Gut-Brain Axis: The Role of Gastrointestinal Issues in Parkinson’s Disease

Abstract

Parkinson’s Disease (PD) is a complex neurodegenerative disorder traditionally identified by motor symptoms. However, non-motor manifestations such as lower gastrointestinal (GI) disturbances are increasingly recognized as early indicators and contributors to disease progression. This review examines the gut-brain axis and the role of lower GI issues, particularly constipation and gut dysbiosis, in the pathogenesis and management of PD. The “bottom-up” hypothesis suggests that PD may originate in the gut, with misfolded alpha-synuclein aggregating in the enteric nervous system before appearing in the brain. This pathological process is closely associated with gut dysbiosis, which contributes to increased intestinal permeability, systemic inflammation, and neuroinflammation via the vagus nerve and disrupted blood-brain barrier. Dysbiosis not only alters microbial diversity but also leads to the overproduction of neurotoxic metabolites, like lipopolysaccharides (LPS) and short-chain fatty acids (SCFAs). These biochemical changes create a pro-inflammatory environment that accelerates neurodegeneration. The review examines integrative interventions, including dietary strategies such as the Mediterranean diet and supplementation with probiotics, prebiotics, and synbiotics, which have shown promise in modulating gut microbiota and reducing inflammation. Lifestyle factors, such as exercise and stress reduction, also support gut health and symptom management, with structured multimodal exercise regimens showing significant benefit in motor function.

Introduction

Parkinson’s Disease (PD) is a progressive neurodegenerative disorder primarily characterized by motor symptoms such as tremors, rigidity, and bradykinesia. Affecting approximately 1% of individuals over the age of 60, PD is one of the most prevalent neurodegenerative diseases globally.¹ However, non-motor symptoms, including lower GI disturbances like constipation, often precede motor symptoms by years and can significantly impact patients’ quality of life.² Recent research has increasingly recognized the importance of non-motor symptoms in the early identification and holistic management of PD.³

The gut-brain axis, a bidirectional communication network linking the GI tract and the central nervous system (CNS), plays a pivotal role in the pathophysiology of PD. Evidence supports a “bottom-up” model of disease progression, where pathological changes in the gut may precede and contribute to neurodegeneration in the brain.⁴ The presence of misfolded alpha-synuclein, a hallmark of PD, in the enteric nervous system (ENS) years before the onset of motor symptoms strongly supports this hypothesis.⁵ Furthermore, gut dysbiosis, defined as an imbalance in the microbial composition, has been linked to chronic inflammation and increased intestinal permeability (IP), both of which can exacerbate neurodegenerative processes through the gut-brain axis.⁶

The goal of this review is to bridge the disciplines of neurology and gastroenterology by exploring current research on the relationship between lower GI dysfunction and PD. Specifically, it will examine how conditions such as constipation and gut dysbiosis interact with the gut-brain axis to influence the onset and progression of PD. Therefore, this review aims to explore the relationship between lower GI disturbances (particularly constipation, gut dysbiosis, and the gut-brain axis) and PD’s disease progression. It seeks to enhance the understanding of the gut’s role in neurodegenerative diseases and highlight the potential for gut-based interventions to improve patient outcomes. By examining the intersection of gut health and neurological diseases, this review aims to promote a deeper understanding of the gut-brain connection and its role in neurodegenerative conditions.

PARKINSON’S DISEASE AND LOWER GASTROINTESTINAL SYMPTOMS

Non-Motor Symptoms in PD

While PD is primarily characterized by motor symptoms such as tremors and bradykinesia, non-motor symptoms, particularly GI dysfunction, are now recognized as critical components of the disease. Lower GI disturbances, such as constipation, slow colonic transit, and incomplete bowel emptying, often precede the motor manifestations of PD by years.² These symptoms are not only secondary effects of motor impairments but rather integral to the pathophysiology of PD. It is suggested that non-motor symptoms, including GI dysfunction, significantly impact patients’ quality of life, exacerbate disease burden, and may serve as early biomarkers for the onset of PD.⁷ Furthermore, these symptoms can complicate medication absorption, particularly levodopa, impacting treatment effectiveness.⁷

GI dysfunction is thought to arise from neuropathological changes within the ENS, including the presence of aggregated alpha-synuclein proteins (Figure 1), a diagnostic biomarker often used in PD.⁸

Figure 1.

