Unravelling the interplay between microbiome, inflammation, metabolic dysregulation and endometrial carcinogenesis

Abstract

Background Inflammatory and metabolic cues have long been associated with the pathogenesis of endometrial cancer. Increasing evidence implicates the reproductive tract microbiota with health and disease states, however its role in metabolic and inflammatory dysregulation in the context of endometrial oncogenesis is poorly described.

Aims The overarching goal of this thesis was to explore diabetes and microbial dysbiosis as complicit factors in endometrial cancer. The first aim was to critically appraise the strength of epidemiological evidence for associations between diabetes and anti-diabetic interventions and the risk of endometrial cancer and other gynaecological or obstetric outcomes. The second aim was to investigate if genuine microbial signals from low bacterial biomass sites of the upper genital tract can be detected above background and if so, determine if they exist as a microbial continuum along the length of female genital tract and rectum of endometrial cancer patients and patients with benign intra- or extrauterine pathology. The third aim was to test the hypothesis that endometrial cancer patients harbour a distinctive microbial fingerprint in their genital tract and rectum compared to benign controls that contributes to endometrial cell proliferation and inflammation in a 3-dimensional endometrial organoid model. Lastly, this thesis aimed to validate benign and malignant endometrial organoids as tools for disease modelling by interrogating their phenotypic, genetic and epigenetic resemblance to parent tissue.

Results An umbrella review of existing meta-analyses demonstrated suggestive evidence supporting a positive association between diabetes and endometrial cancer and improved survival in metformin users. Increased endometrial cancer mortality among diabetic patients was only supported by weak evidence. Metataxonomics-based characterisation of microbiota and qPCR showed that a subset of benign and endometrial cancer patients harbour microbial communities distinguishable from background contaminants. A microbial continuum along the genital tract is most evident in benign patients compared to endometrial cancer patients, whereas vaginal microbiota is poorly correlated with rectal microbiota in both cohorts. Endometrial cancer is associated with reduced cervicovaginal and rectal bacterial load and compositionally characterised by Lactobacillus depletion, increased microbial diversity and enrichment of Porphyromonas, Prevotella, Peptoniphilus and Anaerococcus in the lower genital tract and endometrium. Microbiome-host interactions were studied using 3D endometrial organoid models, which were shown to be morphologically and (epi)genetically consistent with progenitor tissue. L. crispatus supernatant decreases endometrial cancer organoid viability at high concentrations and does not significantly affect inflammatory pathways in benign or endometrial cancer organoids as measured by cytokine secretion.

Discussion & Conclusion Metabolic dysregulation and microbiota alterations are associated with endometrial cancer. L. crispatus, a female genital tract commensal, does not interfere with inflammatory signalling in endometrial organoids. Further demystifying which host pathways altered microbiota might influence could provide insights in the context of microbiota manipulation for clinical purposes.