REPROBIOMA is a project funded by the European Union and the Agència Valenciana de la Innovació (AVI) with a budget of €810,418.19.

This project seeks collaboration and cooperation among various agents of the Valencian Innovation System for the development of a joint innovative solution, specifically from the Institute of Agrochemistry and Food Technology (IATA-CSIC), DARWIN, KOROTT, and Instituto Bernabeu.

Problem

According to the World Health Organization (WHO), nearly 17.5% of adults experience infertility at some point in their lives, making it urgent to increase access to affordable and quality infertility care for those in need.

These estimates show that the prevalence of infertility varies little from one region to another, with similar rates in high-, middle-, and low-income countries, demonstrating that it is a significant public health problem worldwide.

The composition of the vaginal microbiota has a significant impact on sexual and reproductive health. It varies among women and changes depending on the different phases of life.

A healthy vaginal microbiota is dominated by species of the genus Lactobacillus, which help achieve favorable pH conditions that promote fertility.

One of the key functions of these lactobacilli is the activation of glycogen metabolism, which transforms into lactic acid in vaginal epithelial cells, creating an acidic vaginal pH that generates an unfavorable environment for the growth of pathogenic bacteria, thus preventing vaginal dysbiosis.

An increase in microbiota diversity and a reduction in the percentage of lactobacilli are associated with a wide range of harmful effects, including a higher risk of acquiring sexually transmitted infections and a higher likelihood of experiencing chorioamnionitis, preterm birth, and worse perinatal outcomes.

Alterations in the vaginal flora, such as bacterial vaginosis (BV) caused by Gardnerella vaginalis infection, are linked to a higher risk of miscarriage. Other pathogenic microorganisms like Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma tuberculosis have been associated with lower gestation rates, causing subclinical changes related to risk factors for subfertility. However, there are still many unknown factors in the relationship between the microbiome and fertility, needing further investigation into the pathophysiological mechanisms of this relationship.

Solution

The main objective of the REPROBIOMA project is the development of a new strategy for the identification and characterization of precision probiotic strains, through metagenomic and metataxonomic analysis, for the development of functional foods that increase fertility and the success rate of Assisted Reproductive Technologies (ART).

Throughout the project, key bacteria in the vaginal microbiota of fertile women (healthy individuals) will be identified, analyzing their functional capacity and the mechanisms of action they use to benefit reproduction. Once the most suitable probiotic strains (precision probiotics) are selected, those that can be scaled to industrial production will be chosen. Finally, the utility of the strains to enhance reproductive health will be tested through clinical trials in patients with fertility issues undergoing ART. If the clinical trial is successful, the industrial scaling of the production of precision probiotics and commercialization of the product will proceed.

This is a novel, creative, and systematic research aimed at generating new knowledge about the role of the vaginal microbiota in health. Furthermore, if successful, the developed methodology could be extrapolated and applied to other pathologies where the microbiome plays a significant role.

Results

Based on the metagenomic analysis of vaginal microbial communities and an extensive process of isolation and functional characterization of more than 200 strains, the research team conducted a broad in vitro screening that enabled the identification of 11 strains with strong inhibitory activity against vaginal pathogens, as well as immunomodulatory properties in cell cultures, together with other functions relevant to reproductive health. Following a production optimization phase and stability testing, four probiotic strains were selected which, when combined as a consortium, demonstrated potential reproductive benefits. With these strains, a stable and long-term viable multi-strain dietary supplement was developed, specifically designed to support the balance of the vaginal microbiome.

The project also encompassed pre-industrial optimization and manufacturing of the final product format, as well as its evaluation in a randomized, double-blind, placebo-controlled clinical trial in women undergoing assisted reproductive technologies, together with molecular monitoring of the vaginal microbiome. Although the clinical trial has not yet been completed, preliminary results suggest a potential benefit in subgroups of patients with an altered vaginal microbiome, improving pregnancy rates in these cases and thereby reinforcing a personalized approach in Assisted Reproduction treatments.

Completion Year: 2025