Abstract
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Introduction: Postural instability and gait difficulty (PIGD) symptoms are among the most debilitating manifestations of advanced Parkinson’s disease (PD) due to being non-responsive to dopaminergic therapy and the scarce availability of alternative treatment options. Growing recognition of metabolic underpinning for PD pathology points towards an untapped potential of dietary interventions. Tributyrin is a dietary supplement which is naturally present in butter and is converted by the gut microbiome into butyrate, which in turn plays an important role both as an alternative source of energy and a signaling molecule. The aim of the present exploratory study was to examine whether a 30-day tributyrin supplementation leads to significant changes in brain availability of butyrate (as measured by 11C-butyrate PET imaging) in a sample of controls and PD patients, and whether these changes are associated with improvement in dopamine-refractory motor symptoms of PD.
Methods: Two healthy control participants and eight PD patients underwent 80-minute dynamic 11C-butyrate PET imaging before and after a 30-day of 500 mg thrice daily tributyrin supplementation. Eroded cerebral white matter reference region was used to generate 11C-butyrate parametric images using PET frames taken 10 and 50 minutes post-injection. PD participants underwent a UPDRS motor symptom examination, which was used to calculate PIGD scores as a sum of items 3.10 (gait), 3.11 (freezing of gait), and 3.12 (postural stability) divided by a maximal possible score of 12 points. SPM voxel-wise paired-samples t-test was first used to determine whether significant changes in 11C-butyrate brain uptake were observed after 30-day tributyrin supplementation. A voxel-wise SPM correlation was subsequently performed between 11C-butyrate uptake in brain voxels that demonstrated significant changes in 11C-butyrate and within-subject changes in PIGD scores as a function of treatment. Cluster-level FDR-corrected significance threshold of P < 0.05 with cluster forming threshold of 50 voxels was used for both voxelwise analyses.
Results: 30-day tributyrin supplementation was associated with widespread decreases in 11C-butyrate uptake from pre to post-treatment scans, most pronounced in the cerebellum, fronto-temporal cortices, and bilateral insulae (Figure 1A). Post-hoc mixed linear model of cluster-averaged DVR values confirmed these findings (Figure 1B). Within-subject changes in brain 11C-butyrate uptake were visibly detectable on the pre and post-treatment parametric images (Figures 1C & 1D), and likely reflect lower availability of butyrate binding sites due to greater availability of cold (non-radioactive) brain butyrate molecules from the dietary intervention. Without considering brain changes in 11C-butyrate uptake, there was a trend for an improvement in PIGD symptoms following supplementation (p<0.1). Lastly, increased availability of brain butyrate following tributyrin treatment in temporal, parahippocampal, prefrontal, anterior cingulate, and insular cortices, along with cerebellum, putamen, claustrum, and thalamus (Figure 2), was found to associate with a greater decrease in PIGD symptoms.
Conclusions: Our PET imaging results demonstrate critical evidence of brain target engagement by the tributyrin dietary supplementation. Regions where greater changes in brain butyrate availability were associated with greater improvements in typical dopamine-refractory PIGD symptoms are known to be associated with sensorimotor postural and attentional motor gait functions. These findings suggest that butyrate might play an important role in supporting neuroplasticity and compensatory processing related to the preservation of motor control after loss of nigrostriatal dopaminergic innervation. Further research is needed to elucidate the precise contributions of butyrate to these presumed compensatory processes, and to replicate its effectiveness in treating dopamine-refractory PIGD symptoms in a larger cohort of PD patients.
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