Schematic Representation of α-Synuclein Accumulation and Aggravation from the ENS to the Brain⁸

These aggregates are observed in the gut long before they appear in the CNS, implicating the GI tract as a potential origin for the disease.^5,9 Additionally, chronic constipation, affecting 20-89% of PD patients, has been associated with systemic inflammation and increased IP, further linking GI dysfunction to the progression of neurodegeneration through the gut-brain axis.^6,10 Dysregulated gut microbiome leads to inflammation and allows harmful substances to cross the intestinal barrier, potentially contributing to the aggregation of alpha-synuclein in the gut.⁶ This process may play a role in the initiation and progression of neurodegeneration in PD.

Prevalence and Nature of GI Dysfunction in PD

GI dysfunction is reported in approximately 70–80% individuals with PD.² Lower GI disturbances, such as delayed gastric emptying and constipation, are among the most common complaints and often emerge years before the classic motor symptoms.⁹ This high prevalence underscores the importance of early screening and recognition of GI symptoms in individuals at risk of PD.

The nature of GI dysfunction in PD is multifaceted. In addition to motor issues in the gut, such as impaired peristalsis, non-motor changes, like microbial imbalances, are increasingly implicated.⁶ Dysbiosis disrupts the delicate balance between beneficial and pathogenic gut bacteria, fostering a proinflammatory environment and promoting the accumulation of neuro-reactive and potentially neurotoxic metabolites. These include lipopolysaccharides (LPS), p-Cresol, ammonia, hydrogen sulfide, and phenylacetylglutamine, which may exacerbate neurodegeneration.⁴ This microbial imbalance is often driven by an overgrowth of pathogenic bacteria such as Clostridium, Desulfovibrio, and Bacteroides, which are known to produce these toxic compounds. In contrast, beneficial short-chain fatty acids (SCFAs), especially butyrate, are significantly reduced in dysbiosis, compromising gut and brain barrier integrity and increasing neuroinflammation.⁴ Lubomski et al.⁶ found that in PD patients, dysbiosis is characterized by reduced levels of Bifidobacterium and Lactobacillus and increased pro-inflammatory bacteria such as Proteobacteria and Enterobacteriaceae. Proteobacteria are gram-negative bacteria that produce LPS, which can be released systemically, leading to a pro-inflammatory response. LPS leads to elevated IP by increasing zonulin levels, which are proteins in the tight junctions.¹¹ Elevated LPS stimulates the release of zonulin, which leads to the disassembly of zonulin and other tight junction proteins, hence enhancing IP. These findings highlight the complexity and role of GI dysfunction in PD and its progression.

The Gut as a Possible Origin of Parkinson’s Disease

“Bottom-up” Model of PD Progression

Research supports the “bottom-up” model in PD progression, where the disease is proposed to originate in the gut and progress to the brain. This hypothesis suggests that pathological changes in the GI tract may precede and contribute to neurodegeneration in the CNS, specifically, the gut-brain axis is thought to facilitate this progression.¹² The vagus nerve, a critical pathway of this axis, is believed to transport pathological proteins, such as misfolded alpha-synuclein, from the ENS to the brainstem.¹³ Animal studies have shown that shortening the vagus nerve can prevent this transmission, further implicating its role in disease progression.¹⁴

Alpha-Synuclein Aggregation in the Gut

Alpha-synuclein, a protein that forms toxic aggregates in PD, has been identified in the gut years before motor symptoms appear. These aggregates are present in the ENS, specifically in the Meissner and Auerbach plexuses, suggesting that PD may initiate in the GI tract.⁵ This early presence of alpha-synuclein provides a unique opportunity for the early detection of PD, potentially allowing interventions before neurodegeneration becomes widespread.¹⁵ Non-invasive techniques, such as colonoscopic biopsies, help identify these protein aggregates, thus offering promising diagnostic potential.¹⁶ Since alpha-synuclein protein aggregates are found in colonoscopic biopsies, this suggests that neurodegenerative processes may begin in the gut as early signs of PD, often before motor symptoms appear.

Together, the bottom-up model and evidence of alpha-synuclein deposition in the gut highlight the importance of GI health in understanding PD. These findings suggest that therapeutic strategies targeting the gut could significantly delay disease progression.

