, which neutralize pathogens and block epithelial adherence, respectively [25,26]. Beneath this layer lies the gut-associated lymphoid tissue (GALT), a network of immune hubs including Peyer's patches (PPs) and isolated lymphoid follicles [27]. PPs, concentrated in the ileum, feature B-cell follicles, T-cell zones, and follicle-associated epithelium lined with M cells that sample luminal antigens to initiate adaptive immunity [28,29].

Despite these defenses, the intestinal barrier remains vulnerable to disruption through a few main mechanisms: (1) Epithelial damage: Transient breaches caused by enterocyte apoptosis or injury (e.g., infections, toxins) are rapidly repaired in healthy individuals. However, in individuals with allergies or infections and chronic damage (e.g., in celiac disease or inflammatory bowel disease), the body's repair mechanisms cannot keep pace with the damage, leading to intestinal contents leaking out and causing a condition known as leaky gut [30]. (2) Certain destructive proteins like gluten directly damage enterocytes or mimic the structure of enterocyte receptors, binding to the cell surface receptor such as CXCR3 and inducing tight junction disassembly [31]. Although some proteins may block normal receptor–carrier interactions, impairing nutrient absorption and barrier integrity [32]. (3) Intestinal cells form tight junctions composed of various proteins that are not permanently solid but can toggle between open and closed states. Disruption of this regulation can result in health issues [33]. One key regulator is zonulin, which is upregulated by gluten exposure in genetically susceptible individuals, triggering tight junction disassembly and paracellular leakage [8,34]. Elevated zonulin levels correlate with conditions like celiac disease and PD, linking gut permeability to systemic inflammation and neurodegeneration. A molecule is critical for opening tight junctions and supporting immune system function.

The intestinal barrier's integrity relies on synergistic interactions between epithelial cells, tight junctions, mucus, and GALT. Dysregulation at any level via genetic susceptibility, environmental triggers (e.g., gluten) [9], or microbial dysbiosis, which compromises gut homeostasis, fostering systemic inflammation and neuropathology. Targeting these mechanisms offers therapeutic potential for diseases rooted in gut–brain axis dysfunction, such as PD.

The integrity of the intestinal epithelial barrier is dependent on tight junction proteins. The dysregulation of these structures, often mediated by pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and aberrant immune cell activity, leads to a pathological increase in permeability, clinically described as "leaky gut." [35,36]. Studies suggest that TNF-α suppresses tight junction barrier function via NF-kB (Nuclear factor kappa B) pathway activation, leading to decreased levels of the tight junction protein ZO-1 [37]. The compromised integrity of the tight junction barrier, leading to increased permeability, results from the downregulation of key proteins. Research using Caco-2 cell models has demonstrated that NF-kB-mediated tight junction disruption is associated with elevated expression and activity of myosin light chain kinase (MLCK). The MLCK gene's promoter harbors a binding site for NF-κB. Through its activation, TNF-α can stimulate the promoter, enhancing MLCK transcription. This process ultimately leads to increased permeability of tight junctions [38,39]. IL-1β, on the other hand, increases tight junction permeability through the activation of the NF-κB pathway, mirroring the effects of TNF-α. Yet the differences are notable. While IL-1β activates MLCK through the extracellular signal-regulated kinases 1/2 (ERK1/2) signaling pathways, it does not affect the ZO-1 protein level as TNF-α does. Instead, IL-1β treatment results in the suppression of occludin, another critical tight junction protein [40].

This increased permeability permits the translocation of luminal antigens, bacteria, and their products, such as LPS, into the systemic circulation. Such translocation can trigger systemic inflammation, fostering the emergence of inflammatory bowel disease (IBD) and metabolic disorders [41,42]. In patients with IBD, altered intestinal permeability is often observed even in asymptomatic individual years before clinical symptoms manifest. For instance, a study reports increased paracellular permeability in patients with quiescent IBD usually exhibit increased paracellular permeability, suggesting that permeability changes can occur independently of overt inflammation [43]. When the mucus layer is compromised due to dysbiosis or inflammation, its protective function diminishes, leading to greater exposure of epithelial cells to harmful substances. This exposure can exacerbate permeability issues initiated by tight junction disruption, allowing pathogens to penetrate more easily and further aggravating inflammation.

