Chronic intestinal inflammation drives colorectal tumor formation triggered by dietary heme iron in vivo

Abstract

The consumption of red meat is associated with an increased risk for colorectal cancer (CRC). Multiple lines of evidence suggest that heme iron as abundant constituent of red meat is responsible for its carcinogenic potential. However, the underlying mechanisms are not fully understood and particularly the role of intestinal inflammation has not been investigated. To address this important issue, we analyzed the impact of heme iron (0.25 µmol/g diet) on the intestinal microbiota, gut inflammation and colorectal tumor formation in mice. An iron-balanced diet with ferric citrate (0.25 µmol/g diet) was used as reference. 16S rRNA sequencing revealed that dietary heme reduced α-diversity and caused a persistent intestinal dysbiosis, with a continuous increase in gram-negative Proteobacteria. This was linked to chronic gut inflammation and hyperproliferation of the intestinal epithelium as attested by mini-endoscopy, histopathology and immunohistochemistry. Dietary heme triggered the infiltration of myeloid cells into colorectal mucosa with an increased level of COX-2 positive cells. Furthermore, flow cytometry-based phenotyping demonstrated an increased number of T cells and B cells in the lamina propria following heme intake, while γδ-T cells were reduced in the intraepithelial compartment. Dietary heme iron catalyzed formation of fecal N-nitroso compounds and was genotoxic in intestinal epithelial cells, yet suppressed intestinal apoptosis as evidenced by confocal microscopy and western blot analysis. Finally, a chemically induced CRC mouse model showed persistent intestinal dysbiosis, chronic gut inflammation and increased colorectal tumorigenesis following heme iron intake. Altogether, this study unveiled intestinal inflammation as important driver in heme iron-associated colorectal carcinogenesis.

Dietary Inflammatory Index, Obesity, and the Incidence of Colorectal Cancer: Findings from a Hospital-Based Case-Control Study in Malaysia

“…It is generally recognised that specific food items are more likely to trigger chronic gut inflammation, which eventually induces cancer cell proliferation. For instance, a pro-inflammatory western-style diet high in red meat, processed meat, fat, and refined grains may trigger the inflammatory process in the colon that leads to colorectal carcinogenesis, whereas anti-inflammatory diets rich in fruits, vegetables, and fibre may reduce gut inflammation and thus protect against CRC risk [ 6 , 7 , 8 , 9 , 10 , 11 ]. Therefore, assessing the potential impact of diet on inflammation could aid in the development of dietary strategies to reduce inflammation and the risk of CRC.…”

Effects of pork sausage on intestinal microecology and metabolism in mice

“…Many researchers agree that cancer patients have significantly higher levels of Proteobacteria than healthy people. [29][30][31] At the genus level (Fig. 2(B)), 10 bacterial genera were identified as dominant bacteria with the average relative abundance greater than 2%, including Lactobacillus, Lachnospiraceae, Desulfovibrio, Bacteroides, Alistipes, Clostridium_sensu_stricto_1, Streptococcu, Alloprevotella, Helicobacter, and Faecalibacterium.…”

Reduction, removal or replacement of sodium nitrite in a model of cured and cooked meat: a joint evaluation of consequences on microbiological issues in food safety, colon ecosystem and colorectal carcinogenesis

“…Fecal water samples were analysed for NOCs using an Ecomedics CLD88 NO-Analyzer (Eco Physics GmbH, Hürth, Germany) as published recently with slight modifications. [33] See supplementary material for more details.…”