Temporal relationship between alterations in the gut microbiome and the development of polycystic ovary syndrome‐like phenotypes in prenatally androgenized female mice

Abstract

It has been recently recognized that prenatal androgen exposure is involved in the development of polycystic ovary syndrome (PCOS) in adulthood. In addition, the gut microbiome in adult patients and rodents with PCOS differs from that of healthy individuals. Moreover, recent studies have suggested that the gut microbiome may play a causative role in the pathogenesis of PCOS. We wondered whether prenatal androgen exposure induces gut microbial dysbiosis early in life and is associated with the development of PCOS in later life. To test this hypothesis, we studied the development of PCOS-like phenotypes in prenatally androgenized (PNA) female mice and compared the gut microbiome of PNA and control offspring from 4 to 16 weeks of age. PNA offspring showed a reproductive phenotype from 6 weeks and a metabolic phenotype from 12 weeks of age. The αdiversity of the gut microbiome of the PNA group was higher at 8 weeks and lower at 12 and 16 weeks of age, and the βdiversity differed from control at 8 weeks.However, a significant difference in the composition of gut microbiome between the PNA and control groups was already apparent at 4 weeks. Allobaculum and Roseburia were less abundant in PNA offspring, and may therefore be targets for future interventional studies. In conclusion, abnormalities in the gut microbiome appear as early as or even before PCOS-like phenotypes develop in PNA mice.Thus, the gut microbiome in early life is a potential target for the prevention of PCOS in later life. K E Y W O R D S androgens, delayed effects of prenatal exposure, gastrointestinal microbiome, polycystic ovary syndrome How to cite this article: Kusamoto A, Harada M, Azhary JMK, et al. Temporal relationship between alterations in the gut microbiome and the development of polycystic ovary syndrome-like phenotypes in prenatally androgenized female mice.

Pathophysiology of polycystic ovary syndrome revisited: Current understanding and perspectives regarding future research

“…We found that abnormalities appear in the gut microbiome as early as or even before PCOS‐like phenotypes manifest in PNA offspring 102 (Figure 4). Specifically, the reproductive phenotype of PCOS became apparent at puberty in the PNA offspring, which was followed by the appearance of the metabolic features of PCOS in young adulthood.…”

“…We then studied the temporal relationship between the alterations in the gut microbiome and the development of PCOS‐like phenotypes. 102 The PCOS‐like reproductive phenotype was identified through the assessment of estrous cyclicity, ovarian histology, and serum testosterone concentration, and the metabolic phenotype was assessed using the measurement of body mass, the size of visceral adipocytes, insulin tolerance, and fasting blood glucose (FBG) concentration. We performed next‐generation sequencing (NGS) of fecal bacterial 16S rRNA genes to characterize the gut microbiomes of mice.…”

“…As a first step in testing this hypothesis, we compared the gut microbiomes of PNA mice induced by the injection of dihydrotestosterone (DHT) into pregnant dams and control mice when they were prepubertal (4 weeks of age); at puberty (6 weeks); and during their adolescence (8 weeks), young adulthood (12 weeks), and adulthood (16 weeks). We then studied the temporal relationship between the alterations in the gut microbiome and the development of PCOS‐like phenotypes 102 . The PCOS‐like reproductive phenotype was identified through the assessment of estrous cyclicity, ovarian histology, and serum testosterone concentration, and the metabolic phenotype was assessed using the measurement of body mass, the size of visceral adipocytes, insulin tolerance, and fasting blood glucose (FBG) concentration.…”

Metabolic Syndrome and PCOS: Pathogenesis and the Role of Metabolites

“…Accordingly, the abundance of bacteria in PCOS with IR are different from PCOS-alone and healthy patients [69]. Moreover, some studies reported that prenatal androgen exposure may cause gut microbial dysbiosis and it may lead to PCOS in later life [70,71].…”

Alterations of Gut Microbiome and Fecal Fatty Acids in Patients With Polycystic Ovary Syndrome in Central China

“…Previous studies have implicated that the alteration of gut microbiota may be involved in various diseases, including type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic fatty liver disease (Canfora et al, 2019), and the incidence of these diseases also increased in PCOS (Azziz et al, 2016;Kumarendran et al, 2018;Zeng et al, 2021). Importantly, gut dysbacteriosis is found in clinical studies and animal research of PCOS (Lindheim et al, 2017;Liu et al, 2017;Kusamoto et al, 2021;Liang et al, 2021;Lin et al, 2021). Gut microbiota could be served as a key diagnostic biomarker in PCOS and cause insulin resistance (Yang et al, 2021).…”