Multiorgan and gut microbial alterations in ovariectomized mice: a multiomics analysis.

INTRODUCTION: Postmenopausal metabolic dysfunction is increasingly recognized as a multisystem disorder associated with estrogen deficiency, yet how gut microbial, metabolic, and tissue-level alterations co-occur across organs remains incompletely characterized.

METHODS: Here, we used an ovariectomy (OVX) mouse model and an integrated multiomics strategy to characterize systemic alterations in gut microbiota, metabolites in colonic contents and circulation, and tissue-level molecular profiles across the colon, liver, skeletal muscle, and bone.

RESULTS: OVX mice showed higher body weights at multiple postoperative time points, lower serum estradiol concentrations, differences in selected inflammatory and bone-turnover markers, representative histological differences across multiple tissues, and OVX-Sham differences in femoral microarchitecture. Shotgun metagenomic profiling showed significant differences in gut microbial composition, with lower evenness-sensitive diversity and differences in dominant taxa. Metabolomic profiling of colonic contents demonstrated global differences in the luminal metabolic profile, including lower relative abundances of major short-chain fatty acids, differences in bile acid composition, and prominent tryptophan-related features. At the host interface, colonic transcriptomic analysis identified annotations related to epithelial membrane polarity, vesicle trafficking, endoplasmic reticulum protein processing, and bile acid- and energy-sensing pathways. Among the 19 differential circulating bile acids and short-chain fatty acids, most were lower in OVX mice. Feature-level analyses identified multiple hepatic metabolite and bile acid differences, whereas the hepatic transcriptome did not show significant global separation; differential-expression and gene-set enrichment analyses nonetheless identified selected differences related to lipid metabolism, energy metabolism, and molecular transport. Distal tissues also displayed molecular differences, including a significant global transcriptomic difference in skeletal muscle and a significant global metabolomic difference in bone; differential bone metabolites were annotated to energy-, amino-acid-, lipid-, and cyclic guanosine monophosphate-protein kinase G (cGMP-PKG)-related pathways.

DISCUSSION: Collectively, these findings define a gut-associated, multiorgan pattern of OVX-related remodeling characterized by concurrent microbial, metabolite, and tissue-level differences. This descriptive, associative, and hypothesis-generating dataset provides a reference for future studies testing the relevance of these OVX-associated patterns to menopause-associated metabolic dysfunction.