The Gut-brain axis (GBA) plays a crucial role in neuroendocrine homeostasis, and its dysregulation due to estrogen deficiency is associated with cognitive decline, mood disorders, and gut microbiome disturbances in postmenopausal women. The gut microbiome involved in estrogen metabolism, known as the estrobolome, regulates β-glucuronidase activity, which influences estrogen reactivation and systemic availability. Reduced estrobolome function and altered β-glucuronidase activity in post-menopause may exacerbate GBA dysfunction. Thus, strategies that modulate the estrobolome and enhance β-glucuronidase may be beneficial in improving postmenopausal GBA dysfunction. With this background, our study aims to determine the effect of soy isoflavone (SIF) on GBA dysfunction in estrogen-deficient rats. To induce GBA dysfunction, rats were first bilaterally ovariectomized (OVX) and, after one week, treated with SIF (40 and 80 mg/kg)/17β-estradiol (17βE2) for 28 days. In OVX rats, one-month administration of SIF maintained estrogen receptor-β (ER-β) expression over estrogen receptor-α (ER-α), preserved gut eubiosis by modulating the estrobolome, increased β-glucuronidase enzyme and GUSB gene levels. Additionally, SIF also restores physiological and neurobehavioral parameters. In addition to this, SIF regulates mucosal integrity, tight junction genes, inflammatory markers, oxidative stress, monoamine neurotransmission, hypothalamic-pituitary axis regulations, and apoptosis. Comparative profiling of SIF with 17βE2 shows that 17βE2 improves gut and brain health, while preserving serum estradiol levels and uterine horn weight. This may enhance the feminizing side effects of 17βE2. However, SIF did not show any uterotrophic effect. SIF at doses of 40 and 80 mg/kg may offer a safer alternative to 17βE2 for managing GBA dysfunction in postmenopausal women.