Gut Dysbiosis and Its Role in Neurodegeneration

Gut Microbiome in PD

Gut dysbiosis refers to an imbalance in the microbial composition of the gut, characterized by a reduction in microbial diversity and alterations in the relative abundance of beneficial and pathogenic bacteria. In PD, gut dysbiosis has emerged as a crucial factor influencing the onset and progression. Studies demonstrate significant differences in the gut microbiome composition of PD patients compared to healthy individuals. Individuals with PD often exhibit an increase in pro-inflammatory bacteria such as Enterobacteriaceae and a decrease in butyrate-producing bacteria like Faecalibacterium and Roseburia.¹⁷ SCFAs, especially butyrate, are vital for maintaining gut barrier integrity and reducing inflammation, suggesting that gut dysbiosis contributes to the processes underlying PD.⁷

Mechanisms Linking Dysbiosis to Neurodegeneration

Gut dysbiosis is closely linked to chronic inflammation and immune system dysregulation, which are major contributors to neurodegeneration. Systemic inflammatory responses can affect the brain via the gut-brain axis, triggering microglial activation and contributing to neuronal damage, allowing bacterial metabolites and toxins to reach the CNS, exacerbating neuroinflammatory processes and accelerating PD progression.⁴ In addition, an increase in LPS levels can impair tight junction proteins in the blood-brain barrier (BBB), which then facilitates peripheral immune cells and pro-inflammatory cytokines to enter the CNS, where they can activate microglial cells.¹⁸

Dysbiosis and Constipation

Constipation, one of the most common non-motor symptoms of PD, has a bidirectional relationship with gut dysbiosis. Slow bowel motility alters the gut microbial environment, favoring the overgrowth of pathogenic bacteria and reducing microbial diversity.² Pathogenic bacteria further aggravate constipation, contributing to a self-perpetuating cycle of gut dysbiosis and impaired motility. This altered microbial balance worsens dysbiosis, contributing to inflammation and neurodegeneration. Additionally, constipation-associated changes in gut motility can impair nutrient absorption and the production of key neuroprotective metabolites, further impacting disease progression. Reduced gut motility is also related to low serotonin levels in the gut. Ninety to ninety-five percent of serotonin is found in the GI tract, primarily within epithelial enterochromaffin cells (ECs).¹⁹ Several gut bacteria play a role in serotonin production in the gut. The most important bacteria that influence serotonin production in the gut are those that either directly produce serotonin or stimulate its release from ECs, such as Clostridia, which are shown to be low in PD patients.^20,21 Ruminococcus gnavus and Clostridium ramosum, Clostridia species, and Bifidobacterium can influence serotonin production by upregulating gene expression of genes that produce serotonin. Supplemented probiotics such as Lactobacillus acidophilus, Bifidobacterium longum, Lacticaseibacillus rhamnosus, and Limosilactobacillus reuteri are also highly significant in maintaining serotonin balance.²² Furthermore, low serotonin in the gut impairs motility and affects the absorption of critical nutrients like vitamins B12, iron, and calcium, which are essential in neuroprotection.³

The Gut-Brain Axis and Neuroinflammation

Communication Pathways

The gut-brain axis serves as a critical communication network between the GI tract and the CNS, with the vagus nerve acting as a primary pathway (Figure 2). The vagus nerve not only transmits sensory information from the gut to the brain but also plays a role in regulating inflammatory responses. In PD, alpha-synuclein aggregates have been shown to pass along the vagus nerve from the gut to the brainstem, contributing to the progression of neurodegeneration.⁵ Disruptions in this pathway can lead to increased susceptibility to inflammatory signals. Moreover, both human and preclinical studies suggest that alpha-synuclein plays a central role in initiating neuroinflammation in PD. Pathological forms of alpha-synuclein are closely associated with elevated pro-inflammatory markers, such as MHC-1 and CD68, and with immune cell activation involving IBA1-reactive microglia and CD3 T-cells near degenerating neurons.²³

Figure 2.

