Western Versus Heart Healthy Dietary Pattern Alters Genes Expression Associated with Lipid Metabolism, Interferon Signaling and Inflammation in Jejunum of Ossabaw Pigs

Abstract Objectives A gastrointestinal tract (GI) that allows for bacterial translocation has been associated with enhanced systemic inflammation and may play a critical role in the development of coronary artery disease (CAD). Diet quality and statin therapy are established modulators of CAD, but their effect in GI health is relatively unexplored. Jejunal mucosa gene expression was compared in Ossabaw pigs fed a heart healthy-type diet (HHD) and Western-type diet (WD), with and without statin therapy. Methods Pigs (N = 32) were randomized into 4 groups and fed isocalorically for 6 months: WD (high in saturated fat, refined carbohydrate, cholesterol, and low in fiber) or HHD (high in unsaturated fat, whole grains, fruits and vegetables, fiber, supplemented with fish oil, and low in cholesterol), with or without statin therapy. RNA sequencing was conducted in isolated jejunal mucosa at the end of the study. Principal component analysis, hierarchical clustering and xCell analysis were used to cross-check and ensure consistent sampling. Two-factor edgeR analysis and Ingenuity Pathway Analysis were used to identify genes, pathways, and biological functions altered by diet and/or statin. Independent of groups, Spearman's correlation coefficients were calculated to identify associations between genes of interest and atherosclerotic lesion severity in the coronary arteries or cardiometabolic risk factors (serum triglyceride, LDL, HDL, TNF-α, hsCRP). Results HHD and WD resulted in differential expression of genes related to lipid metabolism (SCD, FADS1, SQLE) in the jejunal mucosa. The expression of these genes was associated with atherosclerotic lesion severity and serum lipoprotein concentrations. Higher interferon signaling and inflammation were observed in pigs fed WD versus HHD. In the jejunal mucosa, 7 genes related to inflammation were significantly associated with serum TNF-α and/or hsCRP concentrations. There was no significant effect of statin on gene expression, nor diet x statin interaction. Expression of genes related to jejunum permeability was unaffected by diet or statin. Conclusions Gene expression in the jejunum of Ossabaw pigs was altered by dietary patterns, but not statin, and linked to atherosclerotic lesion severity associated with lipid metabolism and inflammatory markers. Funding Sources USDA-ARS-NEA, JM-USDA-HNRCA, and Tufts University.