Loss of aryl hydrocarbon receptor potentiates FoxM1 signaling to enhance self‐renewal of colonic stem and progenitor cells

The aryl hydrocarbon receptor (AhR), a ligand‐activated transcription factor that senses xenobiotics, diet, and gut microbial‐derived metabolites, is increasingly recognized as a key regulator of intestinal biology. However, its effects on the function of colonic stem and progenitor cells remain largely unexplored. Here, we observed that inducible deletion of AhR in Lgr5 + stem cells increases the percentage of colonic stem cells and enhances organoid initiating capacity and growth of sorted stem and progenitor cells, while AhR activation has the opposite effect. Moreover, intestinal‐specific AhR knockout increases basal stem cell and crypt injury‐induced cell proliferation and promotes colon tumorigenesis in a preclinical colitis‐associated tumor model by upregulating FoxM1 signaling. Mechanistically, AhR transcriptionally suppresses FoxM1 expression. Activation of AhR in human organoids recapitulates phenotypes observed in mice, such as reduction in the percentage of colonic stem cells, promotion of stem cell differentiation, and attenuation of FoxM1 signaling. These findings indicate that the AhR‐FoxM1 axis, at least in part, mediates colonic stem/progenitor cell behavior. Synopsis The aryl hydrocarbon receptor (AhR), a ligand‐activated transcription factor, senses cues from environmental toxicants and dietary/microbiota‐derived tryptophan metabolites. Here, AhR signaling is implicated in the maintenance and functionality of colonic stem/progenitor cells via regulation of FoxM1 expression, subsequently affecting colon tumorigenesis. AhR knockout expands the intestinal stem cell population. AhR activation decreases the clonogenic capacity of colonic stem/progenitor cells both in mice and human organoids. AhR acts as a transcriptional suppressor of FoxM1 to control cell proliferation. Loss of AhR in intestinal epithelial cells promotes colitis‐associated colon tumorigenesis. Graphical Abstract Suppression of FoxM1 expression provides diet metabolite‐sensing transcription factor AhR with an intestinal crypt‐specific role in preventing colon tumorigenesis.