Functional Equivalence and Conserved Sexual Dimorphism in the Gut Microbiome: A Cross-Species Meta-analysis

The murine model is a standard system in translational microbiome research, yet its functional equivalence to the human microbiome remains debated. To evaluate its translational validity, we conducted a comparative whole-genome shotgun (WGS) metagenomic meta-analysis, integrating an initial retrieval of 520 datasets from 5 independent cohorts (BioProjects) across Homo sapiens (n = 202), Mus musculus (n = 75), and Drosophila melanogaster (n = 243) samples. Taxonomic and functional profiles were evaluated using strict bioinformatic quality control and batch-effect mitigation. Taxonomic profiling revealed pronounced divergence driven by host-specific ecological constraints and filtering. However, metabolic reconstruction demonstrated substantial functional equivalence, supporting the functional redundancy hypothesis for core mammalian metabolic circuits. We also noted a methodological vulnerability in our dataset: a low-depth murine sample clustered with invertebrate profiles, suggesting that technical noise or insufficient depth might artificially compress mammalian functional diversity. Comparative analysis identified sex-biased metabolic pathways conserved across mammalian hosts. Specifically, we observed a consistent enrichment of steroid metabolism in females and mineralocorticoid regulation in males. These findings indicate that functional conservation between humans and mice is modular rather than global. Consequently, the translational value of the murine model lies in domain-specific functional equivalence rather than taxonomic imitation. Moreover, the conservation of sex-specific metabolic signatures suggests that biological sex is a fundamental organising principle of microbiome function. This study highlights the necessity of mapping conserved metabolic modules and rigorously controlling inter-study variance to effectively deploy murine models in biomedical research.