Changes in the makeup and density of the intestinal mucus barrier play a critical role in modulating gut permeability. One notable example involves reduced expression of the mucin protein MUC2, which has been closely linked to heightened intestinal leakage. MUC2 is essential for forming a protective mucus gel layer [44], when its synthesis and secretion are decreased, gut microbiota come into direct contact with the epithelial barrier, which results in a greater number of bacteria attaching to the epithelium, highlighting the essential function of MUC2 in preserving the integrity of the mucosal barrier [45].

Additionally, the mucus layer is influenced by the gut microbiota, which produces metabolites that enhance mucin production and support barrier integrity. Pathogenic bacteria, such as enteropathogenic E. coli (EPEC), Citrobacter rodentium, and Salmonella typhimurium, can disrupt the protective mucus barrier, leading to dysbiosis characterized by decreased Firmicutes and Verrucomicrobia, alongside increased Bacteroidetes and facultative anaerobes, which can adhere to or invade host epithelial cells beneath the mucus layer, further exacerbating inflammation [46]. When the epithelial barrier is compromised, gut-associated lymphoid tissue (GALT) becomes activated, resulting in the release of additional pro-inflammatory cytokines. While this immune response is crucial for combating pathogens, chronic activation can perpetuate inflammation and further disrupt tight junction integrity. The interplay between the immune system and the intestinal barrier is critical, as sustained inflammation can create a cycle where increased permeability triggers immune activation, which in turn causes more damage to the epithelial barrier. The dysregulation of particular immune populations, including T helper 17 (Th17) cells and their cytokines IL-17 and IL-22, plays an important role in disrupting tight junctions and increasing permeability. Th17 cells can dysregulate tight junction protein expression, resulting in compromised barrier integrity. This disruption can create a feedback loop, increased permeability triggers further immune activation, exacerbating intestinal inflammation [47]. On the other hand, IL-17 has been associated with increased gut permeability, as demonstrated by studies where researchers neutralized IL-17 in animal models, leading to heightened intestinal permeability [48].

The passage of harmful substances (e.g., bacterial toxins) from the intestines into the bloodstream, a consequence of increased gut permeability, can initiate a systemic inflammatory response. This mechanism has been associated with the pathogenesis of both PD and IBD. Emerging research underscores the pivotal role of genetic susceptibility factors, such as LRRK2 (leucine-rich repeat kinase 2) variants, which are strongly associated with both PD and IBD [49,50]. LRRK2 mutations may disrupt gut homeostasis, leading to increased permeability and systemic inflammation, which could contribute to the progression of PD via the gut–brain axis [51]. Mutations in the LRRK2 gene, particularly the G2019S and N2081D variants, are the most common genetic contributors to PD and have also been linked to increased incidence of IBD [52]. These shared genetic risks highlight overlapping pathophysiological pathways involving gut–brain axis dysregulation. Higher levels of LRRK2 have been detected in inflamed colonic tissue from Crohn's disease patients and peripheral immune cells from sporadic PD patients, suggesting that LRRK2 plays a key role in regulating inflammatory processes. Additionally, genome-wide association studies have identified LRRK2 as a common susceptibility locus for both conditions, emphasizing its involvement in immunity, inflammation, and autophagy-related pathways [53]. Recent studies have increasingly altered gut permeability as a mechanistic nexus in diverse conditions, including IBD, metabolic disorders, and neurodegenerative diseases. Heightened gut permeability facilitates the translocation of luminal antigens (e.g., LPS, misfolded α-synuclein) into the systemic circulation, triggering immune activation and autoimmune responses. In PD, such breaches in barrier integrity may exacerbate neuroinflammatory processes by allowing neurotoxic substances to infiltrate the central nervous system (CNS), thereby accelerating the degeneration of dopaminergic neurons.

