Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Lindheim, L.
The gut microbiome in polycystic ovary syndrome: Next-generation sequencing studies of women and mice
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp. 142
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Gorkiewicz Gregor
- Obermayer-Pietsch Barbara
- Stadlbauer-Köllner Vanessa
- Altmetrics:
- Abstract:
- Polycystic ovary syndrome (PCOS) is a complex endocrine disorder characterized by androgen excess, impaired ovulation, and multifollicular ovarian appearance. PCOS affects a significant percentage of women of reproductive age and is associated with long-term reproductive and metabolic health consequences. The etiology of PCOS is still unclear and comprises genetic, intrauterine, and lifestyle-related factors. We investigated whether the gut microbiome, an important determinant of human health and disease, is involved in the pathophysiology of this disorder. We conducted the first published study on the stool and saliva microbiome of women with PCOS using next-generation sequencing. We hypothesized that the gut microbiome contributes to PCOS pathophysiology through an impaired gut barrier, which allows leakage of bacterial endotoxin into the systemic circulation, driving the inflammatory processes which promote insulin resistance and hyperandrogenemia. We further hypothesized that gut bacterial metabolism of hormonally active dietary isoflavones can have a modulating effect on PCOS symptom severity. Women with PCOS showed decreased fecal bacterial richness and an altered stool microbiome profile with reductions in the relative abundance of several bacterial genera associated with leanness. The saliva microbiome was largely unchanged. Women with PCOS showed some signs of gut barrier dysfunction, pointing to a potential mechanism by which gut bacteria may drive the disease phenotype. Bacterial production of the isoflavone metabolite equol did not differ between women with PCOS and control women. In a second approach, we utilized a mouse model combining a high-fat/high-sucrose (HF/HS) diet with dihydrotestosterone (DHT)-induced pre-natal androgenization (PNA) to reproduce the metabolic, reproductive, and behavioral features of human PCOS. We hypothesized that both HF/HS diet and PNA cause lasting changes in the gut microbiome of these mice. We found sex-dependent effects of maternal diet, PNA, and offspring diet on fecal bacterial richness and taxonomic composition. We performed fecal microbiota transplantation (FMT) to determine whether disturbed estrous cyclicity and increased anxiety-like behavior seen in female PNA offspring could be transferred to healthy wild-type recipients. FMT did not cause reproductive dysfunction, but affected anxiety-like behavior in a donor-discordant manner in one group of recipients. In conclusion, reduced bacterial richness and shifts in fecal global microbiome composition are recurrent findings in both human and mouse studies of PCOS. An impaired gut barrier might be involved in the pathophysiology of the syndrome in some PCOS phenotypes. The restoration of gut bacterial diversity, community stability, and gut barrier integrity should be considered as an adjuvant treatment approach for PCOS.