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.