Abstract
ObjectiveWe explored the gut microbiome and serum metabolome alterations in patients with premature ovarian insufficiency (POI) and the effects of hormone replacement therapy (HRT) with the aim to unravel the pathological mechanism underlying POI.MethodsFecal and serum samples obtained from healthy females (HC, n = 10) and patients with POI treated with (n = 10) or without (n = 10) HRT were analyzed using 16S rRNA gene sequencing and untargeted metabolomics analysis, respectively. Peripheral blood samples were collected to detect serum hormone and cytokine levels. Spearman’s rank correlation was used to evaluate correlations between sex hormones and cytokines and between the gut microbiota and serum metabolites. To further confirm the correlation between Eggerthella and ovarian fibrosis, the mice were inoculated with Eggerthella lenta (E. lenta) through oral gavage.ResultsThe abundance of genus Eggerthella significantly increased in the fecal samples of patients with POI compared to that observed in the samples of HCs. This increase was reversed in patients with POI treated with HRT. Patients with POI showed significantly altered serum metabolic signatures and increased serum TGF-β1 levels; this increase was reversed by HRT. The abundance of Eggerthella was positively correlated with altered metabolic signatures, which were, in turn, positively correlated with serum TGF-β1 levels in all subjects. Estrogen ameliorated ovarian fibrosis induced by E. lenta in mice.ConclusionsThe interactions between the gut microbiota, serum metabolites, and serum TGF-β1 in patients with POI may play a critical role in the development of POI. HRT not only closely mimicked normal ovarian hormone production in patients with POI but also attenuated gut microbiota dysbiosis and imbalance in the levels of serum metabolites and TGF-β1, which are reportedly associated with fibrosis. The findings of this study may pave the way for the development of preventive and curative therapies for patients with POI.
Highlights
Premature ovarian insufficiency (POI) refers to ovarian functional decline before 40 years of age characterized by abnormal menstruation, elevated levels of follicle-stimulating hormone (FSH) (>25 U/L), and low serum levels of estradiol (E2) [1]
Serum FSH level was significantly increased in patients with POI compared to those in HCs; this increase was not reversed by HRT (Figure 2A)
Serum levels of the cytokines IFN-g, IL-6, IL-17a, IL-1b, and TNF-a were not significantly affected by POI, except for TGF-b1, whose level was significantly increased in patients with POI compared to that in HCs
Summary
Premature ovarian insufficiency (POI) refers to ovarian functional decline before 40 years of age characterized by abnormal menstruation (amenorrhea or too frequent menses), elevated levels of follicle-stimulating hormone (FSH) (>25 U/L), and low serum levels of estradiol (E2) [1]. The underlying cause of POI in approximately 90% of patients with 46, XX normal karyotype who are younger than 40 years remains unelucidated [2]. Several studies have reported alterations in the gut microbiota of patients with ovarian dysfunction, especially in patients with polycystic ovary syndrome (PCOS) [3, 4]. The gut microbiota may affect metabolite levels in various metabolic pathways in patients with PCOS, especially in lipid metabolism, which, in turn, may further aggravate the imbalance of the intestinal microbiota [5]. Only one recent report identified altered microbial profiles in the gut microbiome of patients with POI. The relationship between POI and the intestinal microbiota remains to be examined
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