The human GM primarily comprises four phyla: Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria, with Bacteroidetes and Firmicutes being the most dominant (Parker et al., 2020; Sun et al., 2021). Firmicutes have immune-regulating effects, while Firmicutes, Bacteroidetes, and Ruminococcus influence the production and metabolism of estrogens. Studies have reported that Verrucomicrobia is a species of significant research value, within which Akkermansia belongs, and is considered to play a crucial role in the human intestinal microbiota, exhibiting probiotic properties (Gómez-Gallego et al., 2016). The Lachnospiraceae family plays a vital role in intestinal health by engaging in the digestion and metabolism of dietary fiber, carbohydrates, and sugar transport. Recent studies have highlighted metabolites such as short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), bile acids, polyphenols, and indoles as being closely linked to host health (Vallianou et al., 2019; Yang X. et al., 2021; Figure 2). TMAO, produced by the metabolism of choline in food by intestinal microorganisms, is a key factor in inducing atherosclerosis. This discovery has advanced research on the relationship between intestinal microbial metabolites and extraintestinal organ damage (Koeth et al., 2013). Changes in these differential microbiotas, such as Firmicutes, Bacteroidetes, Verrucomicrobia, Proteobacteria, Lachnospira, and Ruminococcus, and their compositional structure may be one of the pathogenic mechanisms of ovarian dysfunction (Lin et al., 2019).

Short-chain fatty acids, mainly acetic, propionic, and butyric acids, constitute over 95% of the total (O’Riordan et al., 2022). As messengers between the GM and the host, SCFAs exert extensive physiological effects on the host (Shen et al., 2019). They preserve intestinal barrier integrity, reduce colon pH, suppress harmful bacterial growth, and are involved in glucose and lipid metabolism (Ji et al., 2019). Lactobacillus and Bifidobacterium, recognized as beneficial bacteria, exert their beneficial effects by producing SCFAs and are widely used in probiotic preparations. SCFAs are essential for immune regulation and promoting inflammatory responses in pathological processes (LeBlanc et al., 2017). They can directly or indirectly inhibit LPS-activated TLR-4/NF-κB pathways, increase the expression of local cellular pro-inflammatory factors, and downregulate IL-8 and MCP-1, thereby achieving localized pro-inflammatory and overall anti-inflammatory effects (Lin et al., 2015; Segain et al., 2000). SCFAs regulate the distribution and localization of zonula occludens-1 and occludin in the intestinal barrier by influencing the endocannabinoid system, reducing the entry of endotoxin into the bloodstream, and thus controlling inflammation, intestinal barrier function, and intestinal peptide secretion (Muccioli et al., 2010). The endocannabinoid system is associated with female infertility, participating in the physiology and pathophysiology of the endometrium and placenta, influencing the successful implantation of blastocysts and the maintenance of early pregnancy, and holding a pivotal position in human reproduction (Maia et al., 2020). SCFAs affect oxidative damage in reproductive organs through autophagy-related pathways, influencing processes such as the origin of oocytes, the formation of ovarian reserve, follicle recruitment, and the selection of dominant follicles, which are crucial for follicular development (Kumariya et al., 2021). SCFAs also influence the hypothalamic-pituitary-ovarian (HPO) axis. In female obese rats, they can notably reverse precocious puberty, inhibit hypothalamic gonadotropin-releasing hormone (GnRH) secretion, and postpone gonadal axis development via the Kiss1-GPR54-PKC-ERK1/2 pathway (Wang et al., 2022).

Gut microbiota forms a mutualistic symbiotic relationship with the host and participates in various biological processes of the host through multiple mechanisms, including digestion and metabolism of food, development, and immunity (Rudi and Zhao, 2021). Changes in the composition of related microbial species and alterations in internal environmental homeostasis may trigger associated diseases (Wan et al., 2022). The function of the gut microbiota is not limited to the intestine; it can secrete various cytokines, induce inflammation and metabolic changes, and affect the immune system and neuroendocrine system functions (Melamed et al., 2022). The secretion and production of metabolites are the primary ways in which GM participates in the pathophysiological processes of the host. These metabolites can exert local effects in the intestine or enter the blood circulation through the intestinal barrier to affect the functions of multiple extraintestinal organs (Wang et al., 2019). GM can regulate the activity of various enteroendocrine cells and affect the gut-brain axis function. The gut-brain axis can further influence the structure of GM through the immune system (Cheng et al., 2023). GM influences systemic diseases via immune, neuroendocrine, and metabolic pathways (Manor et al., 2020). The human microbiome holds great potential in disease prevention and control: firstly, the composition or functional genes of the human microbiome can be used to predict the occurrence, progression, and outcome of related diseases; secondly, interventions and adjustments can be made to the microbiome to achieve disease prevention and treatment goals (Helmink et al., 2019; Matson et al., 2021; Weersma et al., 2020).

Gut microbiota generally maintains a dynamic balance, interacting with the host and influencing the occurrence and progression of diseases by regulating the metabolism of substances such as sugars, lipids, and amino acids. Imbalances in gut microbiota may contribute to the onset of associated diseases (Takeuchi et al., 2023). Like other organs, the normal function of GM depends on its stable composition (Hörmannsperger et al., 2012). GM dysbiosis is primarily driven by environmental and host-related factors, such as antibiotic use, changes in dietary structure, immune activation, and stress states (Janczyk et al., 2007; Mountain, 1988). GM dysbiosis occurs when these factors disrupt the gut microbial ecosystem beyond its resistance and recovery capabilities, with effects ranging from transient to permanent and from benign to harmful (Fassarella et al., 2021). GM dysbiosis is mainly classified into three types: (1) Overproliferation of pathogens. In a healthy gut, pathogens exist at relatively low abundances, but in intestinal infection and inflammation states, Enterobacteriaceae bacteria can overproliferate; (2) Reduce or complete loss of commensal bacteria. This situation can be improved by exogenous supplementation of commensal bacteria. For example, in the case of Clostridium difficile infections, colonization with Clostridium scindens can improve the severity of the disease; (3) Decreased gut microbiota diversity. The impact of GM on reproductive organs is primarily through circulatory transport, where GM products or product-induced endocrine, oxidative stress, and inflammatory factors are transported to the reproductive organs, affecting reproductive function (Dey and Ray Chaudhuri, 2023; Yang et al., 2022).

