Characterization of the gut microbiota in polycystic ovary syndrome with dyslipidemia.

BACKGROUND: Polycystic ovary syndrome (PCOS) is an endocrinopathy in childbearing-age females which can cause many complications, such as diabetes, obesity, and dyslipidemia. The metabolic disorders in patients with PCOS were linked to gut microbial dysbiosis. However, the correlation between the gut microbial community and dyslipidemia in PCOS remains unillustrated. Our study elucidated the different gut microbiota in patients with PCOS and dyslipidemia (PCOS.D) compared to those with only PCOS and healthy women. RESULTS: In total, 18 patients with PCOS, 16 healthy females, and 18 patients with PCOS.D were enrolled. The 16 S rRNA sequencing in V3-V4 region was utilized for identifying the gut microbiota, which analyzes species annotation, community diversity, and community functions. Our results showed that the ß diversity of gut microbiota did not differ significantly among the three groups. Regarding gut microbiota dysbiosis, patients with PCOS showed a decreased abundance of Proteobacteria, and patients with PCOS.D showed an increased abundance of Bacteroidota compared to other groups. With respect to the gut microbial imbalance at genus level, the PCOS.D group showed a higher abundance of Clostridium_sensu_stricto_1 compared to other two groups. Furthermore, the abundances of Faecalibacterium and Holdemanella were lower in the PCOS.D than those in the PCOS group. Several genera, including Faecalibacterium and Holdemanella, were negatively correlated with the lipid profiles. Pseudomonas was negatively correlated with luteinizing hormone levels. Using PICRUSt analysis, the gut microbiota community functions suggested that certain metabolic pathways (e.g., amino acids, glycolysis, and lipid) were altered in PCOS.D patients as compared to those in PCOS patients. CONCLUSIONS: The gut microbiota characterizations in patients with PCOS.D differ from those in patients with PCOS and controls, and those might also be related to clinical parameters. This may have the potential to become an alternative therapy to regulate the clinical lipid levels of patients with PCOS in the future.

Gut bacteriome and mood disorders in women with PCOS.

