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The consumption of red meat is probably carcinogenic to humans and is associated with an increased risk to develop colorectal cancer (CRC). Red meat contains high amounts of heme iron, which is thought to play a causal role in tumor formation. In this study, we investigated the genotoxic and cytotoxic effects of heme iron (i.e., hemin) versus inorganic iron in human colonic epithelial cells (HCEC), human CRC cell lines and murine intestinal organoids. Hemin catalyzed the formation of reactive oxygen species (ROS) and induced oxidative DNA damage as well as DNA strand breaks in both HCEC and CRC cells. In contrast, inorganic iron hardly affected ROS levels and only slightly increased DNA damage. Hemin, but not inorganic iron, caused cell death and reduced cell viability. This occurred preferentially in
non-malignant HCEC, which was corroborated in intestinal organoids. Both hemin and inorganic iron were taken up into HCEC and CRC cells, however with differential kinetics and efficiency. Hemin caused stabilization and nuclear translocation of Nrf2, which induced heme oxygenase-1 (HO-1) and ferritin heavy chain (FtH). This was not observed after inorganic iron treatment. Chemical inhibition or genetic knockdown of HO-1 potentiated hemin-triggered ROS
generation and oxidative DNA damage preferentially in HCEC. Furthermore, HO-1 abrogation strongly augmented the cytotoxic effects of hemin in HCEC, revealing its pivotal function in colonocytes and highlighting the toxicity of free intracellular heme iron. Taken together, this study demonstrated that hemin, but not inorganic iron, induces ROS and DNA damage, resulting in a preferential cytotoxicity in non-malignant intestinal epithelial cells. Importantly, HO-1
conferred protection against the detrimental effects of hemin.
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
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.