In recent years, a wealth of evidence has been published supporting the significant contribution of cervicovaginal microbiota to genitourinary and reproductive health outcomes. It was first found that the microbial taxonomic composition differs between women with POF and healthy individuals. We found the vaginal microbiota to be increasingly diverse with increased species richness in the case of POF, and a significant shift in overall microbial diversity was observed. However, a previous cross-sectional study of microbiota failed to identify obvious differences between individuals in terms of vaginal microbiota diversity[28, 29]. The strength of our study lies in the comprehensive description of microbial communities associated with POF achieved through the use of 16S rRNA sequencing; particularly, the association with clinical characteristics of POF; and the utilisation of predictive models to identify bacterial taxa that are differentially expressed in POF.
Previous studies on the vaginal microbiota in the case of POF have mainly involved amine test (or the Whiff test), whereas our study focused on differences at the level of the genus. One of the most attractive features of 16S rRNA gene sequence informatics is the potential for genus identification. Dysbiosis of the vaginal microbiota was characterised by the altered abundance of 34 genera in POF. The combination of these 34 associated taxa were able to discriminate patients with POF from the control group with high accuracy. We noted that vaginal-microbiota-based analysis displayed a similar predictive ability for the disease as the classifier based on POF-associated genetic variants (which had an AUC of 0.841, sensitivity of 71.4%, specificity of 100%, and cut-off rate of 43.2%), implying that the microbial signature that we identified could represent a powerful tool for the prediction of POF. Our results of the changes in relative abundance of particular genera in the context of POF confirm that species of the dominant vaginal genus, Their dominance in the vaginal niche indicate that Lactobacillus are the dominant facultative anaerobes of the genital tract, supported by their presence in most women[31, 32].
In women with higher levels of basal FSH and lower levels of basal E2, there were fewer Lactobacillus in the vagina than the control group. Eade et al. evaluated the presence of Lactobacillus spp in confluent monolayers of endocervical, ectocervical, and vaginal epithelial cells and they found that the majority of Lactobacillus caused a significant decrease in the expression of AMPs, although Lactobacillus increased in the vaginal. The expression of AMPs, which include cathelicidins, defensins, can also promote IL-22 secretion and thus prevent autoimmune disease. A previous study has suggested that Lactobacillus can reinforce the mononuclear phagocytic response by inducing production of the autophagy-promoting factors. Studies have also shown that inflammatory ageing and the autoimmune response are closely related to POF [15, 36]. Our results suggest that reduced colonization of Lactobacillus may accelerate the development of POF disease through the induction of immune responses by some inflammatory factors.
Moreover, it was our first found that the relative abundance of Lactobacillus and some Anaerobic bacteria in the vagina were correlated with the FSH level and AMH level. FAH level and AMH level had previouely been deemed determined the ovarian reserve[37, 38].
As previously studied, hormonal change caused menstruation and menopause, result in a drastic decreases in Lactobacillus in the vaginal microbiota. In this case, infections by Gardnerella vaginalis (GV) are increased 8. GV has a significant importance in vaginal immunity. In fact, the overgrowth of anaerobic species during menopause can increase the immunity molecules release such as NF-κB, TNFα༌COX-2, iNOS. Our result also found that the higher level of genera Prevotella, Gardnerella. Abnormal vaginal microbiota may have adverse effect on the Pregnancy. And we observed the negative correlation between anaerobic species and Lactobacillus. These bacteria exploit the same class of environmental resources in a similar way and are defined as an ecological “guild”. Guild members do not necessarily share taxonomic similarities, but they adapt to the changing environment to co-exist to affect female reproductive function by altering the concentration of inflammatory factors.
Our functional analysis showed that the pathways involved in metabolism, immune and apoptosis were related to POF. However, the 16S rRNA gene sequencing does not clear the functionally important changes of the microbiota due to the technical flaw. Because little is known about the relationship between POF and vaginal microbiota, further research is required to deepen our understanding of this subject.
When we compared the vaginal microbiota of menopausal women with that of women with POF, we found that although the three most abundant genera were the same, the relative abundance of Lactobacillus is reduced in the case of menopause, which supports previous research. It is well known that menopause and POF have similar clinical manifestations. Menopause is a natural physiological phenomenon caused by age, but POF is mostly related to genetics and immunity. Our results further validate the important role of relative abundance in Lactobacillus during the development of ovarian insufficiency.
In conclusion, our study provides novel insights into the potential dysbiosis of vaginal microbiota that occurs in patients with POF. Future treatments for POF may, therefore, target the reproductive tract microbiota and involve probiotic treatment to slow follicular atresia, which may improve the success rate of IVF. However, the present study had several limitations which should be addressed in future studies. First, the sample size was small and we couldn’t trace the date of the POF diagnosed. Second, we could not clarify detailed roles of specific constituents of the vaginal microbiota in the pathogenesis of POF. Third, the inclusion of a disease verification model could reveal more accurate information related to the composition of the microbiome and its functions. Therefore, future multicenter studies involving larger study populations and animal models are needed in order to explore potential mechanisms underlying the association of the vaginal microbiota with POF. Genomics represents a potential approach to elucidate associations between the vaginal microbiota and disease, and analysis of the gut microbiota may help to explain other pathologies and improve many aspects of prevention and treatment.