STUDY QUESTION: How does the gut bacteriome differ based on mood disorders (MDs) in women with polycystic ovary syndrome (PCOS), and how can the gut bacteriome contribute to the associations between these two conditions? SUMMARY ANSWER: Women with PCOS who also have MDs exhibited a distinct gut bacteriome with reduced alpha diversity and a significantly lower abundance of Butyricicoccus compared to women with PCOS but without MDs. WHAT IS KNOWN ALREADY: Women with PCOS have a 4- to 5-fold higher risk of having MDs compared to women without PCOS. The gut bacteriome has been suggested to influence the pathophysiology of both PCOS and MDs. STUDY DESIGN, SIZE, DURATION: This population-based cohort study was derived from the Northern Finland Birth Cohort 1966 (NFBC1966), which includes all women born in Northern Finland in 1966. Women with PCOS who donated a stool sample at age 46 years (n = 102) and two BMI-matched controls for each case (n = 205), who also responded properly to the MD criteria scales, were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 102 women with PCOS and 205 age- and BMI-matched women without PCOS were included. Based on the validated MD criteria, the subjects were categorized into MD or no-MD groups, resulting in the following subgroups: PCOS no-MD (n = 84), PCOS MD (n = 18), control no-MD (n = 180), and control MD (n = 25). Clinical characteristics were assessed at age 31 years and age 46 years, and stool samples were collected from the women at age 46 years, followed by the gut bacteriome analysis using 16 s rRNA sequencing. Alpha diversity was assessed using observed features and Shannon's index, with a focus on genera, and beta diversity was characterized using principal components analysis (PCA) with Bray-Curtis Dissimilarity at the genus level. Associations between the gut bacteriome and PCOS-related clinical features were explored by Spearman's correlation coefficient. A P-value for multiple testing was adjusted with the Benjamini-Hochberg false discovery rate (FDR) method. MAIN RESULTS AND THE ROLE OF CHANCE: We observed changes in the gut bacteriome associated with MDs, irrespective of whether the women also had PCOS. Similarly, PCOS MD cases showed a lower alpha diversity (Observed feature, PCOS no-MD, median 272; PCOS MD, median 208, FDR = 0.01; Shannon, PCOS no-MD, median 5.95; PCOS MD, median 5.57, FDR = 0.01) but also a lower abundance of Butyricicoccus (log-fold changeAnalysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC)=-0.90, FDRANCOM-BC=0.04) compared to PCOS no-MD cases. In contrast, in the controls, the gut bacteriome did not differ based on MDs. Furthermore, in the PCOS group, Sutterella showed positive correlations with PCOS-related clinical parameters linked to obesity (BMI, r2=0.31, FDR = 0.01; waist circumference, r2=0.29, FDR = 0.02), glucose metabolism (fasting glucose, r2=0.46, FDR < 0.001; fasting insulin, r2=0.24, FDR = 0.05), and gut barrier integrity (zonulin, r2=0.25, FDR = 0.03). LIMITATIONS, REASONS FOR CAUTION: Although this was the first study to assess the link between the gut bacteriome and MDs in PCOS and included the largest PCOS dataset for the gut microbiome analysis, the number of subjects stratified by the presence of MDs was limited when contrasted with previous studies that focused on MDs in a non-selected population. WIDER IMPLICATIONS OF THE FINDINGS: The main finding is that gut bacteriome is associated with MDs irrespective of the PCOS status, but PCOS may also modulate further the connection between the gut bacteriome and MDs. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the European Union's Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie Grant Agreement (MATER, No. 813707), the Academy of Finland (project grants 315921, 321763, 336449), the Sigrid Jusélius Foundation, Novo Nordisk Foundation (NNF21OC0070372), grant numbers PID2021-12728OB-100 (Endo-Map) and CNS2022-135999 (ROSY) funded by MCIN/AEI/10.13039/501100011033 and ERFD A Way of Making Europe. The study was also supported by EU QLG1-CT-2000-01643 (EUROBLCS) (E51560), NorFA (731, 20056, 30167), USA/NIH 2000 G DF682 (50945), the Estonian Research Council (PRG1076, PRG1414), EMBO Installation (3573), and Horizon 2020 Innovation Grant (ERIN, No. EU952516). The funders did not participate in any process of the study. We have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Beyond the reproductive tract: gut microbiome and its influence on gynecological health.

PURPOSE OF REVIEW: The analysis of microbiome in association with female health is today a "hot topic" with the main focus on microbes in the female reproductive tract. Nevertheless, recent studies are providing novel information of the possible influence of the gut microbiome on gynecological health outcomes, especially as we start to understand that the gut microbiome is an extended endocrine organ influencing female hormonal levels. This review summarizes the current knowledge of the gut microbes in association with gynecological health. RECENT FINDINGS: The gut microbiome has been associated with endometriosis, polycystic ovary syndrome, gynecological cancers, and infertility, although there is a lack of consistency and consensus among studies due to different study designs and protocols used, and the studies in general are underpowered. SUMMARY: The interconnection between the gut microbiome and reproductive health is complex and further research is warranted. The current knowledge in the field emphasizes the link between the microbiome and gynecological health outcomes, with high potential for novel diagnostic and treatment tools via modulation of the microenvironment.

Gut Microbiome Composition in Polycystic Ovary Syndrome Adult Women: A Systematic Review and Meta-analysis of Observational Studies.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder that is frequently linked to anovulation in women who are experiencing infertility. Intestinal flora, also known as the "second genome" of the host, is closely associated with chronic metabolic diseases. Recently, there has been increasing attention on the connection between PCOS and the gut microbiome, and experiments have been conducted. However, the results were unsatisfactory and inconsistent. This review aims to provide a comprehensive overview of the literature investigating the associations between the gut microbiome and PCOS in adults. The goal is to identify whether there are changes in the composition of the gut microbiome in individuals with PCOS. This is the first systematic review to focus on functional alterations in the gut microbiome, which could provide insights into potential mechanisms of microbial involvement in the development of PCOS. We found that there was no significant change in gut microbiome biodiversity in PCOS. Meta-analyses of three studies revealed a significantly higher abundance of Proteobacteria (1.12, 95% CI, 0.21, 2.02, I2 = 0%) in adults with PCOS. At the genus level, Bacteroides, Enterococcus, and Escherichia-Shigella were found to be enriched in patients with PCOS. Species such as Ruminococcus gnavus group, Parabacteroides distasonis, and Bacteroides fragilis showed an increase in PCOS. Metabolic pathways associated with glucose, lipid metabolism, bile acid metabolism, and protein absorption were found to be enriched in individuals with PCOS. The gut microbiome in PCOS is not characterized by lower diversity, but the composition is altered at the phylum, family, genus, or species level. Consequently, the metabolic pathway differs according to the phenotype of PCOS.

