Hereditary hemochromatosis promotes colitis and colon cancer and causes bacterial dysbiosis in mice

Hereditary hemochromatosis (HH), an iron-overload disease, is a prevalent genetic disorder. As excess iron causes a multitude of metabolic disturbances, we postulated that iron overload in HH disrupts colonic homeostasis and colon-microbiome interaction and exacerbates the development and progressio...

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Bibliographic Details
Published in:	Biochemical journal Vol. 477; no. 19; p. 3867
Main Authors:	Sivaprakasam, Sathish, Ristic, Bojana, Mudaliar, Nithya, Hamood, Abdul N, Colmer-Hamood, Jane, Wachtel, Mitchell S, Nevels, Anna G, Kottapalli, Kameswara R, Ganapathy, Vadivel
Format:	Journal Article
Language:	English
Published:	England 16-10-2020
Subjects:	Animals Colitis - genetics Colitis - metabolism Colitis - microbiology Colitis - pathology Colonic Neoplasms - genetics Colonic Neoplasms - metabolism Colonic Neoplasms - microbiology Colonic Neoplasms - pathology Dysbiosis - genetics Dysbiosis - metabolism Dysbiosis - microbiology Dysbiosis - pathology Gastrointestinal Microbiome Hemochromatosis - genetics Hemochromatosis - metabolism Hemochromatosis - microbiology Hemochromatosis - pathology Hemochromatosis Protein - deficiency Hemochromatosis Protein - metabolism Mice Mice, Knockout Proteobacteria - classification Proteobacteria - growth & development iron/heme overload colitis HFE-null mouse colon cancer hemochromatosis dysbiosis
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Summary:	Hereditary hemochromatosis (HH), an iron-overload disease, is a prevalent genetic disorder. As excess iron causes a multitude of metabolic disturbances, we postulated that iron overload in HH disrupts colonic homeostasis and colon-microbiome interaction and exacerbates the development and progression of colonic inflammation and colon cancer. To test this hypothesis, we examined the progression and severity of colitis and colon cancer in a mouse model of HH (Hfe-/-), and evaluated the potential contributing factors. We found that experimentally induced colitis and colon cancer progressed more robustly in Hfe-/- mice than in wild-type mice. The underlying causes were multifactorial. Hfe-/- colons were leakier with lower proliferation capacity of crypt cells, which impaired wound healing and amplified inflammation-driven tissue injury. The host/microflora axis was also disrupted. Sequencing of fecal 16S RNA revealed profound changes in the colonic microbiome in Hfe-/- mice in favor of the pathogenic bacteria belonging to phyla Proteobacteria and TM7. There was an increased number of bacteria adhered onto the mucosal surface of the colonic epithelium in Hfe-/- mice than in wild-type mice. Furthermore, the expression of innate antimicrobial peptides, the first-line of defense against bacteria, was lower in Hfe-/- mouse colon than in wild-type mouse colon; the release of pro-inflammatory cytokines upon inflammatory stimuli was also greater in Hfe-/- mouse colon than in wild-type mouse colon. These data provide evidence that excess iron accumulation in colonic tissue as happens in HH promotes colitis and colon cancer, accompanied with bacterial dysbiosis and loss of function of the intestinal/colonic barrier.
ISSN:	1470-8728
DOI:	10.1042/BCJ20200392