Facilitation of mucosal healing by estrogen receptor β in ulcerative colitis through suppression of branched-chain amino acid transport and subsequent triggering of autophagy in colonic epithelial cells

Colonic mucosal healing is the ultimate goal of ulcerative colitis (UC) treatment, but it remains difficult to realize. Given the higher incidence of UC in males and the beneficial effect of estrogen on UC, we conducted this study to examine the therapeutic potential of estrogen receptor <i>β</i> (ER<i>β</i>), the primary ER subtype in colon, on mucosal healing in UC. Our study is the first to report that ER<i>β</i> activation degree was positively correlated with mucosal healing in patients with UC. Furthermore, ER<i>β</i> activation enhanced mucosal healing in mice with dextran sulfate sodium-induced and biopsy-induced colonic injuries. Mechanistically, ER<i>β</i> activation promoted autophagy of colonic epithelial cells by inhibiting branched-chain amino acid transport, leading to focal adhesion kinase (FAK) activation. Activated FAK promoted focal adhesion turnover and colonic epithelial cell migration, ultimately facilitating mucosal healing. ER<i>β</i> ^-/- colitis mice exhibited impaired mucosal healing compared to wild-type littermates, highlighting the crucial effect of ER<i>β</i>. Importantly, combination with ER<i>β</i>-agonist diarylpropionitrile enhanced the amelioration of 5-aminosalicylic acid, a standard UC treatment agent, against mouse colitis. These findings attest to the crucial role of ER<i>β</i> activation in colonic mucosal healing and may further inform the development of novel strategies for UC treatment.