Polycystic ovary syndrome: Insights into its prevalence, diagnosis, and management with special reference to gut microbial dysbiosis.

Polycystic ovary syndrome (PCOS) represents major endocrine and metabolic disorder among women largely characterized by hyperandrogenism and oligomenorrhea precipitates serious complications such as type 2 diabetes, early atherosclerosis, infertility, and endometrial cancer. Several etiological theories were proposed to define the exact cause of the PCOS, which is characterized, by the hypothalamic-pituitary axis, ovarian morphology, and release of adrenal steroid hormones, metabolic syndrome, and hereditary factors. The review explored the role of dysbiosis and the mechanisms through which microbial dysbiosis can affect PCOS development. In recent time, various research groups highlighted the role of microbial gut dysbiosis associated with obesity as potential etiological factor for the PCOS. In the present review, we reviewed the mechanisms attributed to the microbial dysbiosis and treatment approaches to deal with the situation.

Dysbiotic alteration in the fecal microbiota of patients with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common disease associated with high androgen and infertility. The gut microbiota plays an important role in metabolic diseases including obesity, hyperglycemia, and fatty liver. Although the gut microbiota has been associated with PCOS, little is known about the gut microbial structure and function in individuals with PCOS from Northeast China. In this study, 17 PCOS individuals and 17 age-matched healthy individuals were recruited for community structure and function analysis of the gut microbiota. The results showed that PCOS individuals have reduced diversity and richness of the gut microbiota compared with healthy individuals. Beta diversity analysis showed that the community structure of the gut microbiota of individuals with PCOS was significantly separated from healthy individuals. At the phylum level, PCOS individuals have reduced Firmicutes and Bacteroidota and increased Actinobacteriota and Proteobacteria compared with healthy individuals. At the family and genus levels, the composition of the gut microbiota between PCOS patients and healthy individuals was also significantly different. In addition, PICRUSt2 showed that individuals with PCOS have different microbial functions in the gut compared with healthy individuals. We finally confirmed that Bifidobacterium was enriched in the fecal samples of PCOS patients, while other 11 genera including Bacteroides, UCG_002, Eubacterium__coprostanoligenes_group_unclassified, Dialister, Firmicutes_unclassified, Ruminococcus, Alistipes, Christensenellaceae_R_7_group, Clostridia_UCG_014_unclassified, Roseburia, and Lachnospiraceae_unclassified were depleted compared with healthy individuals. These results indicate that individuals with PCOS have altered community structure and functions of the gut microbiota, which suggests that targeting the gut microbiota might be a potential strategy for PCOS intervention. IMPORTANCE: Gut microbiota plays a critical role in the development of PCOS. There is a complex and close interaction between PCOS and gut microbiota. The relationship between the pathogenesis and pathophysiological processes of PCOS and the structure and function of the gut microbiota needs further investigation.

Gut Microbiome and Polycystic Ovary Syndrome: Interplay of Associated Microbial-Metabolite Pathways and Therapeutic Strategies.

