Ketogenic Diet Interventions in Parkinson's Disease: Safeguarding the Gut Microbiome

Study Overview
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Brief Summary
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Parkinson's Disease (PD) is the second most common neurodegenerative disorder with common gut-related symptoms, which are attributed to alterations in the gut microbiome - the collection of microorganisms that live within the gut. Classical ketogenic diets (KD) have shown to be beneficial in PD and non-PD populations but are associated with alterations in the gut microbiome that are characteristic of a perturbed system. This study aims to investigate the safety of modified Mediterranean-ketogenic interventions that are thought to be safer alternatives to the classical KD, as it relates to the gut microbiome health in patients with PD. We hypothesize that the modified Mediterranean-ketogenic interventions will not be associated with any significant perturbation of the gut microbiome in PD patients.

Detailed Description
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Background: Parkinson's disease (PD), the second most common and the most rapidly growing neurodegenerative disease worldwide [1,2]. Gut-related symptoms are common and often the initial symptoms, suggesting a possible intestinal origin of PD [4]. Over a dozen studies have demonstrated gut dysbiosis in PD with reduced diversity, increased pro-inflammatory capacity, and decreased Short-Chain Fatty Acids (SCFA) production as key characteristics [5-10] and persistently increased relative abundance of Akkermansia [5-17]. Emerging evidence suggests that both ketogenic [18-23] and Mediterranean diets [24-30] have beneficial and likely complementary effects in PD. Mediterranean diets (MeDi) are primarily but not exclusively plant-based [24]. Their promotion of high fiber content intake promotes the production of SCFA and are associated with improved gut microbiome health [25]. Ketogenic diets (KD) are high in fat, adequate in protein and very low in carbohydrates [31]. KD can provide ketone bodies (KB) [32] as an alternative fuel source to glucose, the utilization of which is perturbed in the PD brain [33]. Another method for inducing the state of ketosis is by consumption of ketogenic medium-chain triglycerides (MCTs) [43]. MCTs are converted to KBs, which can readily cross the blood-brain barrier and be used as an energy source [43]. Pilot trials in PD report improved Unified Parkinson's Disease Rating Scale (UPDRS) scores [20], cognitive performance [21] and non-motor symptoms [22] with KD interventions [23]. Several studies of classical KDs in non-PD populations have observed significant alterations in the gut microbiome, including an increase in Akkermansia [47] and a decrease in fecal SCFA levels [50]. By combining the principles of MeDi with ketogenic interventions, we hope to leverage the gut-health promoting aspects of the former with bioenergetics benefits of the latter, in a safe manner. To the best of our knowledge, no clinical trials have been performed into combined ketogenic and Medi-stye dietary interventions in PD yet. Design: A proof of concept, random order, cross-over study in participants with PD examining two 8-week interventions: (1) the Mediterranean ketogenic diet (MeDi-KD) and (2) the Mediterranean diet supplemented with medium-chain triglycerides (MeDi-MCT), separated by an 8-week washout period. Hypothesis: Neither the MeDi-MCT nor the MeDi-KD (pre-post comparison) will be significantly associated with measures of gut microbiome dysbiosis such as increased gut inflammation, impaired gut-barrier integrity, and reduced SCFA content. Retention rates for both diets will be at least 75%.

Official Title
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Ketogenic Diet Interventions in Parkinson's Disease: Safeguarding the Gut Microbiome

Conditions
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Parkinson Disease

Intervention / Treatment
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* Behavioral: Mediterranean-Ketogenic Diet
* Dietary Supplement: Mediterranean diet supplemented with medium-chain triglyceride oil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 40-85 years PD diagnosis based on Movement Disorder Society (MDS) criteria [52] Hoehn & Yahr score of 1 to 3 On stable dopaminergic medication for at least one month Exclusion Criteria: Atypical parkinsonism Medical or psychiatric conditions that would prevent full participation in the nutrition intervention Significant dysphagia Diabetes on insulin Anti-coagulation on warfarin Inflammatory bowel disease Dementia defined by Montreal Cognitive Assessment (MoCA) Scores of less than 21 Inability to fill in electronic questionnaires or understand study instructions Use of immunomodulatory agents Probiotic use in the last 4 weeks (except for dietary sources such as yoghurt, kefir etc.), or antibiotic use in the last 3 months prior to the trial Use of MCT oil or on ketogenic diet in last 8 weeks prior to the trial Allergic to MCT oil, coconut oil, or coconut

