Aerobic Exercise Mitigates Perimenopausal Dysfunction and Is Associated With Gut Microbiota Remodeling and Multi‐Organ Crosstalk

Perimenopause represents a multifactorial physiological transition characterized by metabolic disruption, inflammation, oxidative stress, bone loss, reproductive decline, and heightened anxiety risk. This study establishes a letrozole-induced perimenopausal zebrafish model to evaluate whether aerobic exercise (AE) is associated with restored systemic homeostasis alongside gut microbiota remodeling. AE normalized estradiol levels, improved lipid and redox profiles, reduced pro-inflammatory cytokines, and elevated IL-10 expression, indicating recovery of metabolic-immune balance. Behavioral and neurochemical analyses revealed reduced cortisol and restored monoamine turnover, consistent with alleviated anxiety-like behavior. Histological and biochemical assays demonstrated enhanced scale mineralization, increased alkaline phosphatase activity, decreased tartrate-resistant acid phosphatase, and reduced oocyte apoptosis, reflecting improved skeletal and reproductive function. 16S rRNA sequencing confirmed that AE reshaped gut microbial structure, enriching Bacillota and Cetobacterium while depleting Pseudomonadota and Legionella. Correlation analyses linked these microbial shifts with systemic biochemical and behavioral restoration, revealing a coordinated gut-brain-bone-ovary network. These findings identify AE as a system-level intervention that alleviates perimenopausal dysfunction and is accompanied by microbiota remodeling and coordinated multi-organ changes, providing a framework for future combinatorial strategies integrating exercise with dietary or pharmacological interventions to sustain female health during midlife transition.