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Background Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, characterized by a constellation of motor and non-motor symptoms. The etiology of PD is not fully understood, however, the early presence of gastrointestinal symptoms and alterations in the gut microbiome suggest a possible intestinal origin. Another pathophysiological feature of PD is an inefficient utilization of glucose by neuronal cells as the main energy source leading to bioenergetic deficits of the brain. Dietary interventions such as the Mediterranean (MeDi) diet and the ketogenic diet (KD) have shown promise in alleviating the gastrointestinal symptoms and bioenergetics deficits of PD, respectively. Nonetheless, classical KDs may unfavorably alter the gut microbiome, e.g., by decreasing short-chain fatty (SCFA) acid levels. Hence, combining the principles of the MeDi and KD may allow us to harness the potential benefits of both these dietary interventions, while maintaining gut health. Methods This study will utilize an open-label, randomized, cross-over design to investigate the safety and feasibility of the Mediterranean-ketogenic diet (MeDi-KD) and MeDi diet supplemented with medium-chain triglycerides (MeDi-MCT) in 50 participants diagnosed with PD. Participants will be randomized to start with either the MeDi-KD or the MeDi-MCT intervention. They will adhere to the respective dietary regimens for 8 weeks followed by an 8-week washout period wherein they will return to their pre-study dietary habits. Following the washout period, the participants will start the other dietary intervention for another 8 weeks. Fecal and blood samples will be collected before and after each intervention to examine the biomarkers associated with gut health. The primary outcome measure of this study will be changes from baseline in fecal SCFA levels, particularly butyrate. Discussion The primary objective of this study is to investigate the safety of two Mediterranean-ketogenic interventions with respect to gut microbiome health in patients with PD. This study will provide preliminary evidence and guidance for subsequent large-scale clinical trials investigating multi-pronged dietary interventions to treat PD. If successful, it will de-risk future studies on ketogenic interventions by providing vital information about the safety, tolerability, adherence, and feasibility of the MeDi-KD and MeDi-MCT. Trial Registration ClinicalTrials.gov Identifier: NCT05469997