مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
Investigation of Factors Affecting Gut-Testis Axis Signaling Pathways
Investigation of Factors Affecting Gut-Testis Axis Signaling Pathways
Mohammad Hossein Madahali,1,*Fateme Keshtparvar,2
1. PhD student of Anatomical Sciences; Isfahan University of Medical Sciences 2. Master student of Anatomical Sciences; Isfahan University of Medical Sciences
Introduction: The gut-testis axis represents a bidirectional communication pathway between the gut microbiome and the testes, influencing male reproductive health through intricate molecular mechanisms. This axis involves microbial metabolites, hormonal regulation, immune modulation, and oxidative stress control, all of which impact testicular function. Dietary interventions, including probiotics, prebiotics, and specific nutrients, offer potential strategies for reshaping the gut microbiota and enhancing male fertility by targeting these pathways. Understanding the gut-testis axis can pave the way for innovative therapeutic approaches to address male reproductive disorders.
Methods: The present study was conducted by reviewing related articles in Web of Science, Scopus, and PubMed databases.
Results: The gut-testis axis represents a bidirectional communication network where gut microbiota and their metabolites influence testicular function through immune, endocrine, and metabolic pathways. Emerging research highlights several factors modulating these signaling mechanisms:
Gut Microbiota Composition and Dysbiosis
• Probiotic supplementation (e.g., Bifidobacterium animalis subsp. lactis NJ241) enhances gut barrier integrity by increasing Akkerman Sia municipia abundance and trans-ferulic acid levels, reducing intestinal permeability and systemic inflammation[1].
• Dysbiosis disrupts microbial metabolite production, impairing immune tolerance and hormone regulation, which exacerbates testicular dysfunction[2].
Inflammatory and Immune Pathways
• TLR4 signaling mediates colitis-induced testicular damage by elevating pro-inflammatory cytokines like IL-6 in serum and testicular tissues[1].
• Endotoxins (e.g., lipopolysaccharides) from pathogenic gut bacteria trigger systemic inflammation, contributing to oxidative stress and impaired spermatogenesis[2].
Microbial Metabolites
• Short-chain fatty acids (SCFAs) and bile acids modulate estrogen metabolism and immune cell activity, influencing reproductive hormone balance[3].
• Trans-ferulic acid, produced by beneficial microbes, strengthens gut barrier function and mitigates testicular inflammation[1].
Hormonal and Genetic Regulation
• Hypothalamic-pituitary-testis (HPT) axis activity is developmentally regulated, with stage-specific genes (e.g., cAMP signaling and GnRH secretion pathways) critical for spermatogenesis[4].
• Sex hormone signaling is epigenetically modulated by gut-derived metabolites, affecting testosterone synthesis and sperm motility[2].
Oxidative Stress
• Gut dysbiosis increases reactive oxygen species (ROS) production, overwhelming antioxidant defenses and damaging sperm DNA[2].
Interventions Targeting the Axis
• Probiotics/prebiotics: Restore microbial balance, reduce inflammation, and enhance spermatogenesis[1][2].
• Fecal microbiota transplantation (FMT): Resets gut microbiota composition, improving systemic immune and metabolic profiles[2].
These findings underscore the gut-testis axis as a therapeutic target for addressing male infertility and reproductive disorders linked to gut health. Future research should focus on translational applications of microbiota-modulating therapies in clinical settings.
Molecular mechanisms link intestinal microbiota to testicular function
The molecular mechanisms linking intestinal microbiota to testicular function involve complex interactions mediated by microbial metabolites, hormonal regulation, immune modulation, and oxidative stress management. Here's a synthesis of key pathways:
1. Microbial Metabolite Signaling
• Polyamines (e.g., spermine, spermidine) are critical for spermatogenesis. Gut microbiota, particularly g_Ruminococcus, enhance polyamine metabolism, which correlates with increased testis index, testosterone levels, and sperm motility[5][6]. Disruption of polyamine synthesis due to dysbiosis impairs testicular function[5].
• Short-chain fatty acids (SCFAs) from bacteria like Akkerman Sia and Bacteroides promote glycolysis in Sertoli cells, providing lactate as an energy substrate for spermatogenic cells[7][8]. SCFAs also upregulate insulin-like growth factor 1 (IGF-1), which supports Leydig cell steroidogenesis[7].
• Bile acids modulated by Barnesiella and Clostridium regulate blood glucose via the FXR-SHP-FOXO1 pathway, ensuring substrate availability for testicular glycolysis[7].
2. Hormonal Regulation
• Hypothalamic-pituitary-testis (HPT) axis: Gut microbiota influence gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) secretion. Probiotics like Bacillus amyloliquefaciens enhance IGF-1, which amplifies FSH signaling in Sertoli cells via the PI3K/AKT pathway[7][8].
• Steroidogenesis modulation: Gut bacteria (e.g., Clostridium scindens) express hydroxysteroid dehydrogenases (HSDH), which modify sex hormones. For example, 3β-HSDH from Mycobacterium neoaurum degrades testosterone, while 11β-HSDH in Leydig cells regulates steroidogenic genes[7][8].
• Enterohepatic recirculation: Gut microbes (e.g., Clostridia) deglucuronidate androgens like dihydrotestosterone (DHT), enabling their reabsorption and activity in the testes[7][9].
