PCOS (Polycystic ovarian syndrome) is a global problem as it affects approximately 116 million (8–13 %) women worldwide (World Health Organization, 2023) and the incidence rate of the women with PCOS struggling with spontaneous conception was 16.4 % (Johnson, Bond and Bench-Capon, 2018). The prevalence rate of PCOS is over 9 % in various countries like United States, Spain, Brazil, Mexico, Iran and continents like Africa, and Asia (Yasmin et al., 2022). According to study by Bharali et al., PCOS prevalence in India, was close 10 % using Rotterdam's criteria and AES (The Androgen Excess Society) criteria, while it was 5.8 % using NIH (National Institute of Health, 2019) criteria (Bharali et al., 2022). Diagnosing PCOS has various clinical challenges. PCOS confirms after presence of two out of three features—hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology as per Rotterdam diagnosis criteria although its limitations and controversies (Smet and McLennan, 2018). Lack of early diagnosis cause delayed treatment of PCOS resulting severe physiological changes in women over lifetime (Gibson-Helm et al., 2016). Delayed diagnosis of PCOS has long-term, multi-system consequences that significantly affect metabolic, reproductive, cardiovascular, and psychological health. Without early intervention, insulin resistance and hyperinsulinemia worsen over time, increasing the risk of type 2 diabetes, metabolic syndrome, and obesity. A study by Mei-Lien Pan et. al. 2017 found that PCOS is a significant risk factor for the development of POI (premature ovarian insufficiency) (Pan et al., 2017). A study by (Shetty et al., 2023) states that there is an increased risk of endometrial cancer in women with PCOS. Therefore early diagnosis is very important in case of PCOS to avoid future complications.

Recent year studies are more focused on exploring the role of the gut microbiome in the pathophysiology of PCOS (Sun et al., 2024; Sun et al., 2023b; Yu et al., 2022). The gut microbiome has been studied as a key metabolic and endocrine homeostasis modulator. It impacts the physiology of the host via composite crosstalk with the host immune system, metabolism, and neuroendocrine axis (Cox et al., 2022). By studying potential mechanisms of Gut-PCOS axis this review seeks to improve our understanding of PCOS pathophysiology and identify innovative opportunities for therapeutic intervention.

PCOS is characterized by polycystic ovaries, anovulation, and hyperandrogenism. It impacts multiple physiological functions and leads to menstrual dysfunction (Walker et al., 2020), infertility (Pan et al., 2017), hirsutism (Spritzer et al., 2022), acne (Gainder and Sharma, 2019), obesity and metabolic syndrome (Chen and Pang, 2021). PCOS women have increased risk of developing type 2 diabetes (Anagnostis et al., 2021) and cardiovascular disease which remains as topic of debate (Yan et al., 2022). Menstrual irregularities in PCOS can be classified as oligomenorrhea (infrequent menstrual periods) and amenorrhea (absence of menstrual periods) indicating ovarian dysfunction. Hyperandrogenism exhibits as hirsutism (male-pattern hair growth on face), acne, and androgenic alopecia (male-pattern baldness) as clinical phenotype (Spritzer et al., 2022). PCOS is associated with multiple metabolic abnormalities beyond reproductive signs like insulin resistance, impaired glucose tolerance, dyslipidemia and metabolic syndrome (Harris et al., 2017). Bulsara et al., states that PCOS linked to disturbed hypothalamic-pituitary-ovarian (HPO) axis causing excess androgen production and impaired folliculogenesis. Whereas Insulin resistance leads to hyperandrogenism by stimulating ovarian androgen and disrupting follicular development (Bulsara et al., 2021).

