Gut–Testis Axis and Male Reproductive Health : Int J Mol Sci | May 2026

Introduction

Emerging evidence suggests that the gut microbiome may play a central regulatory role in male reproductive physiology through a proposed “gut–testis axis.” This concept integrates microbial metabolism, systemic inflammation, endocrine signalling and immune regulation as interconnected determinants of spermatogenesis and sperm quality. With idiopathic infertility accounting for a substantial proportion of male infertility cases, understanding microbiome-mediated reproductive dysfunction has become an important translational research priority.

Problem Statement

Although associations between diet, metabolic disease and impaired fertility are increasingly recognised, the mechanistic pathways linking gut microbial dysbiosis to testicular dysfunction remain incompletely understood. Existing human studies are largely observational, and causal relationships between microbiome alterations and reproductive impairment require further validation.

Summary

This comprehensive review synthesises current mechanistic, translational and clinical evidence linking gut microbial dysbiosis to impaired male reproductive health. The authors propose that disruption of intestinal microbial homeostasis contributes to infertility through multiple converging pathways involving endocrine dysfunction, oxidative stress, inflammation, barrier disruption and altered microbial metabolite production.

Central to this framework is the concept that beneficial commensal bacteria, particularly short-chain fatty acid (SCFA)-producing taxa such as Bifidobacterium, Lactobacillus and Faecalibacterium, maintain intestinal integrity, regulate immune homeostasis and support metabolic signalling. SCFAs, especially butyrate, appear critical for preserving blood–testis barrier integrity, Sertoli cell maturation and seminiferous tubule development. Germ-free animal models demonstrated impaired gonadotropin production, increased blood–testis barrier permeability and defective spermatogenesis, all of which improved following colonisation with butyrate-producing organisms.

The review further highlights amino acid-derived microbial metabolites, particularly L-citrulline, as regulators of testicular homeostasis and nitric oxide signalling. Dysbiosis-associated depletion of L-citrulline impaired Sertoli cell function, promoted oxidative stress and disrupted spermatogenesis in experimental models. Restoration of these pathways through dietary supplementation improved sperm quality and DNA repair responses, supporting a direct microbiota–metabolism–testis connection.

Conversely, expansion of proinflammatory pathobionts and endotoxin-producing Gram-negative bacteria was strongly linked to reproductive dysfunction. Lipopolysaccharide-mediated activation of Toll-like receptor pathways in Leydig cells, Sertoli cells and spermatozoa induced inflammatory cytokine production, oxidative stress and apoptosis. These processes impaired testosterone synthesis, disrupted hypothalamic–pituitary–gonadal axis regulation and reduced sperm motility, viability and fertilisation capacity.

Several fecal microbiota transplantation studies provided important causal evidence for the gut–testis axis. Transfer of dysbiotic microbiota from high-fat diet, alcohol exposure or metabolic syndrome models into healthy animals reproduced impaired spermatogenesis, reduced sperm motility, mitochondrial dysfunction and inflammatory activation within reproductive tissues. In contrast, microbiota-restorative interventions including high-fibre diets, alginate oligosaccharides, probiotics and microbiota transplantation from healthy donors improved microbial composition, enhanced antioxidant pathways, restored retinoid and bile acid metabolism, and improved sperm quality.

Human evidence remains relatively limited but supports similar trends. Western dietary patterns rich in saturated fats, processed foods and refined sugars were consistently associated with poorer semen parameters, while omega-3 fatty acids, fruits and vegetables correlated with improved sperm morphology and motility. Men with metabolic disorders and testosterone deficiency exhibited enrichment of proinflammatory and endotoxin-producing taxa alongside reduced beneficial SCFA-producing organisms. Several microbial taxa, including Prevotella and Ruminiclostridium, demonstrated associations with abnormal sperm parameters and systemic inflammatory profiles.

Importantly, the review emphasises major limitations in the field, including heterogeneity in microbiome profiling techniques, lack of longitudinal studies, substantial confounding variables and incomplete mechanistic understanding of how microbial metabolites influence testicular physiology. Despite these limitations, the accumulating evidence strongly supports the gut microbiome as a promising therapeutic target for male infertility and reproductive dysfunction.