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.
Acknowledgments
This project has received funding from the National Natural Science Foundation of China (U21A20344; 81902938; 82100588). We acknowledge funding and support from Natural Science Foundation of Guangdong Province, China (2020A1515011248), and funding from Guang Dong Basic and Applied Basic Research Foundation (2019A1515110032). This project was also supported by National Key Clinical Discipline and Guang Dong Cheung Kong Philanthropy Foundation. The image in Supplementary Data Figure 8 were created using BioRender.
Author contributions
C.L., J.G., Q.Z., G.C., S.Y., and Z.L. performed the experiments; J.Y. and W.Z helped analyze the data; Z.H., J.G., and P.L. supervised the project; C.L. and J.G. wrote and revised the manuscript.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials. The 16S rDNA-sequencing data was deposited in the Sequence Read Archive (SRA; https://www.ncbi.nlm.nih.gov/sra) under the accession number: PRJNA907929.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2221978