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

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