In addition to the role of LRRK2, the integrity of the intestinal barrier may also be compromised by various other genetic mutations and environmental factors, thereby increasing the risk of PD development. PINK1 and PRKN, two genes involved in mitochondrial quality control and mitophagy, are also associated with early-onset PD symptoms [54]. Loss-of-function mutations in these genes impair mitochondrial homeostasis in intestinal epithelial cells, rendering them more susceptible to oxidative stress and apoptotic signaling, which can weaken the epithelial barrier [55,56]. Recent study using PINK1-deficient mouse models have provided compelling evidence that mitochondrial dysfunction can initiate PD-related pathology through the gut. Loss of PINK1 impairs the clearance of damaged mitochondria, leading to the release of mitochondrial DAMPs that activate innate immune pathways, including NF-κB and the NLRP3 inflammasome [57]. In a PD mouse model triggered by Citrobacter rodentium infection, PINK1 knockout mice exhibited exaggerated innate immune activation and upregulation of pro-inflammatory cytokines (e.g., TNF-α, IL-1β). This dysregulated environment promoted robust activation of T cells, which in turn amplified epithelial stress through cytokine secretion, notably IFN-γ and IL-17A. These cytokines are known to disrupt tight junction proteins and weaken epithelial integrity, leading to increased intestinal permeability [58]. These findings suggest that mitochondrial dysfunction may directly or indirectly compromise intestinal epithelial integrity, thereby creating a permissive environment for systemic inflammation and neurodegeneration via the gut–brain axis. Elucidating the interplay between LRRK2-mediated pathways, mitochondrial dysfunction, gut permeability, and neuroinflammation is critical for identifying novel therapeutic targets to disrupt disease progression in both PD and IBD.

Intestinal permeability allows harmful substances like bacteria, toxins, or inflammatory molecules to enter the bloodstream, triggering systemic inflammation that can exacerbate neuroinflammation. This inflammation may compromise the BBB, which normally protects the brain from harmful agents. Converging experimental and clinical data support a link between increased intestinal permeability and compromised BBB integrity, largely mediated by gut microbiota dysbiosis and its downstream effects. For example, increased BBB permeability has been observed in mouse models of colitis induced by DSS or TNBS, as well as in models of antibiotic-induced dysbiosis [59,60,61,62]. Germ-free mice display heightened BBB permeability accompanied by reduced tight junction proteins (occludin, claudin-5), a phenotype reversed by microbiota colonization [63]. In vitro, gut-derived LPS induces endothelial injury via microglial activation [64]. In humans, elevated plasma markers of gut (zonulin, LPS) and BBB (claudin-5) permeability correlate with psychiatric disorders [65], suggesting that gut barrier dysfunction facilitates translocation of microbial products that drive neuroinflammation and BBB breakdown [66]. The breakdown of the BBB has profound pathological consequences that significantly contribute to neurodegenerative diseases such as PD and Alzheimer's disease (AD) [67,68]. When BBB integrity is compromised, neurotoxic molecules, immune cells, and inflammatory mediators infiltrate the CNS, disrupting neurotransmitter balance and impairing synaptic function. Pro-inflammatory cytokines such as TNF-α and IL-1β have been shown to weaken BBB tight junctions, leading to increased permeability [69]. Furthermore, the BBB restricts the transport of neurotrophic factors (e.g., Brain-Derived Neurotrophic Factor, Neurotrophin-3, and Nerve Growth Factor), which are essential for neuronal survival and plasticity. The influx of harmful substances into the brain can lead to direct neuronal injury as well. Research has shown that exposure to blood-derived factors promotes neuroinflammation and tissue injury that can lead to neuronal death [70], contributing to the progressive loss of neuronal populations characteristic of neurodegenerative diseases [71]. Ultimately, these processes lead to neuronal death. This is exacerbated by chronic inflammation resulting from BBB dysfunction, which initiates a cascade of mitochondrial damage, oxidative stress, and neurovascular disruption that accelerates neurodegeneration [72]. However, the precise pathways vary by disease stage and remain under active investigation.

