Dietary iron modulates gut microbiota and induces SLPI secretion to promote colorectal tumorigenesis

Abstract

Dietary iron intake is closely related to the incidence of colorectal cancer. However, the interactions among dietary iron, gut microbiota, and epithelial cells in promoting tumorigenesis have rarely been discussed. Here, we report that gut microbiota plays a crucial role in promoting colorectal tumorigenesis in multiple mice models under excessive dietary iron intake. Gut microbiota modulated by excessive dietary iron are pathogenic, irritating the permeability of the gut barrier and causing leakage of lumen bacteria. Mechanistically, epithelial cells released more secretory leukocyte protease inhibitor (SLPI) to combat the leaked bacteria and limit inflammation. The upregulated SLPI acted as a pro-tumorigenic factor and promoted colorectal tumorigenesis by activating the MAPK signaling pathway. Moreover, excessive dietary iron significantly depleted Akkermansiaceae in the gut microbiota; while supplementation with Akkermansia muciniphila could successfully attenuate the tumorigenic effect from excessive dietary iron. Overall, excessive dietary iron perturbs diet – microbiome–epithelium interactions, which contributes to intestinal tumor initiation.

Dose-Responsive Effects of Iron Supplementation on the Gut Microbiota in Middle-Aged Women

“…Akkermansia species are typical mucin-degrading bacteria with proven benefits in maintaining gut barrier function, short-chain fatty acid production, and in counteracting intestinal inflammation [ 45 , 46 ]. Decreases of Akkermansia have also been observed in specific-pathogen-free mice fed a high iron diet [ 47 ] and in colorectal cancer mice with excessive iron intake [ 48 ]. In addition to Akkermansia , species of Faecalibacterium also colonize the mucus layer.…”

Nutritional Support: The Use of Antioxidants in Inflammatory Bowel Disease

“…In addition, the number of bacteria such as Proteobacteria increases, while the number of Lachnospiraceae decreases, with which iron may exacerbate dysbiosis in IBD [150]. Due to the irritation and affected permeability of the intestinal barrier fromexcessive iron, epithelial cells secrete increased amounts of secretory leukocyte protease inhibitor (SLPI), which, in large amounts, can be a pro-cancer factor [151]. In addition, some microbial communities also show an association with parameters associated with ferroptosis [152].…”