3. Immune and Inflammatory Pathways
• Lipopolysaccharides (LPS) from pathogenic bacteria (e.g., Escherichia coli) trigger systemic inflammation via TLR4 signaling, increasing pro-inflammatory cytokines (IL-6, TNF-α) that disrupt the blood-testis barrier and inhibit steroidogenesis[7][8].
• Vitamin K-producing bacteria counteract LPS-induced inflammation by stabilizing IκB, thereby preventing NF-κB-mediated suppression of steroidogenic genes (e.g., Cyp11a1)[8].
4. Oxidative Stress Management
• Dysbiosis elevates reactive oxygen species (ROS), overwhelming antioxidant defenses (e.g., glutathione) and damaging sperm DNA[10]. Probiotics like Lactiplantibacillus plantarum and selenium-enriched Aspergillus oryzae enhance testicular antioxidant capacity by modulating gut microbiota[11][12].
5. Direct Microbial Interactions
• Specific taxa: Ruminococcus abundance correlates with improved spermatogenesis and testosterone synthesis[6][7], while Akkermansia enhances gut barrier integrity, reducing endotoxin leakage[7].
Interventional Strategies
• Probiotics/prebiotics: Restore microbial balance, elevate SCFAs, and reduce inflammation[7][11].
• Fecal microbiota transplantation (FMT): Resets dysbiosis-linked metabolic and immune dysfunction[9].
These mechanisms highlight the gut-testis axis as a therapeutic target for male infertility, with microbiota-modulating interventions offering promise in clinical settings.
Interventions dietary and modulate the gut-testis signaling pathways
Dietary interventions can modulate gut-testis signaling pathways by altering gut microbiota composition, enhancing beneficial metabolite production, and reducing systemic inflammation. Here are the key mechanisms and strategies:
1. Probiotics and Prebiotics
• Probiotic supplementation (e.g., Bifidobacterium animalis subsp. lactis NJ241) increases Akkermansia muciniphila abundance, boosting trans-ferulic acid levels and improving gut barrier integrity. This reduces intestinal permeability and systemic inflammation (e.g., lower IL-6), rescuing spermatogenesis in colitis models[13].
• Lactobacillus strains (L. rhamnosus, L. fermentum) combined with prebiotics like fructooligosaccharides (FOS) enhance antioxidant defenses (catalase, SOD) and reduce oxidative stress, improving sperm motility and testosterone levels in obese mice[14][15].
2. Dietary Composition
• High-fat diets (HFD) induce gut dysbiosis, elevating lipopolysaccharides (LPS) from pathogenic bacteria (e.g., Escherichia coli). LPS triggers TLR4/NF-κB signaling in testes, causing inflammation and ferroptosis (iron overload, lipid peroxidation)[16]. Switching to balanced diets or supplementing SCFAs (e.g., sodium butyrate) reverses these effects by restoring microbial balance and reducing LPS leakage[14][13].
• Fiber-rich diets promote SCFA production (e.g., acetate, butyrate), which enhances glycolysis in Sertoli cells and supports spermatogenic cell energy needs. SCFAs also upregulate IGF-1, aiding Leydig cell steroidogenesis[14][17].
3. Micronutrient Supplementation
• Vitamin A: Gut microbiota (e.g., Ruminococcaceae) regulate bile acid metabolism, which is critical for vitamin A absorption. Deficiencies disrupt spermatogenesis, but fecal microbiota transplantation (FMT) restores bile acid levels and vitamin A uptake[17].
• Iron: Obesity-induced downregulation of duodenal DMT1 reduces iron absorption, impairing spermatogenesis. Iron supplementation combined with anti-inflammatory diets may mitigate this[18].
• Calcium: Supports sperm motility and capacitation, with gut microbiota influencing calcium availability via metabolic cross-talk[15].
4. Anti-inflammatory and Antioxidant Interventions
• Polyphenol-rich foods (e.g., trans-ferulic acid) reduce testicular inflammation by inhibiting TLR4 signaling[13].
• Selenium-enriched probiotics (e.g., Aspergillus oryzae) enhance glutathione production, countering oxidative stress in testes[14].
5. Fecal Microbiota Transplantation (FMT)
FMT resets dysbiotic microbiota, improving systemic metabolic profiles and restoring spermatogenesis in metabolic syndrome models[17].
Key Pathways Targeted
• TLR4/NF-κB: Dietary interventions reduce LPS-driven inflammation[16][13].
• Bile acid-FXR axis: Modulates vitamin A absorption and steroidogenesis[17].
• SCFA-IGF-1: Enhances energy metabolism and hormone synthesis[14][13].
These strategies highlight the potential of tailored diets to improve male fertility by targeting the gut-testis axis, though clinical validation is needed for broader applications.
Conclusion: The gut-testis axis is a dynamic communication network where intestinal microbiota influence testicular function through microbial metabolites, hormonal regulation, immune modulation, and oxidative stress control. Key molecular mechanisms include microbial production of polyamines and short-chain fatty acids that support spermatogenesis and steroidogenesis, modulation of the hypothalamic-pituitary-testis axis hormones, and regulation of inflammatory pathways such as TLR4/NF-κB signaling. Dietary interventions—particularly probiotics, prebiotics, fiber-rich diets, and micronutrient supplementation—can beneficially reshape gut microbiota composition, enhance metabolite production, reduce systemic inflammation, and restore hormonal and metabolic balance, thereby improving testicular health and male fertility. These insights position the gut-testis axis as a promising target for novel therapeutic strategies addressing male reproductive disorders.
Keywords: gut microbiome -testis - infertility-male fertility