Interestingly, the intestinal epithelial barrier (IEB) and BBB share significant structural and functional similarities, particularly in their reliance on tight junction proteins such as ZO-1, claudin-5, and occludin [73]. Both barriers regulate selective permeability, protecting their respective environments while permitting the transport of essential nutrients and molecules. Emerging evidence suggests that inflammatory mediators known to disrupt the intestinal barrier, including TNF-α, IL-1β, zonulin, IFN-γ, and IL-17A, may also compromise BBB integrity through analogous mechanisms, although direct evidence in PD is still developing [38,69,73]. This establishes a plausible connection between leaky gut syndrome and PD, whereby compromised BBB function could exacerbate neuroinflammatory and neurodegenerative processes. A study by Rahman et al. [73] further supports this connection, demonstrating that exposure to zonulin, IFN-γ, or IL-17A rapidly alters the localization of tight junction proteins, including ZO-1 and Claudin-5, in both barriers. This process involves a rapid disassembly of tight junctions and significant depolymerization of the peri-junctional F-actin cytoskeleton [73]. Further, both barriers show increased permeability to a fluorescein isothiocyanate (FITC)-dextran tracer within 1 h of exposure to these mediators, highlighting the rapid and significant impact on barrier function [73]. Given these shared mechanisms, alterations in IEB permeability due to inflammatory processes may similarly affect BBB integrity. This establishes a logical connection between leaky gut syndrome and PD, as compromised BBB function can exacerbate neuroinflammatory and neurodegenerative processes. Obviously, in PD, particularly in individuals with LRRK2 mutations, this dual barrier dysfunction amplifies the transport of pro-inflammatory signals and potentially misfolded proteins, such as alpha-synuclein, from the gut to the brain [3], thereby promoting neuronal damage and disease progression. Thus, it is hypothesized that dual barrier dysfunction may create a vicious cycle, potentially amplifying the transfer of inflammatory signals and misfolded α-synuclein from the periphery to the brain.

In Parkinson's disease (PD), a destructive feedback loop can emerge where increased permeability of both the gut barrier and the blood–brain barrier (BBB) mutually exacerbate neuroinflammation and accelerate neuronal loss. Gut dysbiosis, an alteration of gut microbial homeostasis, can disrupt the BBB, allowing harmful substances and inflammatory molecules to enter the brain and trigger neuroinflammation and neuronal damage [63,74,75]. Increased intestinal permeability and gut microbiota dysbiosis are closely interconnected in a bidirectional relationship that contributes to numerous inflammatory and metabolic diseases. Dysbiosis is a state of microbial imbalance defined by a decline in beneficial bacteria and a concomitant proliferation of potentially harmful pathobionts. Under these conditions, epithelial barrier function is weakened through diminished short-chain fatty acids (SCFAs), impaired tight-junction protein expression, and promotion of pro-inflammatory mediators such as LPS [16,42,74,76,77]. This leads to increased permeability of the gut lining, allowing microbial products to translocate into systemic circulation and trigger immune activation. Conversely, a compromised intestinal barrier further exacerbates dysbiosis by altering the gut environment, promoting inflammation, and impairing host-microbe signaling. Increased intestinal permeability, also known as "leaky gut," involves the weakening of the intestinal lining. This breakdown enables the passage of harmful substances—including bacterial toxins, microbial fragments, and undigested dietary compounds—into the systemic circulation. This condition is fundamentally connected to an imbalance in the gut's microbial community. This state of dysbiosis disrupts the ecosystem's normal function, resulting in a dysregulated immune response and subsequent inflammatory processes [42]. Dysbiosis degrades protective mucus layers, weakens tight junctions between epithelial cells, and triggers the release of pro-inflammatory cytokines (e.g., TNF-α, IL-6), thereby exacerbating intestinal permeability [16]. Consequently, these interconnected processes can initiate systemic inflammation and are implicated in the pathogenesis of autoimmune disorders (e.g., IBD), metabolic diseases (e.g., type 2 diabetes), and neurological conditions. While research continues to elucidate causal relationships, therapeutic strategies targeting microbiota restoration (e.g., probiotics, dietary fiber) show promise in mitigating both dysbiosis and barrier dysfunction. The vicious cycle of barrier disruption and microbial imbalance underlies conditions such as IBD, obesity, and neurodegenerative disorders, and highlights the gut barrier as a key therapeutic target [7].

