Project description:Gut microbial profiling of uterine fibroids (UFs) patients comparing control subjects. The gut microbiota was examined by 16S rRNA quantitative arrays and bioinformatics analysis. The goal was to reveal alterations in the gut microbiome of uterine fibroids patients.
Project description:Ineffective endometrial matrix remodeling, a key factor in infertility, impedes embryo implantation in the uterine wall. Our study reveals the cellular and molecular impact of human collagenase-1 administration in mouse uteri, demonstrating enhanced embryo implantation rates. Collagenase-1 promotes remodeling of the endometrial extracellular matrix (ECM), degrading collagen fibers and proteoglycans. This process releases matrix-bound bioactive factors, (e.g. VEGF, decorin), facilitating vascular permeability and angiogenesis. Collagenase-1 elevates embryo implantation regulators, including NK cell infiltration and the key cytokine LIF. Remarkably, uterine tissue maintains structural integrity despite reduced endometrial collagen fiber tension. In-utero collagenase-1 application rescues implantation in the heat stress and embryo transfer models, known for low implantation rates. Importantly, ex-vivo exposure of human uterine tissue to collagenase-1 induces collagen de-tensioning and VEGF release, mirroring remodeling observed in mice. Our research highlights collagenase potential to induce and orchestrate cellular and molecular processes enhancing uterine receptivity for effective embryo implantation. This innovative approach underscores ECM remodeling mechanisms critical for embryo implantation
Project description:By comparing the difference in whole transcriptome of uterine fluid exosomes on embryo transfer day between pregnant and unpregnant groups during IVF cycles, novel biomarkers that may predict embryo implantation were identified. This prospective cohort study included78 cases with infertility who underwent routine in vitro fertilization(IVF) and fresh embryo transfer; they were divided into pregnant group and unpregnant group.
Project description:By comparing the difference in whole transcriptome of uterine fluid exosomes on embryo transfer day between pregnant and unpregnant groups during IVF cycles, novel biomarkers that may predict embryo implantation were identified. This prospective cohort study included78 cases with infertility who underwent routine in vitro fertilization(IVF) and fresh embryo transfer; they were divided into pregnant group and unpregnant group.
Project description:Gut microbiome research is rapidly moving towards the functional characterization of the microbiota by means of shotgun meta-omics. Here, we selected a cohort of healthy subjects from an indigenous and monitored Sardinian population to analyze their gut microbiota using both shotgun metagenomics and shotgun metaproteomics. We found a considerable divergence between genetic potential and functional activity of the human healthy gut microbiota, in spite of a quite comparable taxonomic structure revealed by the two approaches. Investigation of inter-individual variability of taxonomic features revealed Bacteroides and Akkermansia as remarkably conserved and variable in abundance within the population, respectively. Firmicutes-driven butyrogenesis (mainly due to Faecalibacterium spp.) was shown to be the functional activity with the higher expression rate and the lower inter-individual variability in the study cohort, highlighting the key importance of the biosynthesis of this microbial by-product for the gut homeostasis. The taxon-specific contribution to functional activities and metabolic tasks was also examined, giving insights into the peculiar role of several gut microbiota members in carbohydrate metabolism (including polysaccharide degradation, glycan transport, glycolysis and short-chain fatty acid production). In conclusion, our results provide useful indications regarding the main functions actively exerted by the gut microbiota members of a healthy human cohort, and support metaproteomics as a valuable approach to investigate the functional role of the gut microbiota in health and disease.
Project description:Uterine fibroids are benign tumours affecting up to 80% of women of reproductive age, with 30% of patients suffering severe symptoms including abnormal uterine bleeding, pain and infertility. Several studies have identified mutations in MED12 or HMGA2 that account for the vast majority of genomic abnormalities in uterine fibroids, however, the processes by which these lead to UFs and HMB remain poorly understood. To systematically correlate genetic, transcriptional and proteomic phenotypes we collected fibroid, myometrium and endometrium tissues from 137 donors undergoing hysterectomy, myomectomy, or transcervical resection. Donors were profiled by genome-wide SNP arrays and their fibroids were genotyped for known mutations using a targeted sequencing approach. Tissues were analysed by RNA-sequencing and proteomics followed by a systems level approach using multiomics factor analysis. Whilst genotyping revealed 39.7% of common MED12 UF mutations, we observe multiple novel exonic and intronic variants of previously known mutated genes like COL4A5 and COL4A6. Systems level analysis of genotype, transcriptomic, and proteomic data between myometrium and fibroid donors identified multiple interrelated gene sets involved in UF pathophysiology, including extracellular matrix deposition and remodelling, protein glycosylation and sulphate biology. Equivalent analysis of endometrium stratified by donor HMB status revealed gene sets implicated in the condition, in particular RNA splicing in MED12 mutant fibroids. A paradigm is proposed, supported by a mouse model of HMB, whereby aberrant production of signalling molecules by MED12 mutant fibroids influences RNA transcript isoform expression in the endometrium, associated with abnormal bleeding. By merging clinical, genetic, transcriptomic, and proteomic information, we highlight multiple pathways which may underlie the pathomechanisms of UF biology and may facilitate the development of novel therapeutic strategies to treat heavy menstrual bleeding
Project description:This study identifies an unknown role for KLF9 signaling in normal uterine development, which is decreased in a mouse model of resistance to thyroid hormone (RTHa), resulting in infertility through ectopic IL-33 expression produced by abnormally differentiated, KLF9-deficient endometrial cells. Utilizing a combination of genetically engineered mouse models, histopathology, spatial transcriptomics, and pharmacological inhibitors, we revealed that infertility in RTHa results from abnormal endometrial differentiation mediated by KLF9 suppression. These abnormally differentiated endometrial cells were the source of ectopic IL-33 overexpression. Increased endometrial IL-33 led to T-cell infiltration, destruction of glands, and endometrial fibrosis, which culminated in infertility. This study uncovers a link between TRa1 and KLF9 signaling for normal endometrial differentiation, reveals a mechanism for ectopic uterine IL-33 in female fertility, and provides new insights on the impact of hypothyroidism in female reproduction.