Abstract
Lactobacilli?dominated vaginal microbiomes are consistently associated with reduced risk of vaginal and sexually transmitted infections, including HPV?related disease and HIV, and recurrent urinary tract infections. Yet the mechanisms underlying this protection remain insufficiently understood, as lactic?acid?mediated pH lowering and other classical antimicrobial effects cannot explain the strong benefits of Lactobacillus?rich communities. This project investigates whether key lactobacilli?derived metabolites, particularly riboflavin and tryptophan?derived indoles, enhance and/or repair epithelial barrier integrity, and modulate innate immune pathways in the female genital tract. Using an advanced, physiologically relevant (cervico)vagina?on?a-chip model, we will dissect how selected Lactobacillus strains and their metabolites shape epithelial and immune responses, including MAIT?cell and AhR?driven pathways. In parallel, immunometabolic profiling of women with spontaneously clearing or persistent HPV infection will identify microbial metabolites and host immune signatures linked to cervicovaginal resilience, with HPV serving as a clinically informative model. By directly linking microbial metabolism to mucosal function, this project will reveal mechanistic drivers of lactobacilli?mediated protection and enable rational development of next?generation live biotherapeutics and biomarker?based tools to improve women?s health.
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