Research consistently demonstrates that heightened intestinal permeability correlates with reduced populations of beneficial gut bacteria, underscoring the microbiome's critical role in gut health. Dysbiosis directly impacts immunity, as gut microbiota regulates about 10% of genes linked to immune and metabolic functions in intestinal epithelial cells [78]. For example, Cani et al. (2008) observed that mice on high-fat diets exhibited increased permeability alosngside diminished Lactobacillus and Bifidobacterium, enabling LPS translocation into the bloodstream, triggering systemic inflammation and insulin resistance [79]. This synergy between dysbiosis and barrier dysfunction exacerbates metabolic disorders. Further elucidating this interplay, Liu et al. (2023) revealed that Akkermansia muciniphila depletion in mice elevated permeability and inflammation, while its restoration via diet improved barrier integrity [80]. Notably, strain-specific effects of Akkermansia were tied to functional genes governing surface protein synthesis [80]. Human studies are not fully consistent, but meta-analyses generally report increased Akkermansia in PD rather than decreases. These discrepancies likely stem from variables like disease stage, geography, diet, medications (e.g., levodopa), or methodological differences. Complementing these insights, Bifidobacterium strains (e.g., B. bifidum) enhance tight junction proteins via PPAR-γ pathway activation [81], reinforcing that microbial diversity is essential for barrier resilience. On the contrary, in the context of gut microbiota dysbiosis, probiotics have shown considerable promise in enhancing intestinal barrier function. Specific probiotic strains, such as Bifidobacterium breve CNCM I-5644, have demonstrated the ability to prevent intestinal hyperpermeability by upregulating tight junction proteins and reducing pro-inflammatory markers in both in vitro studies and animal models of IBS [82]. For example, research has indicated that this strain can enhance the expression of cingulin and tight junction protein 1 in gut barrier-compromised mouse models to maintain tight junction integrity [82]. However, this study does not suggest that CNCM 1-5644 would exhibit similar efficacy in the human intestinal environment.

Further research, including clinical trials, is required to investigate the probiotic's ability to establish and maintain a stable colony in the human gut and its therapeutic potential and safety in human subjects. On the clinical side of the research, a randomized controlled trial investigated the effects of a multi-strain probiotic mixture, including Lactobacillus paracasei HII01, Bifidobacterium breve, and Bifidobacterium longum, on various health parameters in elderly participants. The study found that supplementation with these probiotics significantly improved intestinal barrier function, enhancing permeability by up to 48%. Additionally, the intervention led to a notable increase in high-density lipoprotein (HDL) cholesterol levels and improved obesity-related anthropometric measurements and SCFA levels. Although this study does not specifically investigate PD, its findings on increased intestinal permeability suggest that probiotic supplementation could potentially contribute to improvements in PD by enhancing gut barrier function and dampening systemic inflammation [83].

Increased intestinal permeability initiates a series of events that contribute to neuroinflammation. Disruption of the gut barrier leads to microbiota dysbiosis, triggering chronic inflammation and the release of pro-inflammatory cytokines. These inflammatory signals and microbial byproducts enter circulation, affecting the CNS and contributing to the neuroinflammation processes. PD is increasingly linked to gut microbiota dysbiosis, characterized by altered microbial composition, such as reduced Prevotella and Faecalibacterium and increased Enterobacteriaceae, which may contribute to disease pathology via the gut–brain axis. Dysbiosis can enhance gut permeability, leading to systemic inflammation and potentially promoting misfolded alpha-synuclein propagation from the gut to the brain through the vagus nerve, exacerbating neuroinflammation and motor symptoms [79]. Gastrointestinal symptoms like constipation often precede PD diagnosis, supporting early gut involvement [84]. Microbial metabolites, such as SCFAs, may modulate dopamine metabolism and immune responses, influencing PD progression [85].

