Intestinal ERβ loss: a missing link between estrogen deficiency and cognitive impairment

Estrogen receptor β (ERβ) expression, enriched in the hippocampus and intestinal epithelium, critically modulates cognition. However, the precise role of intestinal ERβ in mediating gut-brain axis homeostasis and cognition remains elusive. In this study, we aimed to investigate the impact of ERβ on cognitive performance through the lens of intestinal epithelial barrier (IEB) permeability. Based on a meta-analysis and a bilateral ovariectomized mouse model, we speculated that long-term estrogen deficiency could significantly inhibit intestinal ERβ expression. Inhibited ERβ expression could increase IEB permeability, thereby triggering lipopolysaccharide-driven systemic inflammation. Moreover, mice with long-term estrogen deficiency exhibited exacerbated cognitive deficits, characterized by poorer spatial learning memory and heavier anxiety-like behaviors. Notably, pharmacological activation of ERβ (via liquiritigenin) could ameliorate these deficits by restoring IEB barrier function and mitigating neuroinflammation. Selective knockout of intestinal epithelial ERβ in mice could phenocopy the observed deficits in gut-brain barriers and cognition, further underscoring its pivotal role in maintaining IEB permeability. Collectively, our findings establish a mechanistic link between estrogen deficiency, IEB dysfunction, and cognitive impairment, highlighting intestinal epithelial ERβ activation as a promising therapeutic strategy for late postmenopausal cognitive impairment.