Chronic inflammation leaves long-lasting impression on gut stem cells, increasing colorectal cancer risk
Research news (March 25, 2026): An NIH-part funded mouse study reported that repeated colitis-like injury can leave a long-lasting, heritable “epigenetic memory” in colonic stem cells, characterized by increased AP-1 transcription factor activity persisting for >100 days after inflammation ended. In tumor-initiation models, mice that had recovered from chronic colitis developed colorectal tumors more rapidly than controls, and pharmacologic/genetic blockade of AP-1 abrogated the pro-tumor effect.
Chronic inflammation may imprint colonic stem cells via AP-1, accelerating tumor growth in mice
Type: Research news (not a regulatory approval)
Date: March 25, 2026
Source: NIH/NCI-funded research; Broad Institute of MIT and Harvard
Reference: Nagaraja S, et al. Nature (2026). DOI: 10.1038/s41586-026-10258-4.
Researchers simulating chronic colitis in mice tracked colonic responses during inflammation and recovery and identified a potential molecular link between chronic gut inflammation and colorectal cancer risk.
Across >52,000 single cells profiled from animals and from organoids derived from injured tissue, the investigators identified an epigenetic alteration in colonic stem cells associated with increased activity of AP-1 transcription factors, which regulate cellular stress responses. This “memory” in the epigenome persisted for more than 100 days after removal of colitis-inducing chemicals.
Using an organoid model built from injured mouse tissue, the team reported that the AP-1–linked epigenetic state was heritable, transmitted from stem cells to progeny during cell division.
To assess cancer relevance, tumor-initiating genes were introduced into mice that were either previously healthy or had recovered from chronic colitis. Tumor growth was substantially faster in the colitis-recovered group. Within tumors from recovered animals, AP-1–associated regenerative programs were reported to be elevated; blocking AP-1 activity eliminated the colitis-associated pro-tumor effect.
Authors noted uncertainty regarding translation to humans, but suggested that, if similar mechanisms occur, assays for epigenetic memories could potentially aid earlier risk stratification and that therapeutics targeting post-colitis AP-1 activity might be explored.