Parkinson’s Link to the Gut–Brain Axis Presents New Treatment Options

Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world, with global cases predicted to rise to 25 million by 2050. PD is caused by a loss of nerve cells in the brain, which reduces dopamine production and leads to hallmark PD symptoms, such as decreased muscle control, tremors, and stiffness. In recent years, there has been a growing recognition of the links between PD–a brain disorder–and gut health. This has led researchers to investigate the gut microbiome as a potential therapeutic target.

The microbiota–gut–brain axis is a bidirectional communication network linking the gut microbiome to the brain via various immune, neural, and metabolic pathways. Emerging evidence suggests that dysregulation of these pathways could play a key role in the development and progression of neurodegenerative diseases. However, determining whether microbiome changes are a cause or consequence of neurodegeneration has remained a challenge. Understanding gut–brain interactions could reshape how neurodegenerative diseases are detected, prevented, and treated.

In recent years, numerous studies have investigated the gut microbiome in PD. “Despite differences in methodology, geography, and dietary preferences, several microbial alterations are consistently observed compared to healthy controls,” Dr. Arnout Bruggeman, a neurologist at Ghent University Hospital, told Technology Networks. “Interestingly, similar patterns have also been identified in patients with idiopathic rapid eye movement sleep behavior disorder, a highly specific prodromal symptom of PD.”

Gut dysfunction is common in PD patients and has been found to occur at the very earliest stages of the disease. “These findings suggest that microbiome alterations may precede the onset of motor symptoms,” Prof. Roos Vandenbroucke, a professor at VIB-UGent, told Technology Networks.

One of the biggest uncertainties remaining in the field is whether alterations in the microbiome drive neurodegeneration, or vice versa. The “bottom-up” hypothesis suggests that PD may originate in the gut, with misfolded α-synuclein aggregating in the enteric nervous system before appearing in the brain. Others outline the possibility of multiple etiologies, with people experiencing either “gut-first” or “brain-first” disease.

These are just some examples of existing hypotheses, and the question of causality remains to be solved. The high complexity of the human microbiome alongside genetic and lifestyle differences among individuals has prevented researchers from establishing causality. As a result, most human studies are observational or not designed to prove causal relationships.

Even without pinpointing a causal connection, researchers have begun investigating ways to therapeutically target the microbiomes of patients with PD.

The potential of fecal microbiota transplantation

Fecal microbiota transplantation (FMT) involves the transfer of microbiota from a healthy donor into a patient’s intestines, often via a liquid or capsule preparation. This is believed to help rebalance the microbiota in the patient’s intestines and is already successfully used for treating diarrhea caused by Clostridioides difficile infection.

FMT represents a promising approach to addressing the gastrointestinal symptoms of PD by inducing long-term changes in gut microbiota composition. “Several animal studies have demonstrated improvements in both motor and non-motor symptoms following FMT,” said Bruggeman. “However, across the six randomized clinical trials published to date, clinical outcomes have been variable, with no consistent or sustained efficacy observed. Direct comparison between these studies is hampered by methodological differences.”

Bruggeman and colleagues conducted a clinical trial, GUT-PARFECT, to test whether FMT could benefit patients with PD. In the trial, 46 patients aged 50–65 with PD were randomly assigned to receive a nasojejunal FMT with either healthy donor stool or, in the control group, their own stool.

Participants were assessed for a year following the procedure, with all but three participants completing all the study visits. The researchers analyzed changes in the participants' Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor score. Clinical evaluations were performed at baseline and at 3, 6, and 12 months post-FMT.

After 12 months, the MDS-UPDRS motor score improved by a mean of 5.8 points in the healthy donor group and by 2.7 points in the control group. The improvement was most pronounced between the 6-to-12 months interval, suggesting that FMT could have long-lasting effects in PD patients. Participants in the healthy donor group also reported reduced constipation.

“While our work does not resolve the question of causality, the GUT-PARFECT study revealed that reductions in constipation preceded improvements in motor symptoms. This temporal pattern suggests that restoration of gut function may precede and potentially facilitate subsequent neurological improvement,” Bruggeman explained.

An important unresolved issue in the study is the large, relatively long-lasting response in the control group, pointing to the need for further studies to confirm the benefits of FMT.

“We are currently preparing a follow-up clinical trial to validate the findings of our initial study in a larger, multicenter patient cohort,” stated Vandenbroucke. The CUPIDGUT project, funded by the Grand Challenges Program at VIB, aims to refine the findings from GUT-PARFECT by analyzing trial data and optimizing a multicenter FMT study.

“Should the beneficial effects on motor function be confirmed, the next critical step will be to elucidate the underlying mechanisms, with the ultimate aim of developing more targeted therapeutic strategies,” Vandenbroucke continued.

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The researchers claim that extensive analyses into mechanisms are currently ongoing, focusing on potential pathways such as inflammatory processes, microbial metabolites, and extracellular vesicles.

Several key questions remain unresolved that need to be addressed before FMT can be more widely implemented in clinical practice. These include determining the optimal method for FMT administration, defining what constitutes an ideal donor, and identifying which patient characteristics define an optimal recipient.

“Although FMT may appear straightforward, it involves a series of critical methodological and safety considerations. Consequently, the design and execution of FMT trials are complex, time-consuming, and often difficult to fund, particularly given the limited engagement of pharmaceutical companies,” Vandenbroucke said.

There is a need for multicenter clinical trials that include patients across a broader range of disease stages, incorporating follow-up periods of at least 12 months, and integrating comprehensive mechanistic endpoints. “These should encompass detailed patient profiling, intestinal phenotyping, and in-depth microbiome characterization. Such approaches will be crucial for identifying patients most likely to benefit from FMT and for selecting optimal donors, ultimately improving therapeutic outcomes in PD,” Bruggeman continued.

Toward precision microbiome therapies

Treatments that broadly alter microbiomes may not be the end goal of this research. Instead, by understanding the mechanisms underpinning the gut microbiome's influence on PD, it may be possible to shift from crude interventions to precision therapeutics.

Next-generation approaches to PD could involve dietary supplementation to promote the growth of beneficial bacteria in people with PD or transplantation with defined microbial consortia. Alternatively, modulating the body’s response to gut microbiota activities might prove simpler and more durable.

For example, one group of researchers identified a mechanism by which Escherichia coli might contribute to Parkinson’s-related pathology in the gut. The bacterium’s growth results in the oxidation of iron and then dopamine, which triggers the clumping of α-synuclein, especially in the presence of gut inflammation.

The researchers developed a laser-induced graphene-based electrochemical sensor chip to track α-synuclein aggregation and dopamine levels over time in specialized gut cells. Using the sensor chips, they identified diet-derived caffeic acid as a potential inhibitor of α-synuclein aggregation. This demonstrates one of many avenues that future targeted therapeutics could take to treat PD; in this case, the possibility of developing functional foods that may help reshape the gut environment.

“The development of sophisticated biotherapeutic microbial cocktails or pharmacological strategies will become increasingly important, particularly if specific microbial or metabolic targets can be identified,” said Vandenbroucke. “Addressing these challenges represents a substantial but potentially transformative step toward reshaping therapeutic strategies for PD.”