Haem iron reshapes colonic luminal environment: impact on mucosal homeostasis and microbiome through aldehyde formation

Abstract

Background The World Health Organization classified processed and red meat consumption as “carcinogenic” and “probably carcinogenic”, respectively, to humans. Haem iron from meat plays a role in the promotion of colorectal cancer in rodent models, in association with enhanced luminal lipoperoxidation and subsequent formation of aldehydes. Here, we investigated the short-term effects of this haem-induced lipoperoxidation on mucosal and luminal gut homeostasis including microbiome in F344 male rats fed with a haem-enriched diet (1.5 μmol/g) 14–21 days. Results Changes in permeability, inflammation, and genotoxicity observed in the mucosal colonic barrier correlated with luminal haem and lipoperoxidation markers. Trapping of luminal haem-induced aldehydes normalised cellular genotoxicity, permeability, and ROS formation on a colon epithelial cell line. Addition of calcium carbonate (2%) to the haem-enriched diet allowed the luminal haem to be trapped in vivo and counteracted these haem-induced physiological traits. Similar covariations of faecal metabolites and bacterial taxa according to haem-induced lipoperoxidation were identified. Conclusions This integrated approach provides an overview of haem-induced modulations of the main actors in the colonic barrier. All alterations were closely linked to haem-induced lipoperoxidation, which is associated with red meat-induced colorectal cancer risk. Electronic supplementary material The online version of this article (10.1186/s40168-019-0685-7) contains supplementary material, which is available to authorized users.

Systemic iron reduction by venesection alters the gut microbiome in patients with haemochromatosis

“…16 These data, and the changes seen in participant faecal microbiome analysis, support previously published data that propose that haem iron, through its impact on mucosal homeostasis, can alter the colonic luminal environment and, hence, the associated microbiome. 17 Strikingly, in a study by Lee et al examining the effect of oral and intravenous iron supplementation on patients with inflammatory bowel disease, 8 oral iron supplementation was associated with decreased abundances of the bacterial species F. prausnitzii, D. formicigenerans and C. aerofaciens; in this study, the reduction in colonic iron was associated with an increase in these exact species, aligning findings with 2 independent approaches. In particular, a depletion of F. prausnitzii has been implicated in several diseases, including fatty liver disease and inflammatory bowel disease, and therapies to augment its abundance would be of potential clinical benefit.…”

“… 16 These data, and the changes seen in participant faecal microbiome analysis, support previously published data that propose that haem iron, through its impact on mucosal homeostasis, can alter the colonic luminal environment and, hence, the associated microbiome. 17 …”

Molecular Aspects of Colorectal Adenomas: The Interplay among Microenvironment, Oxidative Stress, and Predisposition

“…Indeed, diet prevalently based on red meat and animal fats promotes dysbiosis with a selection of bacterial species that alter bile acid metabolism, with proinflammatory and prooncogenic effects [40]. A crucial role in the colorectal adenoma risk is also referred to a diet rich in heme iron contained in red meat that leads to modification gut barrier homeostasis and microbiota associated with the selection of bacteria linked to inflammation and colorectal adenoma [41]. Heme iron induces the oxidation of dietary polyunsaturated fatty acids and the consequent production of unsaturated aldehydes, such as malondialdehyde and 4hydroxynonenal (HNE), which are cytotoxic [42].…”

“…Colon cells harbouring Adenomatous Polyposis Coli (APC) mutations in rats are resistant to apoptosis induced by HNE, suggesting that lipoperoxidation by heme iron confers to these cells a selective survival advantage [70]. Luminal lipoperoxidation is associated with high levels of mucosal inflammation markers, such as the myeloperoxidase activity with ROS production, increased gene expression of interleukin 6 (IL-6) and transforming growth factor β (TGF-β), and enhanced cellular permeability due to reduced expression of the junctional adhesion molecules [41]. e toxicity of the nitrosylated heme iron seems to act for site-specific etiology of colon adenoma.…”

Red Meat-Derived Nitroso Compounds, Lipid Peroxidation Products and Colorectal Cancer

“…The authors concluded that the stronger Nrf2-dependent antioxidant response could explain the tumor promoting effect of red meat in colorectal carcinogenesis, i.e., by inducing a positive selection of preneoplastic cells [40]. In rats fed a diet supplemented with hemin for 21 days, the lipid peroxidation levels in fecal water were significantly higher than those in fecal water of control rats [41]. These higher luminal lipid peroxidation levels were associated with higher mucosal inflammation markers as revealed by an increased colonic myeloperoxidase activity and an enhanced expression of interleukin-6 and transforming growth factor-β as well as a higher DNA damage in the colonic mucosa of hemin-fed rats when compared to control rats [41].…”