Sexual dimorphism in colon is mediated by an androgen-IL33⁺ stromal cell axis

Males and females exhibit pronounced disparity in the epidemiology, clinical progression, and therapeutic outcomes of colonic diseases, but the underlying mechanisms that regulate sexual dimorphism of colon remain poorly understood.

We determined the colon as a pivotal androgen metabolic hub, where gonad-derived androgens drive sex-dimorphic levels, while androgen-metabolizing enzymes maintain androgen homeostasis in colon. We identified IL-33⁺ colonic stromal cells as the dominant AR-expressing population in colon. Mechanistically, sex-biased androgen levels govern the nuclear translocation of androgen receptor and further assembly of AR liquid-liquid phase-separated condensates in the immunomodulatory stromal cells of male colon. Notably, we uncovered AR-directed transcriptional programs via nuclear AR phase separation underlying sex-biased expression of key factors, including SerpinA3N and MT1, thereby defining molecular base for sex disparities through gonad-colon axis.

These findings provide molecular and cellular base for sex disparities through an androgen-IL33⁺ stromal cell axis in colon.