Background <p>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.</p> Results <p>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.</p> Conclusion <p>These findings provide molecular and cellular base for sex disparities through an androgen-IL33⁺ stromal cell axis in colon.</p>