Hormone Replacement Therapy Reverses Gut Microbiome and Serum Metabolome Alterations in Premature Ovarian Insufficiency

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.

Integrated gut microbiota and fecal metabolome analyses of the effect ofLycium barbarumpolysaccharide ond-galactose-induced premature ovarian insufficiency

“…6 Eggerthellaceae is found to promote ovarian fibrosis by increasing TGF-β levels after gavage in mice, while hormone replacement therapy reversed ovarian fibrosis induced by Eggerthellacea . 25 We found that LBP reduced the fecal abundance of Eggerthellaceae in mice. This suggests that Eggerthellaceae may be a potential target bacterium for the treatment of POI.…”

“…Clinical studies have shown that the structure of the gut microbiota is dysregulated in patients with POI, 6 and that the impaired gut microbiota accelerates the degeneration of ovarian function. 25 So we examined whether the ameliorative effect of LBP on POI mice was related to the gut flora. Alpha diversity is an important indicator of the richness and homogeneity of the microbial composition.…”

Spotlight on the Gut Microbiome in Menopause: Current Insights

“…A study of 17β-estradiol hormone therapy in women with POI (n = 20 with POI [10/10 treated/not treated], n = 10 healthy controls) reported that hormone therapy partially attenuated POI-related gut microbiome dysbiosis, in that the elevated abundance of Eggerthella in POI compared with healthy women was reversed with therapy. 76 Studies of hormone therapy and the gut microbiome in naturally menopausal women are needed to determine whether hormone therapy may benefit gut health in post-menopause.…”

Endocrine-Disrupting Chemicals, Gut Microbiota, and Human (In)Fertility—It Is Time to Consider the Triad

“…A further example is that of PCOS patients, in which the GM shows an abnormal Escherichia:Shigella ratio and an excess of Bacteroides compared to healthy women [ 71 ], a condition occurring also in IR and in obese women characterized by an increased Firmicutes:Bacteroidetes ratio [ 56 , 72 ]. Moreover, GM exerts a role in the pathogenesis of thyroid autoimmune disease, a frequent disorder in infertility patients [ 75 , 76 , 77 ], and a relationship between the gut microbiome and premature ovarian insufficiency (POI) has been suggested [ 78 , 79 ].…”