The microbiome-gut-gonad axis: How microbial metabolites orchestrate reproductive physiology, pathology, and therapy

The human microbiome, a dynamic endocrine organ, exerts profound systemic influence through the production of bioactive metabolites. While the microbiome-gut-brain axis is well-established, the direct conduit between the gut microbiota and the reproductive system, the Microbiome-Gut-Gonad Axis, remains an emerging paradigm. This review explored cutting-edge evidence to construct a comprehensive model of the Microbiome-Gut-Gonad axis, focusing on the mechanistic roles of specific microbial metabolites in both physiological reproductive function and the pathogenesis of endocrine disorders. We move beyond mere correlation to elucidate how gut-derived molecules, such as short-chain fatty acids (SCFAs), secondary bile acids, and indole derivatives, directly and indirectly modulate the hypothalamic-pituitary-gonadal (HPG) axis by modulating the production of neuropeptides and hormones (Gonadotropin-releasing hormone (GnRH)) that regulate reproductive functions and also steroidogenesis and gametogenesis. We examine novel mechanisms including: the epigenetic regulation of steroidogenic enzymes by butyrate; the modulation of enterohepatic circulation of estrogens by β-glucuronidase-producing bacteria; and the role of tryptophan metabolites as ligands for aryl hydrocarbon receptor (AhR) in ovarian and testicular function. Furthermore, we critically appraise the disruptive potential of dysbiosis-driven metabolite shifts in PCOS, endometriosis, and male infertility, highlighting microbial metabolite signatures as promising exploratory biomarkers that require standardized, multi-center clinical validation before diagnostic use. At present, these signatures should be considered candidate biomarkers only, because external validation cohorts, assay reproducibility, and clinically meaningful estimates of sensitivity, specificity, predictive values, and clinical utility have not yet been established. Therapeutically, we evaluate innovative interventions, including precision probiotics, postbiotics, and dietary strategies targeting specific bacterial guilds, but these approaches remain investigational because current human evidence is still limited and heterogeneous. Finally, by integrating microbial endocrinology into reproductive medicine, this review establishes a new framework for understanding the etiology of reproductive endocrine disorders and paves the way for microbiome-targeted therapeutic avenues. Importantly, the evidence base is tiered: mechanistic statements in this review are drawn primarily from in vitro and animal studies, human disease links are described separately as observational evidence, and interventional claims are limited to early clinical studies and randomized trial summaries.