Obesity, Iron Regulation and Colorectal Cancer Risk

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.

Typical American Diet with "high" heme/non-heme iron (16 mg) Typical American Diet with "low" iron (8 mg) Plant-based Diet with "high" non-heme iron (16 mg)

A "Typical American" diet with "high" heme/non-heme iron" (18 mg total). Diet is isocaloric and has a macronutrient composition of total fat 35%, carbohydrates 50%, protein 15% of calories and fiber 9g/1000 calories. Subjects consumes the diet for 3 weeks with a minimum 3 week washout before the next diet.

A "Typical American" diet with "low" heme/non-heme iron" (8 mg total). Diet is isocaloric and has a macronutrient composition of total fat 35%, carbohydrates 50%, protein 15% of calories and fiber 9g/1000 calories. Subjects consumes the diet for 3 weeks with a minimum 3 week washout before the next diet.

A plant-based diet with "high" non-heme iron" (18 mg total). Diet is isocaloric and has a macronutrient composition of total fat 35%, carbohydrates 50%, protein 15% of calories and fiber 9g/1000 calories. Subjects consumes the diet for 3 weeks with a minimum 3 week washout before the next diet.

Fecal calprotectin, a proxy for colon tissue inflammation, will be measured from stool an calprotectin immunoassay

Circulating C-reactive protein, Interleukin-6 (IL-6) and Tumor necrosis factor-alpha (TNF-a) will be measured from serum using immunoassays.

Stool samples to analyze the composition of the microbiota, extracted bacterial genomic DNA will be used as a template for polymerase chain reactions targeting the V4 variable regions of the 16S ribosomal ribonucleic acid gene. Amplicons generated from polymerase chain reaction will be run on the Illumina MiSeq sequencing platform to profile microbial communities at the phylum and genus level.

Inclusion Criteria: Self-identify as Hispanic, African American, or Caucasian. Meet body mass index (BMI > = 30.0 kg/m2) and C-reactive protein (CRP) criteria (> 2.0 mg/dl) Post-menopausal (no menstruation in the past 12 months) Weight stable (< 3% weight change in the past 3 months) Non-smoker No major medical problems Have a working phone No known allergies, intolerance, medical, secular or religious dietary restrictions Exclusion Criteria: Chronic constipation (less than three stools per week for several months) History or intestinal cancer, inflammatory bowel disease, celiac disease, or malabsorptive bariatric surgery Previous intestinal surgery H pylori infection or taking H2 blockers (e.g., Zantac, Pepcid) /antacids (e.g., Rolaids) more than 3 times per week Significant blood loss or blood donation in past 3 months Active gastrointestinal bleed Any surgery in the past 3 months Hemochromatosis Sickle cell disease Hereditary polyposis Rheumatoid arthritis Type I or Type II diabetes Smoker Antibiotic use in the past 2 months Excessive alcohol consumption [> 2 standard alcoholic drinks (12 ounces of beer, 5 ounces of wine, 1 shot of hard liquor) per day] Aspirin use >81 mg/day OR >325 mg/every other day Regularly taking probiotics, fiber supplements, Orlistat (over the counter brand name: Alli), or steroids (inhaled or oral)