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

Abstract

Hereditary hemochromatosis (HH), an iron-overload disease, is a prevalent genetic disorder. As excess iron causes 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 colonic microbiome in Hfe-/- mice in favor of the pathogenic bacteria belonging to phyla Proteobacteria and TM7. There was 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 proinflammatory 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.

Extracellular Citrate Fuels Cancer Cell Metabolism and Growth

“…In this way, influx of extracellular citrate could release not only mitochondria from excess citrate synthesis, reduce ROS production (therefore increase resistance to chemotherapy) but also allow the use of other metabolic pathways like PPP in the most beneficial way for cancer cells. It is therefore not surprising that chronic exposure to excess iron as occurs in the genetic iron-overload disease hemochromatosis transforms normal cells into cells with a tumor phenotype (Gnanaprakasam et al, 2013;Bhutia et al, 2020) and also increases the risk of cancer, particularly liver cancer (Grosse et al, 2018) and colon cancer (Sivaprakasam et al, 2020).…”

Atractylenolide I inhibits antibiotic-induced dysbiosis of the intestinal microbiome

“…The role of the gut microbiome in different type of diseases has been discussed in many previous studies. At present, intestinal dysbacteriosis is considered an important factor during the development of diseases (2,4,(19)(20)(21). The therapeutic influences of AT-I have been discussed in numerous studies; however, reports on the effect of AT-I on the gut microbiome are rare.…”

“…Changes in the number of certain beneficial or harmful bacteria can disrupt the balance of intestinal flora, leading to the possibility of colon cancer. By analyzing the difference in bacterial composition in the stool of healthy people and colorectal cancer patients, it was found that a variety of beneficial bacteria and bacterial diversity in the stool of colorectal cancer patients decreased, and the proportion of harmful bacteria increased significantly (21,22).…”

Consequences of NaCT/SLC13A5/mINDY deficiency: good versus evil, separated only by the blood–brain barrier

“…This is evident from the increased incidence of liver cancer in patients with hemochromatosis, a genetic disease of iron overload [ 71 ]. In fact, the connection between excess iron and cancer could go beyond the liver as our recent studies have demonstrated the connection between hemochromatosis and colon cancer in preclinical mouse models [ 72 ]. The publicly available TCGA (the cancer genome atlas) database indicates that SLC13A5 is also up-regulated several fold in pancreatic adenocarcinoma and that the expression levels have a negative correlation with patient survival.…”