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Obesity, Iron Regulation and Colorectal Cancer Risk

ABSTRACT: Obesity is an independent risk factor for colorectal cancer (CRC) although the underlying mechanisms have not been elucidated. Dietary nutrients play a key role in both the prevention and promotion of CRC. While iron is an essential nutrient, excess iron is associated with carcinogenesis. Unlike the systemic compartment, the intestinal lumen lacks an efficient system to regulate iron. In conditions when dietary iron malabsorption and intestinal inflammation co-exist, greater luminal iron is associated with increased intestinal inflammation and a shift in the gut microbiota to more pro-inflammatory strains. However, treatments designed to reduce luminal, including diet restriction and chelation, are associated with lower intestinal inflammation and the colonization of protective gut microbes. Obesity is associated with inflammation-induced, hepcidin-mediated, iron metabolism dysfunction characterized by iron deficiency and dietary iron malabsorption. Obesity is also linked to intestinal inflammation. Currently, there is a fundamental gap in understanding how altered iron metabolism impacts CRC risk in obesity. The investigator’s objective is to conduct a crossover controlled feeding trial of: 1) a "Typical American" diet with "high" heme/non-heme iron", 2) a "Typical American" diet with "low" iron, and 3) a Mediterranean diet with "high" non heme iron and examine effects on colonic and systemic inflammation and the gut microbiome.

DISEASE(S): Obesity,Iron Malabsorption,Colon Inflammation,Malabsorption Syndromes,Diet Modification

PROVIDER: 2274754 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Carotenoids are naturally occurring pigments in plants responsible for the orange, yellow, and red color of fruits and vegetables. Carrots are one of the primary dietary sources of carotenoids. The biological activities of carotenoids in higher organisms are well documented in most tissues but not the large intestine. The gastrointestinal barrier acts as a line of defense against the systemic invasion of pathogenic bacteria, especially at the colonic level. Proteins involved in tight junction assembly between epithelial cells and mucus secretion from goblet cells are essential for maintaining intestinal barrier homeostasis. A high-fat diet can cause gut impairment by inducing barrier permeability, leading to low-grade chronic inflammation via metabolic endotoxemia. Our hypothesis for this study is that the dietary intake of carotenoid-rich foods can alleviate obesity-associated gut inflammation and strengthen the intestinal barrier function. Male C57BL/6J mice were randomized to one of four experimental diets for 20 weeks (n = 20 animals/group): Low-fat diet (LFD, 10% calories from fat), high-fat diet (HFD, 45% calories from fat), HFD with white carrot powder (HFD + WC), or HFD with orange carrot powder (HFD + OC). Colon tissues were harvested to analyze the biochemical effects of carotenoids in carrots. The distal sections were subjected to isobaric labeling-based quantitative proteomics in which tryptic peptides were labeled with tandem mass tags, followed by fractionation and LC-MS/MS analysis in an Orbitrap Eclipse Tribrid instrument. High-performance liquid chromatography results depicted that the HFD+WC pellets were carotenoid-deficient, and the HFD+OC pellets contained high concentrations of provitamin A carotenoids, specifically α-carotene and β-carotene. As a result of the quantitative proteomics, a total of 4410 differentially expressed proteins were identified. Intestinal barrier-associated proteins were highly upregulated in the HFD+OC group, particularly mucin-2 (MUC-2). Upon closer investigation into mucosal activity, other proteins related to MUC-2 functionality and tight junction management were upregulated by the HFD+OC dietary intervention. Carotenoid-rich foods may prevent high-fat diet-induced intestinal barrier disruption by promoting colonic mucus synthesis and secretion in mammalian organisms.

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Obesity, Iron Regulation and Colorectal Cancer Risk

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