Vagina

Persistent infection with high-risk human papillomaviruses (HR-HPV) is the primary cause of cervical cancer, but its progression depends on host and environmental factors beyond viral presence. The vaginal microbiome, particularly the transition from Lactobacillus crispatus-dominated communities to dysbiotic states enriched in Gardnerella, Fannyhessea, and Sneathia, has emerged as a key modulator of HPV persistence, local inflammation, and epithelial transformation. First, community state type IV (CST IV) microbiota strongly predict persistent HR-HPV infection and progression to high-grade lesions, highlighting their potential as non-invasive biomarkers for early risk stratification. Second, cervicovaginal dysbiosis alters mucosal immunity and promotes epigenetic reprogramming of both host and viral genomes, facilitating immune evasion and oncogenesis. Third, restoring Lactobacillus dominance through probiotics or microbial engineering holds translational promise for enhancing HPV vaccine efficacy and reducing cervical cancer burden. These findings position the vaginal microbiome not as a passive bystander, but as an active determinant of HPV-driven carcinogenesis and underscore its diagnostic and therapeutic potential in cervical cancer prevention.

The vaginal tract is a complex environment that changes throughout various life stages. Recent advances have improved our understanding of the vaginal microbiota and the influence of host factors on microbial colonization. The vaginal niche is characterized by unique qualities such as high abundances of glycogen and mucin, low pH, active cellular immunity, and fluctuations in hormone signaling that support a complex microbiota. While traditionally thought to be dominated by Lactobacillus species, emerging research highlights a more diverse microbiota, including both commensal and potentially pathogenic microbes. Given the interconnectedness of the microbial and host factors in this environment, minor shifts can lead to significant downstream effects on health. This review takes an ecosystems approach to explore the multifaceted relationship between the vaginal mucosa, the microbiota, and influences of environmental factors on shaping the two. We discuss the contribution of hormone signaling in shaping microbial communities, concepts of vaginal community stability and dysbiosis, and the emerging understanding of microbial metabolism and cross-feeding dynamics within the vaginal tract. Additionally, we will examine the interactions between microbes and immune cells in the vaginal mucosa, including mechanisms by which the immune system modulates the local environment. By considering the feedback loops between the host and the resident microbiota, we propose key knowledge gaps and suggest interdisciplinary avenues for future research aimed at improving our understanding of vaginal health and disease. Understanding these complex interactions is important for advancing vaginal healthcare across all individuals.

Vaginal dysbiosis is linked to recurrent infections and reproductive complications. Probiotics may restore vaginal microbiota, but there is modest evidence to support vaginal colonization after oral administration. This work aimed to screen a vaginal lactobacilli collection (n = 45) and assess vaginal colonization of selected candidates. Lactobacillus gasseri CECT 30648 (Lg) and Lactobacillus crispatus CECT 30647 (Lc) showed excellent in vitro attributes, including antagonism against 10 urogenital pathogens, resistance to gastrointestinal tract and vaginal environment-including high concentrations of biogenic amines-and adhesion to vaginal epithelium. Forty-eight healthy women (18-45 years old) were randomly allocated to consume daily a capsule containing Lg (109 CFU), a combination of Lg plus Lc (1.5 × 109 CFU), or placebo for up to 18 days (between menses). Volunteers collected vaginal samples every 3 days. The primary endpoint was the presence of probiotic strains in vaginal swabs confirmed by strain-specific quantitative PCR. Secondary variables included vaginal microbiota composition and tolerability, among others. Probiotics were well tolerated. Lg but not Lc was detected in 55.9% of participants in active groups (9 in Lg and 10 in Lg + Lc) throughout the study (P = 0.005 aggregated probiotic groups vs placebo). The sum of relative abundances of non-lactobacilli genera was significantly reduced in the probiotic group after intervention (P = 0.047 vs day 0), and there was a positive transition toward lactobacilli-dominated community state types (P = 0.039 vs day 0). Overall, we show that L. gasseri CECT 30648 exerts a broad-spectrum antimicrobial activity and can colonize the vaginal tract of healthy women, thus showing potential to promote vaginal health. The trial was registered in clinicaltrials.gov (NCT05688397).IMPORTANCEThe use of probiotics to promote vaginal health is increasing because vaginal dysbiosis has been linked to numerous gynecological and reproductive complications. While vaginal administration of probiotics using devices or creams has been widely investigated, there is limited evidence supporting vaginal colonization of a probiotic administered orally. It is therefore imperative to perform extensive in vitro characterization to select a vaginal probiotic that can survive the gastrointestinal transit and effectively colonize the vaginal tract of consumers through the oral-gut-vaginal route. We have identified the strain L. gasseri CECT 30648, which shows great probiotic properties, including antagonism against several relevant urogenital pathogens, can colonize the vaginal tract of >55% of participants, and can modulate vaginal microbiota toward a lactobacillus-dominated status in a randomized controlled clinical trial in healthy premenopausal women. These results suggest that oral consumption of L. gasseri CECT 30648 might be effective in promoting vaginal health.

Females influence offspring paternity through diverse pre- and post-copulatory mechanisms. Sperm discrimination-the differential physiological response to ejaculates based on male or sperm characteristics-can bias fertilization outcomes, but in vivo evidence of this process in large-bodied mammals is lacking. Here, in a study of nine females and four males, we tested whether two aspects of female physiology that affect sperm survival-vaginal immune response and pH-are modulated by male genetic makeup in a non-human primate, the olive baboon (Papio anubis). Our findings suggest post-copulatory differences in vaginal gene expression and pH, with the strongest immune responses and largest pH decreases, harmful to sperm, exhibited by females mating with genetically similar males. These findings are consistent with genetically-based post-copulatory mate discrimination, offering new insights into how interactions between male gametes and the female reproductive tract may shape conception probability in primates.