Contribution of the Microbiome to Western Diet‐Induced Gene Expression Changes in the Intestine and Vasculature

Abstract

Western diet (high fat/sugar) is a core contributor to obesity, which is associated with increased risk for chronic diseases, including cardiovascular disease (CVD). The mechanisms through which Western diet contributes to CVD are heavily studied, and increasing evidence suggests that Western diet alters the gut microbiota leading to dysbiosis(i.e., disruption of microbial homeostasis and accompanying intestinal inflammation), contributing to development of vascular dysfunction, a strong predictor of future CVD. Still, the biological processes linking intestinal dysbiosis with the vasculature are incompletely understood. To identify potential mediators of intestinal‐vascular crosstalk, we investigated the role of the gut microbiome in Western diet‐induced global gene expression changes using transcriptomics. We performed total RNA sequencing on colons and arteries (aorta) from wild‐type (WT) and germ‐free (GF, no microbiome) mice fed standard or Western purified diets for 8 weeks. In the colon, we found ~100 differentially expressed genes in standard diet‐fed WT vs. GF mice, and pathway analyses showed that these genes were associated with several important biological processes including peroxisome proliferator‐activated receptor (PPAR) signaling, adipocyte lipolysis regulation, and AMP‐activated protein kinase (AMPK) signaling (genes and pathways, FDR < 0.1). In colons of Western diet‐fed WT vs. GF mice, we found 163 differentially expressed genes related to cancer signaling, mitogen‐activated protein kinase (MAPK) signaling, and viral immune response (FDR < 0.1). Interestingly, in transcriptome analyses of aortas we found significantly different expression of 314 genes in standard diet‐fed WT vs. GF mice, and these were related to complement/coagulation cascades, transforming growth factor beta (TGF‐β), and advanced glycation end product (AGE) signaling, but most of these differences were absent with Western diet (only 4 significantly different genes in WT vs. GF mice, FDR < 0.1). These data suggest that the microbiome is an important mediator of gene expression in the intestine regardless of diet, but may only be important in arteries under standard diet conditions, and that the microbiome may not be a strong mediator of intestinal‐vascular crosstalk at the protein‐coding gene expression level. We are currently performing in‐depth analyses of non‐coding RNAs (e.g., micro‐RNAs) to further elucidate the mechanisms at play.