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

Parkinson Disease Clinical Trial

— KIM  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05469997
• Other study ID #: H21-03747
• Status: Active, not recruiting
• Phase: N/A
• Start date: March 1, 2023
• Est. completion date: July 2025

Study information

• Verified date: May 2024
• Source: University of British Columbia
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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:

1. 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.

2. Retention rates for both diets will be at least 75%.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 50
• Est. completion date: July 2025
• Est. primary completion date: February 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 45 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Parkinson Disease

Intervention

Behavioral:
• Mediterranean-Ketogenic Diet
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.

Dietary Supplement:
• Mediterranean diet supplemented with medium-chain triglyceride oil
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.

Locations

Country	Name	City	State
Canada	Djawad Mowafaghian Centre for Brain Health	Vancouver	British Columbia

Sponsors (2)

Lead Sponsor	Collaborator
University of British Columbia	Weston Family Foundation

Country where clinical trial is conducted

Canada, 

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Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Changes from baseline in motor and non-motor Parkinson's Disease symptoms after each intervention	Tracking changes from baseline in motor and non-motor Parkinson's disease symptoms using the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS)	Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
Other	Tracking changes from baseline in severity of Fatigue Symptoms after each intervention	Tracking changes from baseline in severity of fatigue symptoms in the study participants using the Fatigue Severity Scale (FSS).	Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
Other	Changes from baseline in apathy symptoms after each intervention	Using Starkstein Apathy Scale (AS) to track changes from baseline in Apathy symptoms in the study participants after each intervention	Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
Other	Changes from baseline in depressive symptoms after each intervention	Using the Beck Depression Inventory II (BDI-II) to track changes in depressive symptoms from baseline in the study participants after each intervention	Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
Other	Changes from baseline in Anxiety symptoms after each intervention	Using the Parkinson's Anxiety Scale (PAS) to track changes in anxiety symptoms from baseline in the study participants after each intervention.	Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
Other	Tracking changes in the quality of life of the study participants after each intervention	Using the Parkinson's disease questionnaire (PDQ-39) to assess changes from baseline in the quality of life of the study participants after each intervention	Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
Other	Assessing changes in capacity for performing physical activities in the study participants after each intervention	Physical Activity Scale for Individuals with Physical Disabilities (PASIPD)	Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
Other	Assessing changes in the the stool consistency of the study participants after each intervention	Using Bristol Stool Chart to track the stool consistency of the study participants as they continue adhering to the study interventions.	24 weeks (weeks 1-24)
Other	Assessing the constipation and irritable bowl symptoms in the study participants	Using the Rome III module to track changes from baseline in constipation and irritable bowel symptoms of the study participants after each intervention.	Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
Other	Determining the dietary habits of the study participants prior to beginning of the study	Using the Canadian version of the Diet History questionnaire (C-DHQ II) to determine the dietary habits of study participants prior to beginning of the study	Preintervention 1 (Baseline 1)
Other	Tracking changes in the cognitive function of the study participants	Using the National Health Institute Toolbox-Cognitive battery (NIHTB-CB) to assess changes from baseline in the cognitive function of the study participants after each intervention.	Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
Primary	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)
Primary	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	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)
Secondary	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)