The sex hormone-gut microbiome axis: mechanistic drivers of sex-disparate bacterial infection outcomes and precision clinical interventions

SUMMARYSex disparities in bacterial infections pose significant challenges in clinical microbiology, influencing diagnostic approaches, antimicrobial stewardship, and patient outcomes. Males frequently exhibit heightened severity in conditions like <i>Helicobacter pylori</i>-associated gastritis and <i>Vibrio cholerae</i> outbreaks, whereas females face amplified risks during reproductive phases for pathogens, such as <i>Listeria monocytogenes</i> and <i>Salmonella</i> spp. Beyond genetic and behavioral factors, the bidirectional sex hormone-gut microbiome axis emerges as a key mechanistic driver: estrogens bolster innate immunity and microbial diversity (e.g., enriching short-chain fatty acid-producing taxa like <i>Bifidobacterium</i>), while androgens and progesterone impose immunosuppressive effects, altering colonization resistance and virulence modulation. Microbial contributions-via β-glucuronidase-mediated hormone deconjugation, bile acid biotransformations, and metabolite signaling-further calibrate host responses, as evidenced in <i>Clostridioides difficile</i> recurrence and enterohemorrhagic <i>Escherichia coli</i> virulence upregulation. This review synthesizes epidemiological, preclinical, and emerging clinical data, highlighting the axis's role in pathogen-specific immune evasion and dysbiosis-driven exacerbations. Clinically, these insights advocate for sex-stratified microbiome diagnostics (e.g., 16S rRNA sequencing for risk profiling) and targeted therapies, including hormone-modulated probiotics to restore barrier function, fecal microbiota transplantation to curb antibiotic-associated vulnerabilities, and selective estrogen receptor modulators to enhance clearance in high-risk cohorts. Despite advances, gaps in human longitudinal studies and pathogen-strain interactions limit translation. Future research integrating multi-omics with clinical trials could refine precision interventions, optimizing infection management in diverse populations and aligning with evolving demands for personalized microbiology.