Fructooligosaccharide ameliorates estrogen-gut-microbiome-brain axis dysfunction in estrogen-deficient rats

Reduced levels of circulating gonadal hormones in post-menopausal women can negatively affect various physiological functions, including brain and gut deficits. There is an urgent need to find novel strategies to mitigate estrogen-gut-microbiome-brain axis (EGMBA) dysfunction. This study aimed to investigate the effect of fructooligosaccharide (FOS), a non-digestible prebiotic fiber, on estrogen deficiency-induced alterations in the EGMBA using an ovariectomized (OVX) rat model. Adult female SD rats were bilaterally OVX to induce estrogen deficiency and associated EGMBA dysfunction. Rats were administered FOS (50 mg kg^-1 p.o.^-1) for 28 consecutive days. To assess EGMBA dysfunction, after 28 days, we performed behavioral tests, biochemical estimations (oxidative stress), molecular estimations (inflammatory markers via ELISA), gene expression analysis (HPA axis, monoamine neurotransmission, apoptosis, gut microbiota alterations, & gut barrier integrity via RT-PCR/qPCR), and histopathological analysis. Administration of FOS significantly improved behavioral outcomes (reducing anxiety and depression, and improving memory). FOS also attenuates oxidative stress and inflammatory markers. FOS regulates apoptosis (upregulation of BCL-2 and downregulation of Bax), HPA axis functioning (corticosterone, GR, MR, & CRH), and monoamine neurotransmission (MAO-A & COMT) in the hippocampus of OVX rats. FOS also promoted healthy cell growth and prevented apoptosis. Additionally, FOS restored gut microbial eubiosis, improved mucus secretion (MUC-2), preserved tight junction protein expression (Lipocalin-2, Claudin, & TLR-4), and maintained the colon microstructure. FOS exerts multifaceted protective effects on the EGMBA by modulating gut and brain functions. These findings support its potential as a non-hormonal therapeutic approach for managing postmenopausal complications.