Bidirectional Interactions Within the Brain-Gut-Microbiome (BGM) System²⁴

Additionally, circulating inflammatory markers such as cytokines and LPS are pivotal mediators in the gut-brain axis (Figure 2).²⁴ LPS can compromise the integrity of tight junction proteins within the BBB. When gut permeability increases due to dysbiosis and tight junction damage, pro-inflammatory cytokines and LPS can enter the bloodstream and cross the BBB, activating microglia and promoting neuroinflammation.¹⁶ When the BBB is compromised, systemic inflammation can exacerbate neuronal damage, accelerating the progression of PD.

Neuroinflammation and PD Progression

A key characteristic of PD is the interplay between GI dysfunction and neuroinflammation, which creates a self-reinforcing feedback loop. Chronic GI dysfunction, driven by dysbiosis and impaired gut motility, perpetuates systemic inflammation through the production of pro-inflammatory metabolites. Triggers like LPS can cause microglia activation; thereafter, microglia release pro-inflammatory cytokines and reactive oxygen species (ROS), which can disrupt neuronal function and integrity. This inflammatory environment is particularly harmful in regions such as the substantia nigra, where dopamine-producing neurons are highly vulnerable.⁶

Neuroinflammation directly contributes to both motor and non-motor symptom worsening in PD. The activation of microglia and astrocytes, coupled with oxidative stress, exacerbates neuronal loss, leading to the hallmark motor deficits of PD, such as bradykinesia and tremors.³ Non-motor symptoms, including cognitive decline and mood disorders, are also linked to the inflammatory pathways mediated by the gut-brain axis, underscoring the integral role of neuroinflammation in the disease’s clinical manifestations.²⁵

Opportunities for Integrative Approaches in PD Management

Dietary Interventions

Dietary modifications offer an integrative health intervention for managing PD by targeting gut health and reducing inflammation. Diets rich in prebiotic fiber, polyphenols, antioxidants, and anti-inflammatory compounds can influence gut microbiota composition, enhance gut barrier integrity, and reduce systemic inflammation.²⁶ Mediterranean diet, characterized by high consumption of fruits, vegetables, whole grains, and healthy fats, has been shown to promote microbial diversity and reduce pro-inflammatory markers.²⁷ Moreover, Zhao et al.²⁸ have shown that high adherence to the Mediterranean diet is associated with a 25% reduction in PD risk with consistent results across age groups, genders, and different regions. Certain key components of the Mediterranean diet, including fresh vegetables, fruits, nuts, seeds, non-fried fish, olive oil, coconut oil, fresh herbs, and spices, are particularly associated with these protective effects. The MIND diet, like the Mediterranean diet, emphasizes the intake of vegetables, berries, and poultry and a reduction in fried foods and sweets, reportedly reduces the risk of PD onset.²⁹ Additionally, consuming flavonoid-rich foods such as tea, berries, apples, red wine, and oranges is also correlated with a reduced risk of PD.³⁰ Furthermore, polyunsaturated fatty acids (PUFAs), especially omega-3 fatty acids, have an inverse relationship with PD risk, highlighting the role of dietary fat intake in brain health.²⁶

Probiotics, Prebiotics, and Synbiotics

The International Scientific Association for Probiotics, Prebiotics, Synbiotics (ISAPP) defines probiotics as live organisms that, when used in proper amounts, provide a health benefit for the host. Prebiotics are defined as substrates that are selectively utilized by host microorganisms, promoting the growth of beneficial bacteria. Synbiotics are categorized into two classes: complementary synbiotics and synergistic synbiotics. Complementary synbiotics consist of a combination of a probiotic and a prebiotic that work independently to provide health benefits. Synergistic synbiotics consist of a combination where the prebiotic enhances the survival and activity of the probiotic, thereby improving the environment for the gut microbiota and overall health.³¹ Specific probiotics, such as L. rhamnosus GG, Bifidobacterium animalis lactis, and Lactobacillus acidophilus, which are butyrate-producing bacteria, can inhibit the destruction of dopaminergic neurons in the ENS, reduce GI symptoms like constipation, and modulate inflammation by restoring gut microbial balance, enhancing SCFA production, and improving gut barrier integrity.³² Probiotics are transient and signaling molecules that improve the growth of beneficial bacteria, thereby supporting microbial diversity.^33,34 Prebiotics can increase the abundance of SCFA-producing bacteria, which are often depleted in PD patients.³⁵ A synbiotic containing Lacticaseibacillus paracasei DG and prebiotic inulin was shown to improve the abundance of butyrate-producing bacteria, Faecalibacterium prausnitzii, and improve constipation in individuals with PD.³⁶ Additionally, daily intake of 5 g of partially hydrolyzed guar gum (PHGG) has been shown to increase SCFAs bacteria and improve constipation significantly.³⁷ PHGG’s ability to help restore microbial balance may offer a non-invasive dietary intervention as part of an integrative management strategy to alleviate PD symptoms. While early evidence is encouraging, gaps remain in understanding the specific probiotic strains, dosages, and long-term effects of these interventions. Thus, more rigorous clinical trials are needed to establish standardized protocols for their use in PD management.

