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Hereditary hemochromatosis promotes colitis and colon cancer and causes bacterial dysbiosis in mice.
- Source :
-
The Biochemical journal [Biochem J] 2020 Oct 16; Vol. 477 (19), pp. 3867-3883. - Publication Year :
- 2020
-
Abstract
- 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.<br /> (© 2020 The Author(s).)
- Subjects :
- Animals
Hemochromatosis Protein deficiency
Hemochromatosis Protein metabolism
Mice
Mice, Knockout
Proteobacteria classification
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
Proteobacteria growth & development
Subjects
Details
- Language :
- English
- ISSN :
- 1470-8728
- Volume :
- 477
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- The Biochemical journal
- Publication Type :
- Academic Journal
- Accession number :
- 32955078
- Full Text :
- https://doi.org/10.1042/BCJ20200392