Increases in the Concentrations of Available Iron in Response to Dietary Iron Supplementation Are Associated with Changes in Crypt Cell Proliferation in Rat Large Intestine , ,

Abstract

High concentrations of iron in the diet have been shown to increase chemically induced colorectal tumors in rats. It is therefore important to understand the influence of dietary iron on the concentration of unabsorbed iron in the large intestine and its distribution between soluble and insoluble pools in the luminal compartment. We sought to investigate this issue and to establish whether iron modifies mucosal cell proliferation, which is thought to influence initiation and progression through the adenoma carcinoma sequence. In the first experiment, four groups of seven rats were fed diets at two concentrations of iron, 29 and 102 mg/kg, with or without the addition of 2.5 g phytic acid/kg. The concentrations of iron in the contents of the large bowel extractable with water ("free iron") or a buffered EDTA solution ("exchangeable iron") were determined. The concentration of freely soluble iron increased approximately 100% with iron supplementation in both the cecum and the colon, and there was an approximately five- to sixfold increase in exchangeable iron at both sites (P < 0. 05). In a second experiment with identical feeding conditions, there was a significantly greater number of cell divisions per crypt in the colon of the high iron group and a significantly greater number of cell divisions in the upper part of the crypt in the cecum. The concentrations of free and exchangeable iron observed in colonic contents in this study are consistent with those reported by others to increase free radical production in fecal material. Further studies are required to determine whether the small changes in crypt cytokinetics are a consequence of oxidative mucosal damage.

Effects of Iron Overload on Growth and Intestinal Mucosa in Rats

“…It has been suggested that chronic iron intake can affect intestinal homeostasis by altering intestinal microbial composition, oxidative stress, inflammation, etc. [13,15,16,[17][18][19] .…”

Iron and colorectal cancer risk in the α‐tocopherol, β‐carotene cancer prevention study

“…3,18 Furthermore, tumor cells have a greater ability than normal cells to grow and survive in the presence of high concentrations of iron 19 ; when iron is deficient, the rate of tumor growth actually decreases. 20 There are two distinct routes of exposure to iron.…”

Dietary Iron Overload: Short- and Long-Term Effects on Cecal Morphometry in Growing Rats

“…Considering that fractional intestinal Fe absorption is frequently low, with minor variations depending on the food matrix or the physiological state, unabsorbed Fe in the small intestine reaches the large intestine in an "available" form within the range required for significant free radical production (8)(9)(10). These effects would impact (a) the mucosal barrier integrity by affecting the cellular dynamics and permeability in intestinal mucosa, as well as (b) the microbial composition and metabolic activity by stimulating the growth and pathogenicity of intestinal bacteria (9,(26)(27)(28).…”

“…Interestingly, only at this time point were these effects significantly associated with liver Fe stores, suggesting that increased liver Fe accumulation could have occurred as morphological changes took place in the intestine. Crypt hyperplasia in the large intestine has been shown in rodent studies after Fe supplementation, such as inorganic salts (9) or heme Fe (27), and could occur as a compensatory response to injury induced by excess Fe in the intestinal lumen (27). Although we used a dietary Fe loading at approximately 10 times the recommended levels for rodents (14), other authors have reported changes in crypt cellularity and lipid peroxidation with milder dietary Fe contents (approximately 100 mg Fe/kg diet) but with longer experiments (.6 mo) (9,10).…”