Despite these gaps, gut-targeted approaches hold promise as complementary strategies to improve quality of life and potentially slow disease progression.

Lifestyle Modifications

Lifestyle interventions such as exercise, stress reduction, and integrative therapies targeting the gut-brain axis are vital components of PD management. Regular physical activity has been shown to improve gut motility, enhance microbial diversity, and reduce systemic inflammation, thereby positively influencing the gut-brain axis.³⁸ Exercise also boosts dopamine production, alleviating motor symptoms while promoting overall well-being. Understanding the optimal dose and type of exercise remains key for maximizing its benefits in PD patients. According to Wang et al.,¹⁴ multimodal, structured exercise programs, such as aerobic exercise (walking), body weight support training, dancing, and sensory training, are most effective. The clinically meaningful dose appears to be 260 minutes/week at moderate intensity, and among the different exercise types, dancing showed the greatest benefits.¹⁴ Stress reduction techniques, including mindfulness and yoga, can lower cortisol levels, which are linked to inflammation and gut permeability.³⁹ By addressing both physical and emotional stressors, these interventions help maintain gut health and support neurological function. Integrative therapies such as acupuncture and biofeedback may also target gut-brain communication pathways, offering additional relief for GI symptoms and enhancing the quality of life in PD patients.³

Emerging Therapies

Pharmacological approaches, such as fecal microbiota transplantation (FMT) and prebiotics/probiotics-based therapies, are emerging therapies in the management of PD.^40,41 FMT involves transplanting gut microbiota from healthy stool donors to restore microbial balance in PD patients. Study shows that FMT in PD patients restores beneficial bacteria: Roseburia, Ruthenibacterium, Peptostreptococcaceae, and Lactobacillaceae, and is associated with gut health and anti-inflammatory effects.⁴⁰ At the same time, levels of Proteobacteria, linked to inflammation, were significantly reduced. Preliminary studies suggest that FMT can reduce inflammation, improve GI symptoms, and even alleviate some neurological symptoms, though more extensive research is needed to establish its efficacy and safety.⁴² Together, lifestyle modifications and emerging therapies represent integrative approaches that hold potential for improving outcomes and enhancing the quality of life for PD patients.

Implications for Integrative Health Professionals

Early Detection and Prevention

Early detection and prevention are critical in addressing PD. Non-motor symptoms, particularly GI disturbances such as constipation, often precede motor symptoms by years, offering an opportunity for earlier identification of at-risk individuals.² Recognizing these early markers can guide timely interventions focused on gut health, potentially delaying the onset of neurodegenerative processes. Practitioners can employ tools like gut microbiome profiling and alpha-synuclein detection in GI tissues to identify patients with early PD. Gut microbiome profiling comprises two key approaches: shotgun metagenomics and 16S rRNA sequencing. Shotgun metagenomics is a comprehensive screening method for analyzing DNA within a microbiome sample, providing a better understanding of microbiome-associated functions.⁴³ In contrast, 16S rRNA sequencing is a targeted approach that identifies bacterial composition within a microbiome sample to study microbial diversity and structure, specific to the genus level.⁴⁴ Furthermore, alpha-synuclein testing involves GI tissue biopsy collection and the application of immunohistochemistry and immunofluorescence staining methods, which allow a direct visualization of alpha-synuclein aggregation.⁴⁵ This allows for preventive care strategies, including dietary adjustments, stress reduction, and lifestyle modifications. However, this testing method is currently only available in research settings.

