Abstract:
The complex interplay between gut microbiota, metabolic health, and male reproductive function is increasingly recognized as a defining axis in obesity-associated infertility, although mechanistic evidences are still mostly pre-clinical. Once viewed as a localized testicular disorder, male infertility now stands at the convergence of microbial, endocrine, and immune dysregulation. Obesity-driven dysbiosis disrupts intestinal barrier integrity, elevates circulating lipopolysaccharides, and induces low-grade inflammation that may infiltrate gonadal tissues. These physiological disturbances are linked to the hypothalamic-pituitary-testicular axis, where reduced sex hormone-binding globulin, insulin resistance, adipokine dysregulation (including leptin resistance), chronic low-grade inflammation, and increased adipose aromatase activity converge to reduce testosterone biosynthesis, in line with contemporary models of male obesity-related secondary hypogonadism. At the molecular frontier, microbial metabolites, short-chain fatty acids, bile acids, indole derivatives, and trimethylamine-N-oxide, emerge as potent mediators linking gut-derived metabolic cues to testicular redox-balance, endothelial health, and spermatogenic efficiency. This review aims to clear the concept how these biochemical and signalling cascades may converge into a hypothesis-generating gut–adipose–testis network, primarily supported by preclinical and observational human studies, bridging metabolic inflammation, oxidative stress, and endocrine imbalance. Importantly, the translational horizon expands toward precision nutrition, microbiome modulation, and multi-omic biomarker discovery, with potential to reshape male preconception care and transgenerational health outcomes, although robust human interventional evidence linking microbiota manipulation to improved testicular endocrine or spermatogenic outcomes is currently lacking. This synthesis calls for randomized mechanistic trials and region-specific microbiome mapping to define causal pathways. This review connects microbial ecology with reproductive endocrinology to offer a broader understanding of male infertility. It emphasizes that infertility is not merely a problem of the testes, but a systemic outcome of metabolic and microbial imbalance that demands a personalized approach to reproductive health.
