Colorectal cancer (CRC) is a heterogeneous disease of the intestinal epithelium that is characterized by the accumulation of mutations and a dysregulated immune response. Up to 90% of disease risk is thought to be due to environmental factors such as diet, which is consistent with a growing body of literature that describes an ‘oncogenic’ CRC-associated microbiota. Whether this dysbiosis contributes to disease or merely represents a bystander effect remains unclear. To prove causation, it will be necessary to decipher which specific taxa or metabolites drive CRC biology and to fully characterize the underlying mechanisms. Here we discuss the host–microbiota interactions in CRC that have been reported so far, with particular focus on mechanisms that are linked to intestinal barrier disruption, genotoxicity and deleterious inflammation. We further comment on unknowns and on the outstanding challenges in the field, and how cutting-edge technological advances might help to overcome these. More detailed mechanistic insights into the complex CRC-associated microbiota would potentially reveal avenues that can be exploited for clinical benefit.
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We thanks N. Ilott for conceiving and generating Fig. 1, as well as M. Friedrich, T. Griseri, S. Leedham, C. Pearson and M. Pohin for their input after reading the manuscript. This work was supported by the Cancer Research UK (CRUK) grant OPTIMISTICC (C10674/A27140). A.J. has received support from the Oxford–Medical Research Council Doctoral Training Partnership (MRC DTP) and the Kennedy Trust for Rheumatology Research. E.H.M. is supported by an MRC Experimental Medicine Grant (MR/N02690X/1).
F.P. discloses the receipt of grants and research support from Roche and Janssen, and consulting fees from GSK, Genentech and Kintai Therapeutics.
Peer review information Nature thanks Nicola Segata and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Janney, A., Powrie, F. & Mann, E.H. Host–microbiota maladaptation in colorectal cancer. Nature 585, 509–517 (2020). https://doi.org/10.1038/s41586-020-2729-3