Colon transcriptome is modified by dietary pattern/Atorvastatin interaction in the Ossabaw pig

Authors: YE, SHAMAO - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MATHAN, NIRUPA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LAMON-FAVA, STEPHANIA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; Solano-Aguilar, Gloria; TURNER, JEROLD - Harvard Medical School; WALKER, MAURA - Boston University Medical Center; ZHI, CHAI - Pennsylvania State University; Lakshman, Sukla; Chen, Celine; Dawson, Harry; Urban, Joseph; LICHTENSTEIN, ALICE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/10/2020
Publication Date: 4/1/2021
Citation: Shumao, Y., Nirupa, M., Lamon-Fava, S., Solano Aguilar, G., Turner, J.R., Walker, M.E., Zhi, C., Lakshman, S., Chen, C.T., Dawson, H.D., Urban Jr, J.F., Lichtenstein, A.H. 2021. Colon transcriptome is modified by dietary pattern/Atorvastatin interaction in the Ossabaw pig. Journal of Nutritional Biochemistry. 90:108577. https://doi.org/10.1016/j.jnutbio.2020.108570.
DOI: https://doi.org/10.1016/j.jnutbio.2020.108570

Interpretive Summary: Diet quality and statin therapy are established modulators of coronary artery disease (CAD) progression, but their effect on the gastrointestinal tract (GIT) and subsequent sequelae that could affect CAD progression are relatively unexplored. To address this gap, Ossabaw pigs were randomly assigned to receive two diets with a similar caloric content but different composition. A Western-type diet (WD; high in saturated fat, refined carbohydrate, and cholesterol, and low in fiber) or a heart healthy-type diet (HHD; high in unsaturated fat, whole grains, fruits and vegetables, supplemented with fish oil, and low in cholesterol), with or without atorvastatin, for six months. At the end of the intervention period, colon samples were harvested and processed for RNA extraction, sequencing and analysis of gene expression. Analysis of gene expression and its putative function were analyzed through biological data mining platform. Gene differential expression and putative enrichment of biological pathways indicated that dietary patterns and atorvastatin therapy differentially altered gene expression, with diet-statin interactions. The statin, Atorvastatin, had a more profound effect on differential gene expression than diet. In pigs not receiving atorvastatin, the WD upregulated “LXR/RXR Activation” pathway compared to pigs fed the HHD. Enrichment analysis indicated that atorvastatin therapy lowered inflammatory status in the HHD-fed pigs, whereas, it induced a colitis-like gene expression phenotype in the WD-fed pigs. No significant association was identified between gene expression phenotypes and severity of atherosclerotic lesions in the left anterior descending-left circumflex bifurcation artery. These data suggested diet quality modulated the response to atorvastatin therapy in colonic mucosa, and these effects were unrelated to atherosclerotic lesion development.

Technical Abstract: Optimizing diet quality in conjunction with statin therapy is currently the most common approach for coronary artery disease (CAD) risk management. Although effects on the cardiovascular system have been extensively investigated, little is known about the effect of these interventions in the colon and subsequent associations with CAD progression. To address this gap, Ossabaw pigs were randomly allocated to receive, for a six-month period, isocaloric amounts of either a heart healthy-type diet (HHD; high in unrefined carbohydrate, unsaturated fat, fiber, supplemented with fish oil, and low in cholesterol) or a Western-type diet (WD; high in refined carbohydrate, saturated fat and cholesterol, and low in fiber), without or with atorvastatin therapy. At the end of the intervention period, colon samples were harvested, mucosa fraction isolated, and RNA sequenced. Gene differential expression and enrichment analyses indicated that dietary patterns and atorvastatin therapy differentially altered gene expression, with diet-statin interactions. Atorvastatin had a more profound effect on differential gene expression than diet. In pigs not receiving atorvastatin, the WD upregulated “LXR/RXR Activation” pathway compared to pigs fed the HHD. Enrichment analysis indicated that atorvastatin therapy lowered inflammatory status in the HHD-fed pigs, whereas, it induced a colitis-like gene expression phenotype in the WD-fed pigs. No significant association was identified between gene expression phenotypes and severity of atherosclerotic lesions in the left anterior descending-left circumflex bifurcation artery. These data suggested diet quality modulated the response to atorvastatin therapy in colonic mucosa, and these effects were unrelated to atherosclerotic lesion development.