- 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.