Human GI (Gastrointestinal) tract is colonised by bacteria that means around 10-fold of the total number of cells by which human body is constructed (Hariri et al., 2024; Thursby and Juge, 2017; Wang et al., 2018). The gut microbiome is a diverse array of microorganism’s commensal to GI tract which consist of bacteria, fungi, viruses, and archaea forming a complex ecosystem (Lloyd-Price et al., 2017). The most common genera innate to the human gut are Lactobacillus, Bifidobacterium, Bacteroides, Clostridium, Fusobacterium, Eubacterium, Ruminococcus, Peptococcus, and Peptostreptococcus (Thursby and Juge, 2017). Other genera like Escherichia coli, Salmonella, Shigella, Campylobacter, and Yersinia are also found in the normal gut (Gorbach, 1996). This large genetic repertoire aids the gut microbiota to cascade essential functions contributing to homeostatic signalling managing all chemical pathways expressing balanced human body. Gut bacteria cause fermentation of dietary fibres and converts them into short-chain fatty acids (SCFAs) like butyrate (Canani, 2011) important for colonic health and energy metabolism. Gut microbiome manages various biochemical pathways like tricarboxylic acid (TCA) cycle also referred as Krebs cycle by producing intermediates like butyrate also modulate the bile acid cycle by lipid digestion, cholesterol metabolism processes, production of vitamin K (Morowitz et al., 2011; Michaudel and Sokol, 2020). By taking part in all these different biochemical mechanisms gut microbiome maintains homeostatic signalling pathways for all metabolic and physiological balance of the body.

To better understand the complicated pathophysiology of PCOS and developing new treatment strategies it is important to understand the link between gut microbiota and PCOS. By studying different factors that are responsible for the change in the composition of gut, its pathway and bodily interactions can understand the intervention planning for PCOS that can help in preventing as well as managing strategies.

Recent advances in understanding the PCOS pathophysiology have explored its multidimensional nature that explains about genetics, endocrinology, metabolism, and environmental factors. The development of phenotypic characteristics of PCOS in women is influenced by multiple factors that have with a significant role attributed to dysbiosis of gut flora. Rutkowska and Diamanti-Kandarakis states that there are various external factors like diet, lifestyle, and exposure to endocrine-disrupting chemicals alter PCOS susceptibility and channels phenotypic expression (Rutkowska and Diamanti-Kandarakis, 2016).

Diet plays a significant role in the pathology of PCOS. Nutritional intake not only affects hormonal balance and insulin sensitivity but also significantly influences gut microbiota composition, which is increasingly recognized as a contributing factor in PCOS development (Rodriguez Paris et al., 2022). Studies from around the world have indicated that women with PCOS consume different amounts of dietary energy than those without the condition (Hajivandi et al., 2020). A diet deficient in prebiotics, probiotics, and synbiotics has been identified as a potential factor contributing to dysbiosis and associated health implications (Zhao et al., 2020). Environmental factors, such as birth mode, early-life diet, and antibiotic usage, can impact gut microbiota composition, leading to lower diversity, decreased SCFA production, and increased gut permeability (Dedrick et al., 2020). Endocrine disruptors can be one of the factor driving towards PCOS. Some endocrine disruptors like such as certain plastics, cosmetics, and cleaning products, can interfere with hormone production and regulation, potentially leading to PCOS. Several studies have found that women with PCOS have significantly higher levels of bisphenol A (BPA) in their blood, urine, or follicular fluid (Srnovršnik et al., 2023). Lifestyle factors like smoking, lack of exercise, sleeping cycles and exposure to air pollution can contribute PCOS. se study demonstrated that sedentary behaviour is prevalent among women with PCOS, and it may be a contributing factor to the development of obesity by altering the gut microbiota and causing gut dysbiosis (Tay et al., 2020). Growing evidence suggests a bidirectional relationship between PCOS and sleep disorders, with poor sleep potentially contributing to the pathogenesis of the condition. This can lead to extreme metabolic stress, oxidative stress, and emotional stress (Fernandez et al., 2018).

A genetic study has identified susceptibility of loci associated with PCOS showing the hereditary basis of the syndrome and highlighting the role of genetic predisposition in its etiology (Saxena et al., 2015). Li et al. (2022), explain the genetic link between PCOS and Type 2 Diabetes (T2D) using genome-wide association studies (GWAS). The study revealed 11 potential PCOS risk variants among which 9 genetic loci were new and the remaining 6 were common to both conditions. The functional analysis conducted states that multiple genes are involved in lipid metabolism, immune response, and insulin signalling with the SCN2A gene co-localized in subcutaneous adipose tissue in PCOS (Li et al., 2022). Disruption GnRH signalling affects intraovarian paracrine pathways that contribute to follicular dysregulation and hyperandrogenism in PCOS women (Jozkowiak et al., 2023; Kang et al., 2000).

