Microbial landscape in female reproductive health: Unravelling its composition and host-microbe interactions
- Signe Altmäe Director
Defence university: Universidad de Granada
Fecha de defensa: 23 June 2022
- Maria Paz Carrasco Jimenez Chair
- Concepción Jiménez López Secretary
- Francisco José Esteban Ruiz Committee member
- José Antonio Horcajadas Almansa Committee member
- Lusine Aghajanove Committee member
Type: Thesis
Abstract
The human body is colonised by more microbes than its own cells, and as more knowledge about the human microbiome is obtained, the clearer its significance in human physiology becomes. Most bacterial communities in humans coexist synergistically with their host. However, an imbalance in this relationship can lead to a disease. In the context of human reproductive health, it is well known that the female reproductive tract, specifically the vaginal milieu, possesses a highly active microbiota dominated by Lactobacillus. Despite the evidence, the complete influence of the microbes of adjacent sites and its association with female fertility remains still unclear. Recent studies have shown that the endometrium (i.e., the inner layer of the uterus) has its own microbial profile. Furthermore, it has been shown that microorganisms of the upper reproductive tract not only influence the functions of the uterus but may also play an important role in the embryo implantation and gynaecological complications such as recurrent implantation failure (RIF). This Doctoral Thesis studies the relationship between the microbiome and the female reproductive health. The objectives of this Doctoral Thesis were: 1) to summarise the existing knowledge of endometrial microbiome studies, the current treatments offered in the clinical setting and the future possibilities for modifying the uterine microbial composition; 2) to highlight the methodological considerations in meta-transcriptome analyses when applying either the poly(A) enrichment or random hexamer primer protocols for RNA sequencing (meta-transcriptomic analysis); 3) to detect the entire cartography of functionally active microorganisms in the endometrium from healthy women and whether there are changes throughout the menstrual cycle; 4) to determine functionally active microorganisms in the receptive phase endometria in women with RIF vs. healthy control women; and 5) to summarise and meta-analyse the current knowledge of the composition and diversity of the microbiome in polycystic ovary syndrome (PCOS). Five studies were carried out to address the objectives, with the main findings being: 1) uterus harbours its own microbial composition that is dysregulated in different gynaecological conditions like infertility, endometriosis, chronic endometritis, endometrial polyps, dysfunctional menstrual bleeding, and endometrial cancer. Nevertheless, the core/consensus endometrial microbiome has not been established. Modulation of endometrial microbiome by antibiotics, pro- and prebiotics is a promising field with high clinical relevance, but it is too early to offer this treatment options for patients (Study I). 2) Many microorganisms are able to generate poly(A) tails in the process of transcription (similar to the host), while several microbes may lack poly(A) tails, therefore the wide application of microbial RNA sequence analysis (meta-RNA-seq) must be supported by a well-prepared protocol for a comprehensive understanding of the entire microbial atlas (Study II). 3) The analysis of the functionally active endometrial microbiota shows that >5300 microorganisms (bacteria, fungi, viruses, and archaea) are present the endometrium of healthy women and changes in composition and function along the menstrual cycle are detected. Microbes have possible metabolic activity in the host-microbiota crosstalk in receptive phase endometrium related to prostanoid biosynthesis pathway and L-tryptophan metabolism. Our study confirms the presence of active microbes in the human endometrium with implications in receptive phase endometrial functions, meaning that microbial dysfunction could impair the metabolic pathways important for endometrial receptivity (Study III) 4) Women suffering RIF have significantly different functionally active microbial profile, where retinol biosynthesis and serotonin degradation metabolic pathways in the host-microbe interactions were dysregulated when compared to healthy controls. Our study confirms the presence of the core microbiota in the human endometrium in health and that in women with implantation failures the microbial composition demonstrates less richness which could impair the metabolic pathways important for endometrial functions (Study IV). 5) The relation between the microbial composition and the aetiology of PCOS is an active field of research. Most of the studies performed in the field focus on gut microbiome analysis, nevertheless the studies are barely comparable and findings inconsistent. Our meta-analysis gathers 17 studies and, in total, microbiome data of 1868 women (737 women with PCOS and 631 controls) were meta-analysed, with a special focus on alpha diversity index and demonstrates that women with PCOS possess lower richness in the gut microbial composition when compared to control women. These findings support the potential importance of microbiome in PCOS development with possible future biomarker/treatment options (Study V).