Differential regulation of brain microvessel transcriptome and brain metabolome by Western and heart-healthy dietary patterns in Ossabaw pig

Diet is a potentially modifiable neurodegenerative disease risk factor. We studied the effects of a typical Western diet (WD) relative to a heart-healthy diet (HHD) on microvessel transcriptomics and metabolomics of the brain temporal region in Ossabaw minipigs. Thirty-two pigs (16 male and 16 females) were randomized to the WD or HHD starting at the age of 4 months and were fed the assigned diet for the following 6 months. The WD and HHD were isocaloric and had the same macronutrient content but differed in macronutrient quality. Within each dietary group, half of the pigs also received a statin. Relative to HHD-fed pigs, WD-fed pigs had 2,172 genes differentially expressed (FDR<0.05) by diet, 796 upregulated and 1,376 downregulated. Gene Set Enrichment Analysis identified 22 gene sets enriched in WD, comprising pathways related to inflammation, angiogenesis, and apoptosis, and 53 gene sets enriched in the HHD, including cell energetics, neurotransmission, and inflammation resolution pathways. Enrichment in arginine, tyrosine, and lysine was observed in WD-fed pigs and enrichment in ergothioneine and S-adenosyl methionine in HHD-fed pigs. Statin treatment had very modest effects on brain vessel transcriptome. Our study suggests a likely contribution of diet to brain pathologies characterized by neuroinflammation and neurodegeneration. Overall design: This study was designed to compare the effects of a Western Diet (WD) to a Heart-Healthy Diet (HHD), with or without a statin (S), on cardiovascular disease in Ossabaw minipigs. Thirty two pigs were randomized to four groups in a 2 x 2 factorial design: WD, WD+statin, HHD, HHD+statin. Differential gene expression analysis was performed using RNAseq on RNA samples from blood microvessels that were isolated from the right brain temporal region and purified to contain neurovascular units which comprise small blood vessel and associated pericytes and perivascular astrocyte end-feet. Differential gene expression analysis of the diet effect was assessed by comparing animals fed a WD (WD and WD+statin groups) to those fed a HHD (HHD and HHD+statin groups). Statin effects were assessed by comparing animals treated with statin (WD+statin and HHD+statin groups) to no statin (WD and HHD groups)