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 (ERβ) deficiency, such as postmenopausal women, but the involvement of ERβ deficiency in UC pathogenesis remains obscure. Here, we showed that colonic ERβ expression level in UC patients was negatively correlated with disease severity. In mice, ERβ knockout induced spontaneous colitis-like symptoms and increased susceptibility to dextran sulfate sodium-induced colitis, with earlier onset and aggravated severity, whereas ERβ overexpression reduced colitis susceptibility. Transcriptomic analysis and subsequent validation in UC patient samples revealed that ERβ 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, ERβ 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 ERβ expression, thereby markedly reducing susceptibility to colitis. In summary, our findings identify ERβ 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.