Polycystic ovary syndrome (PCOS) is a multifaceted disease with an intricate etiology affecting reproductive-aged women. Despite attempts to unravel the pathophysiology, the molecular mechanism of PCOS remains unknown. There are no effective or suitable therapeutic strategies available to ameliorate PCOS; however, the symptoms can be managed. In recent years, a strong association has been found between the gut microbiome and PCOS, leading to the formulation of novel ideas on the genesis and pathological processes of PCOS. Further, gut microbiome dysbiosis involving microbial metabolites may trigger PCOS symptoms via many mechanistic pathways including those associated with carbohydrates, short-chain fatty acids, lipopolysaccharides, bile acids, and gut-brain axis. We present the mechanistic pathways of PCOS-related microbial metabolites and therapeutic opportunities available to treat PCOS, such as prebiotics, probiotics, and fecal microbiota therapy. In addition, the current review highlights the emerging treatment strategies available to alleviate the symptoms of PCOS.

Balancing Act: Exploring the Gut Microbiota-Brown Adipose Tissue Axis in PCOS Pathogenesis and Therapeutic Frontiers.

Polycystic ovary syndrome (PCOS) is a prevalent reproductive, endocrine, and metabolic disease that affects 5-18% of women worldwide, with a rising incidence. Hyperandrogenemia and insulin resistance are two key pathophysiological factors that contribute to PCOS, both of which contribute to a variety of health issues such as menstrual irregularities, obesity, dysfunctional glucose and lipid homeostasis, infertility, mental disorders, and cardiovascular and cerebrovascular diseases. Despite ongoing studies, the origin and pathogenesis of PCOS remain elusive; there is also a clinical need for simpler, more effective, longer lasting, and more comprehensive treatments for women with PCOS. The gut-fat axis, a critical regulatory route for metabolism, endocrine function, and immune response, has received considerable interest in recent years in the research of the etiology and treatment of metabolic illnesses such as type 2 diabetes mellitus and non-alcoholic fatty liver disease. The latest research in PCOS has revealed significant alterations in the homogeneity and phylogenetic diversity of the gut microbiota. Animal research using fecal microbiota transplantation has confirmed the importance of gut microbiota in regulating insulin sensitivity and sex hormone balance in PCOS. Furthermore, studies have shown a decrease in the volume and/or activity of brown adipose tissue (BAT) in PCOS patients, a change that alters adipokine release, leading to insulin resistance and hyperandrogenemia, aggravating PCOS progression. Given the function of BAT in increasing energy expenditure and alleviating metabolic parameters, efforts to activate BAT or induce browning of white adipose tissue have emerged as possible treatments for PCOS. Recent research has suggested that the gut microbiota can influence BAT creation and activity via metabolites such as short-chain fatty acids and bile acids, as well as the gut-brain axis. Cold exposure, healthy dieting, metformin, bariatric surgery, glucagon-like peptide 1 receptor agonists and melatonin have all been shown in basic and clinical studies to modulate BAT activity by influencing the gut microbiota, demonstrating significant clinical potential. However, more studies into the regulation mechanisms of the gut-BAT axis are required to produce more effective, comfortable, and safe tailored therapeutics for PCOS.

Metformin modifies plasma microbial-derived extracellular vesicles in polycystic ovary syndrome with insulin resistance.

INTRODUCTION: This study investigated changes in plasma microbial-derived extracellular vesicles (EVs) in patients with polycystic ovary syndrome and insulin resistance (PCOS-IR) before and after metformin treatment, and aimed to identify bacterial taxa within EVs that were biologically and statistically significant for diagnosis and treatment. METHODS: The case-control study was conducted at Xiamen Chang Gung Hospital, Hua Qiao University. Plasma samples were collected from five PCOS-IR patients of childbearing age before and after 3 months of metformin treatment, and the samples were sequenced. The diversity and taxonomic composition of different microbial communities were analyzed through full-length 16 S glycosomal RNA gene sequencing. RESULTS: After metformin treatment, fasting plasma glucose levels and IR degree of PCOS-IR patients were significantly improved. The 16 S analysis of plasma EVs from metformin-treated patients showed higher microbial diversity. There were significant differences in EVs derived from some environmental bacteria before and after metformin treatment. Notably, Streptococcus salivarius was more abundant in the metformin-treated group, suggesting it may be a potential probiotic. DISCUSSION: The study demonstrated changes in the microbial composition of plasma EVs before and after metformin treatment. The findings may offer new insights into the pathogenesis of PCOS-IR and provide new avenues for research.