Altered intestinal permeability sets the stage for gut microbiota dysbiosis, where the natural balance of beneficial and harmful bacteria is disrupted. This dysbiosis can initiate a cycle of inflammation that not only affects the gut but also has systemic implications. As the gut's barrier function deteriorates, inflammatory signals and microbial byproducts can enter the bloodstream, influencing the CNS (Figure 2). Over time, this continuous state of dysbiosis and inflammation may contribute to the neurodegenerative processes seen in PD. Tight junction components—such as occludin, claudins, and junctional adhesion molecules (JAMs)—play essential roles in maintaining barrier function. Alterations in the expression of claudin-1, claudin-3, and claudin-5, all key sealing proteins, or the upregulation of pore-forming claudin-2, can significantly alter paracellular permeability [86]. Notably, a critical player in this process is the tight junction protein ZO-1, which regulates both intestinal and BBB integrity. Dysfunction of ZO-1 disrupts the tight junctions between epithelial cells in the gut and endothelial cells in the brain's vasculature, effectively weakening these barriers (Figure 2). This loss of structural integrity may enable the uncontrolled passage of harmful substances, leading to neuroinflammation and oxidative stress, alongside α-synuclein misfolding and aggregation—key features of PD pathology. The resulting leakage of inflammatory signals and microbial components into the brain underscores a vital link between leaky gut and PD pathogenesis (Figure 2). The sustained inflammatory response can accelerate dopaminergic neuron degeneration in the substantia nigra, exacerbating motor and cognitive symptoms characteristic of PD. Additionally, microbial metabolites and systemic inflammation may impair mitochondrial function and protein homeostasis, further amplifying neuronal vulnerability. Understanding these links is crucial for unraveling how disturbances in gut health may drive or exacerbate Parkinson's pathology.

Dysbiosis caused by gut barrier dysfunction critically influences the CNS through the gut–brain axis, altering neurotransmitter metabolism and amplifying neuroinflammatory pathways. Clinical and translational studies consistently report that patients with PD exhibit significant changes in gut microbiota composition compared to healthy controls, characterized by depletion of anti-inflammatory taxa and expansion of pro-inflammatory species. An early human study conducted by Petrov et al. (2016) reported that PD patients had a marked reduction in beneficial bacteria like Faecalibacterium prausnitzii and members of the Lachnospiraceae family, which are known key butyrate producers with anti-inflammatory properties [87]. In contrast, a meta-analysis of ten 16S microbiome datasets highlights the unexpected enrichment of Akkermansia and Bifidobacterium, typically beneficial probiotics and raises questions about their role in PD pathology. While Akkermansia is known to support gut barrier integrity and Bifidobacterium have anti-inflammatory properties, their presence in a pro-inflammatory PD microbiome suggests a potential compensatory response or an altered function in disease conditions. These findings underscore the complexity of gut microbial dynamics in PD and the need for further investigation into their mechanistic role [88]. Gastrointestinal symptoms, such as constipation and dysbiosis, frequently manifest before cognitive impairment in PD, suggesting that gut health could be an early marker of disease progression. A clinical analysis by Jones et al. explored the relationship between the frequency of GI symptoms and PD progression. Their findings revealed that nearly 70% of PD patients reported GI issues. Moreover, a significant correlation (p < 0.01) was identified between the severity of GI symptoms and motor symptoms in PD patients, indicating that as GI disturbances intensify, motor symptoms also worsen [89]. This highlights a potential link between gut health and motor function in PD.

