Document Type

Dissertation - Open Access

Award Date

2016

Degree Name

Doctor of Philosophy (PhD)

Department / School

Health and Nutritional Sciences

First Advisor

Moul Dey

Keywords

butyrate cancer stem cells, gut microbiota, histone modifications, phenethyl isothiocyanate, resistant starch type 4

Abstract

Chronic diseases that include seven of the top ten leading causes of premature deaths in the United States demand more than eighty percent of all health care cost. Although typical Western diets--high fat (HF), low fiber and low vegetables-- are frequently associated with increased risk for chronic diseases like obesity, metabolic syndrome (MetS), type 2 diabetes, cardiovascular diseases (CVD), and cancer, there is a lack of mechanistic understanding of a causal relationship between diet and disease phenotypes, particularly in a clinical setting. This dissertation research aimed to address this research gap through the effects of wheat fiber-derived resistant starch type 4 (RS4) in MetS, maternal HF diet on offspring cardiovascular health, and cruciferous vegetablesderived phenethyl isothiocyanate (PEITC) in cancer prevention, using next generation “omics” technologies and molecular nutrition approaches. RS4 flour (30%) enriched differential abundance of 71 bacterial operational taxonomic units in fecal samples obtained from Hutterite participants having MetS. RS4 not only showed butyrogenic effects in humans but also increased cecal mass and butyrate concentration in mice, signifying the role of dietary fiber in bowel health. Butyrate induced tri-methylated lysine 27 on histone 3 (H3K27me3) in the promoter of nuclear factor-kappa-B1 (NFκB1) contributing to epigenetic repression of intestinal inflammation in mice. A genome-wide differential chromatin landscape of histone modifications (H3Ac, H3K4me3, and H3K27me3) was observed in offspring due to their maternal HF (40% kcal) diet, implicating the increased risks for obesity, diabetes, and CVDs beyond one generation. PEITC inhibited cancer stem cell (CSC) marker aldehyde dehydrogenase 1 (ALDH1) with concomitant induction of oxidative stress and apoptosis in cervical CSCs, conferring improved therapeutic outcomes in cancer patients. This dissertation presents a body of translational research work on diet-gene interaction, which is expected to contribute to the fast-growing nutrigenomics knowledgebase and inform about (1) diet-responsive gut microbiota and metabolites, (2) fetal-reprogramming to prevent adult-onset of chronic diseases, and (3) chemo-preventive strategies to improve therapeutic outcomes of cancer by minimizing recurrence and metastasis. Together, these findings will contribute to future dietary recommendations that are expected to be more precise than at current times.

Library of Congress Subject Headings

Nutrition -- Genetic aspects

Nutrient interactions

Nutritionally induced diseases -- Genetic aspects

Genomics

Metagenomics

Diet therapy

Diet in disease

Description

Includes bibliographical references (pages 132-161)

Format

application/pdf

Number of Pages

175

Publisher

South Dakota State University

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Rights Statement

In Copyright