Effect of a high-fat high-fructose diet on the composition of the intestinal microbiota and its association with metabolic and anthropometric parameters in a letrozole-induced mouse model of polycystic ovary syndrome.

OBJECTIVE: It has been suggested that dysbiosis of the gut microbiota is associated with the pathogenesis of Polycystic Ovary Syndrome (PCOS), and that improper diet can aggravate these changes. This study thus aimed to investigate the effects of a high-fat/high-fructose (HF/HFr) diet on the gut microbial community and their metabolites in prepubertal female mice with letrozole (LET)-induced PCOS. We also tested the correlations between the relative abundance of microbial taxa and selected PCOS parameters. RESEARCH METHODS & PROCEDURES: Thirty-two C57BL/6 mice were randomly divided into four groups (n = 8) and implanted with LET or a placebo, with simultaneous administration of a HF/HFr diet or standard diet (StD) for 5 wk. The blood and intestinal contents were collected after the sacrifice. RESULTS: Placebo + HF/HFr and LET + HF/HFr had significantly higher microbial alpha diversity than either group fed StD. The LET-implanted mice fed StD had a significantly higher abundance of Prevotellaceae_UCG-001 than the placebo mice fed StD. Both groups fed the HF/HFr diet had significantly lower fecal levels of short-chain fatty acids than the placebo mice fed StD, while the LET + HF/HFr animals had significantly higher concentrations of lipopolysaccharides in blood serum than either the placebo or LET mice fed StD. Opposite correlations were observed between Turicibacter and Lactobacillus and the lipid profile, CONCLUSION: HF/HFr diet had a much stronger effect on the composition of the intestinal microbiota of prepubertal mice than LET itself.

Síndrome dos ovários policísticos e sua relação com a microbiota intestinal / Polycystic ovary syndrome and its relationship with the intestinal microbiota

Objetivo: Revisar a implicação e a relação existente entre a microbiota intestinal e a síndrome do ovário policístico (SOP). Métodos: Trata-se de uma revisão sistemática de artigos das bases de dados PubMed, Cochrane e Science Direct dos últimos cinco anos, nos idiomas inglês, português e espanhol. Resultados: A disbiose da microbiota intestinal ativa o sistema imunológico do hospedeiro. Tal ativação interfere na função do receptor de insulina, causando hiperinsulinemia, o que aumenta a produção de androgênio ovariano e dificulta o desenvolvimento de um folículo saudável. Além disso, pacientes com SOP apresentam o perfil taxonômico alterado, o qual se associou inversamente com excesso de andrógenos e inflamação da SOP. Foi evidenciado que o uso de probióticos pode regular a resposta inflamatória, diminuir os níveis totais de testosterona e contribuir para que a SOP não prejudique uma possível gravidez. Conclusão: Essa revisão sugere que há íntima associação entre a disbiose microbiana e as alterações patológicas que ocorrem na SOP. Assim, a suplementação de probióticos em tais pacientes pode ter grandes benefícios, como melhora dos sintomas e redução das repercussões da doença.(AU)

Objective: To review the implication and the relationship between the intestinal microbiota and polycystic ovary syndrome. Methods: This is a systematic review of articles from the PubMed, Cochrane and Science Direct databases, from the last five years, in English, Portuguese and Spanish. Results: Dysbiosis of the intestinal microbiota activates the host's immune system. Such activation interferes with the function of the insulin receptor, causing hyperinsulinemia, which increases the production of ovarian androgens and hinders the development of a healthy follicle. In addition, patients with PCOS have an altered taxonomic profile, which is inversely associated with excess androgens and PCOS inflammation. It was evidenced that the use of probiotics can regulate the inflammatory response, decrease the total testosterone levels and contribute so that PCOS does not harm a possible pregnancy. Conclusion: This review suggests that there is a close association between microbial dysbiosis and pathological changes that occur in PCOS. Thus, supplementation of probiotics in such patients can have great benefits, such as improving symptoms and reducing the repercussions of the disease.(AU)