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

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%.

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