Effects of a Mediterranean Diet Intervention on Anti- and Pro-Inflammatory Eicosanoids, Epithelial Proliferation, and Nuclear Morphology in Biopsies of Normal Colon Tissue

Abstract

This randomized trial evaluated the effects of intervention with either a Healthy Eating or a Mediterranean diet on colon biomarkers in 120 healthy individuals at increased colon cancer risk. The hypothesis was that eicosanoids and markers of proliferation would be favorably affected by the Mediterranean diet. Colon epithelial biopsy tissues and blood samples were obtained at baseline and after 6 mo of intervention. Colonic eicosanoid concentrations were evaluated by HPLC-MS-MS, and measures of epithelial proliferation and nuclear morphology were evaluated by image analysis of biopsy sections. There was little change in proinflammatory eicosanoids and in plasma cytokine concentrations with either dietary intervention. There was, however, a 50% increase in colonic prostaglandin E₃ (PGE₃), which is formed from eicosapentanoic acid, in the Mediterranean arm. Unlike PGE₂, PGE₃, was not significantly affected by regular use of non-steroidal anti-inflammatory drugs at baseline, and normal weight subjects had significantly higher colon PGE₃ than overweight or obese subjects. Increased proliferation in the colon at baseline, by Ki67 labeling, was associated with morphological features that defined smaller nuclei in the epithelial cells, lower colon leukotriene concentrations and higher plasma cytokine concentrations. Dietary intervention had little effect on measures of epithelial proliferation or of nuclear morphology. The increase in PGE₃ with a Mediterranean diet indicates that in normal colon, diet might affect protective pathways to a greater extent than proinflammatory and proliferative pathways. Hence, biomarkers from cancer models might not be relevant in a true prevention setting.

ACKNOWLEDGMENTS

We thank all the individuals who volunteered for the Healthy Eating Study for Colon Cancer Prevention. Mary S. Rapai was the coordinator for the study and Maria Cornellier was the study dietitian. We thank Dr. Daniel Normolle for initial study planning and Joel Whitfield for assay of plasma cytokines.

FUNDING

The study was supported by NIH grants RO1 CA120381, P50 CA130810 (GI SPORE), Cancer Center Support Grant P30 CA046592 (Immunology Core Laboratory), the Ann Arbor VA Geriatric Research Center, and the Kutsche Family Endowed Chair. The study used core resources supported by a Clinical Translational Science Award, NIH grant UL1RR024986 (the Michigan Clinical Research Unit), by the Michigan Diabetes Research Center, NIH grant 5P60 DK20572 (Chemistry Laboratory), and the Michigan Nutrition and Obesity Research Center, NIH grant P30 DK089503.