Work

Estrogen receptor β deficiency increases the susceptibility to ulcerative colitis by inducing mitochondrial fission and consequently accelerating senescence of colonic epithelial cells

Year: 2025

Type: article

Abstract: The incidence of ulcerative colitis (UC) is significantly higher among individuals with colonic estrogen receptor β (ER β ) deficiency, such as postmenopausal women, but the involvement of ER β deficiency in UC pathogenesis remains obscure. Here, we showed that colonic ER β expression level in UC patients was negatively correlated with disease severity. In mice, ER β knockout induced spontaneous colitis-like symptoms and increased susceptibility to dextran sulfate sodium-induced colitis, with earlier onset and aggravated severity, whereas ER β overexpression reduced colitis susceptibility. Transcriptomic analysis and subsequent validation in UC patient samples revealed that ER β deficiency in colonic epithelial cells accelerated cellular senescence, which concurrently causing disruption of epithelial barrier and release of proinflammatory cytokines, ultimately increasing susceptibility to colitis. Mechanistically, ER β deficiency induced mitochondrial fission, resulting in mitochondrial DNA leakage and cGAS-STING pathway activation, thereby accelerating colonic epithelial cell senescence. Consistently, pre-administration of the phytoestrogens genistein and arctigenin attenuated mitochondrial fission-induced colonic epithelial cell senescence of mice through upregulating ER β expression, thereby markedly reducing susceptibility to colitis. In summary, our findings identify ER β as a susceptibility gene and therapeutic target for UC, unveil mitochondrial fission induced-colonic epithelial cell senescence as a novel UC pathogenic mechanism, and suggest that high dietary intake of phytoestrogen-rich foods may mitigate susceptibility to UC. ER β deficiency triggers mitochondrial fission-induced colonic epithelial cell senescence, disrupting colonic barrier integrity and exacerbating intestinal inflammation to increase UC susceptibility, while pretreatment of phytoestrogen effectively mitigates the susceptibility. • Colonic ER β expression level was negatively correlated with UC severity • ER β deficiency increased susceptibility of mice to DSS-induced colitis • ER β deficiency accelerated epithelial cell senescence to cause colonic inflammation • ER β deficiency induced mitochondrial fission and cGAS-STING pathway activation • Pretreatment of phytoestrogen reduced the susceptibility of mice to colitis

Source: Redox Biology

DOI: 10.1016/j.redox.2025.103919