Dietary tributyrin supplementation in Parkinson’s disease: An open-label target engagement study

Short-chain fatty acids such as butyrate (key signaling molecules that influence the gut-brain axis and modulate inflammatory, mitochondrial, and transcriptional regulatory processes) are attracting interest as potential treatments for neurodegenerative disorders such as Parkinson's disease. Oral butyrate supplementation in the form of sodium butyrate suffers from limitations, however, as butyrate is rapidly metabolized by colonocytes, resulting in low plasma and brain concentrations. The butyrate prodrug tributyrin, naturally present in butter, is a neutral short-chain fatty acid triglyceride likely to overcome the pharmacokinetic drawbacks of butyrate. Despite these pharmacokinetic advantages, no clinical studies to date have assessed the safety, tolerability, and target engagement of tributyrin as a postbiotic treatment in the setting of Parkinson's disease. Tributyrin's safety profile and potential biomechanistic effects were thus investigated in the setting of Parkinson's disease via an open-label target engagement study. Fourteen individuals with Parkinson's disease and three normal controls completed a 30-day (±7 days) intervention of dietary tributyrin supplementation (500 ​mg taken orally three times daily), demonstrating a reassuring safety profile with high rates of adherence. Ten subjects completed [¹¹C]butyrate PET imaging before and after the intervention to assess for treatment-related changes in brain, liver, heart, and gastrointestinal uptake of butyrate, confirming target engagement (i.e., organ-specific changes in butyrate availability). Systemic anti-inflammatory effects were also observed. Exploratory cognitive, motor, and neurobehavioral clinical testing was conducted before and after the supplementation period, identifying associated improvements in cognitive and motor features of Parkinson's disease. Given these findings, tributyrin warrants further investigation via larger, placebo-controlled trials as a potential complementary therapy for Parkinson's disease.