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This safety study consists of two 8-week interventions (MeDi-MCT and MeDi-KD) in randomized order using a cross-over design, separated by an 8-week washout period. Participants will be randomized into either the MeDi-MCT or the MeDi-KD group for the first phase of the study. After 8-weeks of intervention, they will undergo an 8-week washout period where no interventions will be applied. Subsequently, the participants will commence the second phase of the study by receiving the other study intervention for 8 weeks.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MeDi(KD-MCT)<br>The participants in this arm will first undergo the MeDi-KD intervention followed by the MeDi-MCT intervention, after an 8-week washout period. | Behavioral: Mediterranean-Ketogenic Diet<br>* In the MeDi-KD group, the participants will adhere to a modified Mediterranean-ketogenic diet. The ketogenic component of the diet will require limiting the intake of carbohydrates to about 10% of all calories consumed in a day, while obtaining most of the energy from healthy fats, mostly from plant-based sources ( 70-75% of your daily caloric intake) and lean proteins ( 15-20% of your daily caloric intake). The ketogenic ratio (the ratio of fat to carbohydrates) will be gradually increased during the first week from 1:1 to 3:1. The Mediterranean component of the diet will encourage the participants to consume more green leafy vegetables, nuts, and olive oil, while limiting the consumption of processed or fried food, red meat, full-fat dairy, and sweets.<br>* Other names: MeDi-KD;Dietary Supplement: Mediterranean diet supplemented with medium-chain triglyceride oil<br>* The participants will adhere to the Mediterranean diet. In addition, they will be asked to take two daily doses of medium-chain triglyceride oil (MCT oil). The MCT oil supplement (Nutiva MCT oil, Nutiva Inc.) is approved by Health Canada (NPN: 80086912) and will be used according to its approved condition of use (i.e., source of medium-chain fatty acids which supports energy production in the body at a cellular level [ATP]). Each serving of this product provides 130 Calories from MCTs (14 g) with a C8-C10 ratio of 60:40. Nutiva MCT oil can be mixed into any beverage of choice, but cannot be used for cooking. participants will start the intervention by taking 5 mL of MCT oil twice daily for the first day to acclimate their bodies to the supplement and gradually increase the dose to 14 g BID by the end of week 1. The participants may be asked to increase the dose to 20 mL of MCT twice daily if tolerability remains positive.<br>* Other names: MeDi-MCT;|
| Experimental: MeDi(MCT-KD)<br>The participants in this arm will first undergo the MeDi-MCT intervention followed by the MeDi-KD intervention, after an 8-week washout period. | Behavioral: Mediterranean-Ketogenic Diet<br>* In the MeDi-KD group, the participants will adhere to a modified Mediterranean-ketogenic diet. The ketogenic component of the diet will require limiting the intake of carbohydrates to about 10% of all calories consumed in a day, while obtaining most of the energy from healthy fats, mostly from plant-based sources ( 70-75% of your daily caloric intake) and lean proteins ( 15-20% of your daily caloric intake). The ketogenic ratio (the ratio of fat to carbohydrates) will be gradually increased during the first week from 1:1 to 3:1. The Mediterranean component of the diet will encourage the participants to consume more green leafy vegetables, nuts, and olive oil, while limiting the consumption of processed or fried food, red meat, full-fat dairy, and sweets.<br>* Other names: MeDi-KD;Dietary Supplement: Mediterranean diet supplemented with medium-chain triglyceride oil<br>* The participants will adhere to the Mediterranean diet. In addition, they will be asked to take two daily doses of medium-chain triglyceride oil (MCT oil). The MCT oil supplement (Nutiva MCT oil, Nutiva Inc.) is approved by Health Canada (NPN: 80086912) and will be used according to its approved condition of use (i.e., source of medium-chain fatty acids which supports energy production in the body at a cellular level [ATP]). Each serving of this product provides 130 Calories from MCTs (14 g) with a C8-C10 ratio of 60:40. Nutiva MCT oil can be mixed into any beverage of choice, but cannot be used for cooking. participants will start the intervention by taking 5 mL of MCT oil twice daily for the first day to acclimate their bodies to the supplement and gradually increase the dose to 14 g BID by the end of week 1. The participants may be asked to increase the dose to 20 mL of MCT twice daily if tolerability remains positive.<br>* Other names: MeDi-MCT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline and difference across interventions in measures of fecal and serum calprotectin, a biomarker for gut inflammation. | We will assess changes from baseline in levels of fecal and serum calprotectin, a biomarker for gut inflammation that is found at elevated levels in PD patients, before and after each 8-week intervention. We will also compare the two interventions to determine their relative safety. | Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24) | 
| Changes from baseline and differences across interventions in other measures of gut health, namely short-chain fatty acid production, gut-barrier integrity, and microbial composition. | We will assess changes from baseline in the following biomarkers of gut health before and after each 8-week intervention: Short-chain fatty acid (SCFA)/ butyrate production measured in freshly frozen fecal samples Gut microbiome compositions measure in fecal samples. Levels of zonulin, a biomarker for gut-barrier function, measured in fecal and blood serum samples. We will track any potential adverse events. | Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of participants who completed the study after successful enrollment relative to the total enrolled participants. | We will assess the retention rate of participants with respect to each intervention to determine the feasibility of the proposed dietary interventions. | Post-intervention 1 (Week 8)/Post-intervention 2 (Week 24) | 
| Percent time spent in clinically relevant levels of ketosis ( equivalent to >0.5 mmol/L) by each participant throughout each intervention. | Adherence to the ketogenic dietary interventions will be measured using breath ketone analyzers (Ketonix). The participants will take daily measurements of their breath ketone levels and record them in their study journal. Percent time is determined by the number of days they successfully reach clinically relevant levels of ketosis relative to the total intervention days for each intervention (i.e. 56 days). | Post-intervention 1 (Week 8)/Post-intervention 2 (Week 24) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's Disease, Gut Microbiome, Ketogenic Diet, Mediterranean Diet, Medium-Chain Triglyceride, Life-style Interventions