Multidisciplinary Collaboration

The complex interplay between the gut and brain in PD underscores the need for multidisciplinary collaboration among healthcare providers. Integrative health professionals can work along with neurologists, gastroenterologists, dietitians, and mental health specialists to develop comprehensive care plans for PD patients. By bridging disciplines, practitioners can address both motor and non-motor symptoms holistically, improving outcomes. Collaboration is crucial in implementing novel therapies like FMT or gut-targeted pharmacological interventions, which require coordination between multiple specialties for effective administration and monitoring.³

Personalized Care Strategies

Personalized care strategies are essential in managing the multifaceted symptoms of PD. Integrative healthcare practitioners are positioned to tailor interventions based on individual patient needs, including microbiome profiles, symptom severity, and lifestyle factors. This may involve customized dietary plans, specific probiotics or prebiotics, and targeted exercise programs aiming to enhance gut health and reduce systemic inflammation. Personalized care ensures that patients receive interventions that address their unique challenges and promote their long-term well-being.⁶

By focusing on prevention, collaboration, and personalized care, integrative health professionals can play a pivotal role in managing PD, improving patient outcomes, and advancing holistic approaches to neurodegenerative disease care.

Challenges and Future Directions

Current Research Gaps

While the understanding of the gut-brain axis in PD has advanced, critical research gaps persist. Longitudinal studies are warranted to determine how changes in the gut microbiome contribute to PD progression, and whether these changes precede neurodegeneration or are a result of it. Most current studies are cross-sectional, which limits causal inferences.⁶ Furthermore, gut-targeted interventions, such as probiotics and FMT, lack standardized guidelines regarding strains, dosages, and treatment durations.⁴⁶ These limitations hinder the widespread application of these therapies in clinical settings.

Future Research Opportunities

Future research is needed to determine the causal mechanisms linking gut dysbiosis to neurodegeneration. Understanding the pathways through which gut-derived inflammation and microbial metabolites impact the central nervous system could lead to enhanced and innovative therapies.^3,47 Additionally, biomarkers could enable earlier interventions and improve long-term outcomes for patients at high risk of developing PD. Thus, developing more reliable biomarkers based on gut microbiome profiles (such as metagenomics testing and/or 16S rRNA sequencing) or alpha-synuclein deposits in the gastrointestinal tract holds promise for early detection of PD.

Implications for Integrative Health Practice

Integrative health professionals can play a vital role in expanding the focus on gut health within holistic PD management. Emphasizing gut health through dietary adjustments, stress reduction, and personalized microbiome-targeted therapies offers a proactive approach to managing both motor and non-motor symptoms of PD. Integrative health practitioners are well-suited to bridge disciplines, incorporating emerging insights from gastroenterology and neurology into care strategies. By addressing gut health as a core component of PD treatment, integrative health professionals can develop more effective, patient-centered approaches to manage this complex disease.

Conclusion

This review highlights the growing recognition of the gut-brain axis as a pivotal component in the progression and management of PD. Lower GI disturbances such as constipation and gut dysbiosis are not merely secondary symptoms but are intricately linked to the disease’s pathogenesis. The “bottom-up” model, supported by evidence of alpha-synuclein aggregation in the gut and gut dysbiosis-induced systemic inflammation, suggests that PD may originate in the gut and progress to the brain via the vagus nerve or via the breach of the BBB. Understanding these mechanisms underscores the significance of early detection and preventive care.

Integrative approaches to PD management, including dietary interventions, prebiotics, probiotics, synbiotics, lifestyle modifications, and therapies such as FMT, offer promising avenues to address the gut’s role in PD. By improving gut health and targeting the gut-brain axis, these strategies can potentially slow disease progression, alleviate symptoms, and enhance quality of life. More research studies are needed to explore causal mechanisms, standardize gut-targeted therapies, and develop reliable biomarkers for early detection of PD.

For health professionals, this review offers evidence for adopting a holistic approach to PD care. Multidisciplinary collaboration and personalized care strategies are vital in addressing both motor and non-motor symptoms. Practitioners are uniquely positioned to bridge the gap between neurology and gastroenterology, tailoring interventions based on individual patient needs and leveraging the latest research in gut health.

This review emphasizes the transformative potential of gut-focused therapies in managing PD. By advancing research and integrating emerging insights into clinical practice, the gut-brain axis could become a cornerstone of future PD management, offering new hope to patients and improving outcomes in this complex neurodegenerative disorder.