The mouse model study by Sampson et al. [90] demonstrates that gut microbiota plays a critical role in regulating motor deficits and neuroinflammation in a mouse model of PD. Using Thy1-α-Syn (ASO) mice that overexpress α-Syn, the study demonstrated that gut microbiota is essential for the manifestation of standard motor deficits, including impaired performance on tasks like beam walking, pole climbing, sticky tape removal, and reflexive hindlimb clasping. Germ-free ASO mice exhibited significantly reduced motor deficits compared to their conventionally raised counterpart. Interestingly, Germ-free ASO mice also displayed less α-Syn aggregation in brain regions like the caudoputamen and substantia nigra, which are affected in both the mouse model and human PD. The study also showed that giving germ-free mice certain microbial metabolites by mouth triggered neuroinflammation and motor deficits, indicating that signals originating in the gut can directly impact brain function. Moreover, when ASO mice were colonized with microbiota derived from PD patients, motor impairment was exacerbated relative to mice receiving healthy-donor communities, indicating that PD-linked dysbiosis can influence disease progression. These findings provide compelling evidence that alterations in gut microbiota may profile as potential modifiers of PD course and highlight gut–brain crosstalk in the pathogenesis of neurodegenerative disorders [90].

Parkinson's disease treatment encompasses a range of approaches aimed at managing symptoms and potentially slowing progression, including pharmacological therapies like levodopa/carbidopa, dopamine agonists, and MAO-B inhibitors for motor symptom relief; surgical options such as deep brain stimulation (DBS) for advanced cases; non-pharmacological interventions like physical, speech, and occupational therapies to enhance mobility and quality of life; and emerging therapies such as gene therapy, stem cell therapy, probiotics (microbiota), immunotherapy targeting alpha-synuclein, and focused ultrasound, which are under investigation for neuroprotection or disease modification, alongside lifestyle interventions like diet and cognitive behavioral therapy for holistic management [91]. The following discusses the more detailed potential approaches.

This review highlights the growing recognition of intestinal barrier dysfunction and microbiota dysbiosis as central contributors to Parkinson's disease (PD) pathogenesis. Disruption of tight junctions and degradation of the mucus layer—driven by pro-inflammatory cytokines such as TNF-α and IL-1β—compromises epithelial integrity, allowing microbial products, like lipopolysaccharide (LPS), to enter the systemic circulation. This, in turn, drives chronic inflammation, promotes α-synuclein aggregation, and accelerates dopaminergic neurodegeneration through the gut–brain axis. Microbial shifts further exacerbate this cycle. Reductions in beneficial taxa, such as Faecalibacterium prausnitzii, Lachnospiraceae, and Bifidobacterium breve, alongside altered levels of Akkermansia muciniphila, may weaken barrier function and reduce anti-inflammatory signaling. Meanwhile, the increased abundance of pro-inflammatory genera like certain Bacteroidetes and facultative anaerobes has been associated with greater permeability and immune activation. Yet, the role of specific taxa remains inconsistent across studies, and the precise microbial drivers of gut dysfunction in PD are still unclear.

A key unanswered question is which microbial taxa and functional metabolites are most protective of gut barrier integrity in PD and how their loss contributes to disease onset and progression. To address this, several future directions should be pursued. Longitudinal studies incorporating microbiome sequencing and untargeted metabolomics across disease stages are essential for identifying consistent microbial and metabolic alterations. Mechanistic studies will be essential for understanding how microbial-derived metabolites, especially SCFAs, and the effects of immune mediators influence intestinal permeability, α-synuclein pathology, and neuroinflammation. These insights should inform human clinical trials aimed at evaluating whether targeted dietary interventions, probiotic supplementation, or microbial metabolite restoration can improve gut barrier function and PD symptomatology.

Equally important is the integration of genetic stratification into therapeutic design. Understanding how specific genetic variants modulate responses to microbiota-based therapies may allow for better identification of patient subgroups who are most likely to benefit from specific interventions, including regenerative strategies. Taken together, these efforts may facilitate a shift from symptomatic treatment to a mechanism-based, individualized strategy that targets both peripheral and central drivers of Parkinson's disease.