Estrogen deficiency in postmenopausal women disrupts reproductive, metabolic, brain, and gut health, partly by promoting inflammation, oxidative stress, and gut dysbiosis. Together, responsible for the development of gut-brain axis (GBA) dysfunction. Daily life stressors in women, particularly chronic stress, may further exacerbate this dysfunction; however, their synergistic effects with estrogen deficiency remain poorly understood. The current study aimed to develop an animal model of GBA dysfunction that mimics postmenopausal conditions. To induce GBA dysfunction, female Sprague Dawley rats were bilaterally ovariectomized (OVX) and exposed to chronic unpredictable mild stress (CUMS) for 28 days. To confirm GBA dysfunction, neurobehavioral, biochemical, molecular, and histopathological parameters were performed. We observed significant changes in physiological, & neurobehavioral parameters in OVX, CUMS, and OVX + CUMS group rats. We also observed marked enhancement in oxidative stress, neuroinflammation, and reduced acetylcholinesterase activity in the brain, and increased corticosterone levels in serum of OVX, CUMS, and OVX + CUMS group rats. Furthermore, we also observed a marked increase in pro-inflammatory cytokines, oxidative stress, reduction in MUC-2 and tight junction gene expression in the proximal colon, and changes in gut bacterial abundances in the feces of experimental groups. Histopathological examination revealed pronounced morphological damage in the proximal colon and brain of OVX, CUMS, and OVX + CUMS group rats. Thus, estrogen deficiency and chronic stress for one month synergistically induce GBA dysfunction. This developed animal model provides a robust platform for exploring novel therapeutic strategies to counteract GBA dysfunction arising from estrogen deficiency and chronic stress.
