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

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.

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.

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.

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.