Elevated levels of androgens such as testosterone and dehydroepiandrosterone sulfate (DHEAS) is a primary feature of PCOS also known as hyperandrogenism. Androgens are mainly produced by the ovaries, adrenal gland and peripheral tissues coverts it to testosterone (Sharma and Welt, 2021). HPO is the primary centre affected that governs the menstrual cycle, ovulation, and hormonal homeostasis (Bulsara et al., 2021). The dysregulation in the HPO axis leads to abnormal secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, stimulates excessive secretion of luteinizing hormone (LH) from the anterior pituitary gland and disturbs follicle-stimulating hormone (FSH) causing abnormal follicular development and cyst formation (Tortora and Derrickson, 2017; Franks and Hardy, 2020). This contributes to anovulation and ovulatory dysfunction. Ovulatory dysfunctions can give rise to infertility and menstrual irregularities. There is an increase in the pre-antral follicle density as well as percentage of early-growing follicles. Abnormal proliferation of granulosa cells and uneven development of the oocyte surrounding granulosa cells further characterize these anomalies in anovulatory PCOS (Franks et al., 2008). This characteristic feature is observed on ultrasound imaging. Therefore, lacking the dominant follicle and the failure to undergo timely luteinisation result in the absence of ovulation, leading to irregular menstrual cycles or amenorrhea (absence of menstruation). Beyond reproductive dysfunction and hormonal imbalance metabolic disturbances further contributes to PCOS progression.

Metabolic disturbances (MD) is the another physiological condition that represents insulin resistance, dyslipidemia, obesity, and abnormal glucose metabolism (Fung and Zinkhan, 2021) (Huang, 2009). Insulin resistance is characterized by reduced cellular responsiveness to insulin signalling particularly in peripheral tissues such as skeletal muscle, liver, and adipose tissue insulin-interfering signalling pathways. Insulin resistance leads to compensatory hyperinsulinemia as the pancreas secretes increased amounts of insulin in an attempt to overcome tissue resistance and maintain euglycemia (Rahman, 2021). Hyperinsulinemia exerts multiple metabolic effects, including stimulation of ovarian androgen production, inhibition of hepatic synthesis of sex hormone-binding globulin (SHBG) (Plymate et al., 1988; Baptiste et al., 2010), and promotion of adipose tissue lipogenesis, contributing to the pathogenesis of PCOS (Rosenfield and Ehrmann, 2016). Moghetti et al. (2013) depicts that 71.4 % of the subjects among 137 Caucasian women diagnosed with PCOS were insulin resistant and affected women are more prone to metabolic risk (Moghetti et al., 2013).

The gut microenvironment is an another important factor, when disrupted cause PCOS. The gut microenvironment refers to the intricate ecosystem within the digestive tract, encompassing the gut microbiota (microbes), the intestinal epithelium, and the surrounding immune system that all interact and influence each other to maintain gut health (Iribarren et al., 2022). A microenvironment is constituted of bacteria, epithelial cell and local immune factors that are responsible for maintaining the ecosystem of gut. A meta-analysis conducted by author Li et al. (2023) showed higher counts of Escherichia/Shigella, Fusobacterium, and Bacteroides in PCOS patients. Also showed a with a corresponding reduction in beneficial bacteria like Lactobacillus and Bifidobacterium that are responsible for the same. This microbial imbalance results in greater gut permeability or leaky gut, which allows LPS and other microbial metabolites to translocate into the bloodstream. This evokes systemic inflammation and is implicated in immune activation (Mohammad and Thiemermann, 2021). Depletion in number of good bacteria cause decrease in gut-derived short-chain fatty acids (SCFAs) like butyrate, acetate, and propionate which has also been reported in PCOS. SCFAs has important role in glucose metabolism, lipid homeostasis, and disruption of immune microenvironments (Silva et al., 2020; Pathak et al., 2025) Gut dysbiosis and immune system dysregulation create a self-perpetuating cycle in PCOS by triggering inflammation, metabolic disturbances, and impaired ovarian function.