Gut microbiota is intrinsically linked to ovarian function. The composition and metabolites of gut microbiota can affect the regulation of the HPO axis, thereby influencing the growth and development of ovarian tissue and oocytes (Hwang et al., 2015). Metabolites like SCFAs and bile acids from GM effectively regulate hypothalamic GnRH neuron function (Liao et al., 2021). GnRH is a key pathway in regulating reproductive function. GnRH secreted by the hypothalamus binds to pituitary receptors, stimulating the release of luteinizing hormone (LH) and FSH, LH and FSH stimulate the gonads to synthesize and secrete steroid hormones like testosterone, estrogen, and progesterone, facilitating the development of target organs. Ovarian aging is closely related to mitochondrial dysfunction, and oxidative stress-induced mitochondrial dysfunction is essential to ovarian aging. Mitochondria are crucial for cellular energy metabolism, the cell cycle, and signaling (May-Panloup et al., 2016). There is a dialogue between GM and mitochondria, and mitochondria can induce granulosa cell apoptosis and autophagy, leading to follicular atresia and premature ovarian failure (Bajpai et al., 2018; Thevaranjan et al., 2017; Yadav et al., 2018).

The gut-brain axis serves as a bridge for bidirectional communication between GM and the central nervous system. GM dysbiosis can alter the release of neuroendocrine hormones and affect neurotransmitter activity, subsequently influencing the central nervous system (Shekarabi et al., 2024). Research indicates that reduced levels of Firmicutes and Bacteroidetes can elevate serum glucagon-like peptide-1 (GLP-1) and its expression, which stimulates GnRH neurons. It modulates neurons and the neurotransmitter gamma-aminobutyric acid (GABA) to regulate GnRH secretion (Outeiriño-Iglesias et al., 2015). GM can produce most neurotransmitters in the brain, such as GABA, dopamine, norepinephrine, acetylcholine, and serotonin (5-HT) 0.5-HT can increase cAMP levels in immature oocytes, promoting oocyte meiotic maturation (Stricker and Smythe, 2001). As a precursor of melatonin, 5-HT can divert tryptophan away from the melatonin pathway through the kynurenine pathway, thereby reducing circulating melatonin levels (Davidson et al., 2022; Fernstrom, 2016). Melatonin may postpone ovarian aging by acting as an antioxidant, preserving telomeres, enhancing SIRT expression and ribosomal function, and decreasing autophagy. It safeguards oocytes from oxidative damage and enhances the expression of genes involved in fatty acid β-oxidation and mitochondrial biogenesis, supplying essential energy for oocyte maturation and embryonic development (Jin et al., 2017; Tamura et al., 2017).

Gut microbiota in patients with POF exhibits significant imbalances, and these alterations are associated with the occurrence and progression of the disease (Huang et al., 2024; Figure 4). Cao et al. (2020) in a POF mouse model, a significant increase in gut microbiota α-diversity was observed compared to normal mice. POF mice exhibited lower Helicobacter, Odoribacter, and Alistipes but higher Clostridium XIVa, Barnesiella, Bacteroides, and Mucispirillum (Cao et al., 2020). A comparison of gut microbiota revealed that healthy women had higher Firmicutes, Ruminococcus, and Caldibacillus levels.

In contrast, POF patients exhibited a greater abundance of Bacteroidetes, Butyricimonas, Dorea, Lachnobacterium, and Sutterella (Wu et al., 2021). Differences exist in the gut microbiota of patients with POI compared to a standard control group, with differential bacteria such as Bifidobacterium, Bacillus, and Clostridium being able to produce SCFAs in the human intestine (Wang et al., 2023). Not only does the gut microbiota of POF patients change, but their reproductive tract microbiota also undergoes alterations. Wang et al. (2018) study found notable differences in the diversity and richness of vaginal microbiota between POF patients and healthy women. The relative abundance of lactic acid bacteria was notably lower in POF patients than in postmenopausal women (Wang et al., 2018).

Current research suggests that the relationship between GM and POF is mainly reflected in autoimmune responses, participation in sex hormone regulation, oxidative stress, inflammatory reactions, and ovulation disorders (Sharif et al., 2019). The GM acts as a messenger in the interaction between the host and the external environment, not only maintaining normal intestinal barrier function, resisting the invasion of pathogenic bacteria, participating in the digestion and absorption of nutrients to provide energy for the host, but also producing important metabolites and promoting the maturation of immune cells (Schluter et al., 2020). The GM can mitigate POF by modulating the expression of immune-related cytokines, including regulatory T cells (Treg), interferon-γ (IFN-γ), and T helper 17 cells (Th17) (Colliou et al., 2018; Motedayyen et al., 2018; Yin et al., 2018b). The GM is also broadly involved in hormone metabolism, bone density, and central nervous system regulation, all of which are closely related to the etiology and clinical symptoms of POF. GM’s development prospects and research space are vast, and an in-depth investigation of the relationship between GM and POF holds significant clinical value.

Chemotherapy-induced premature ovarian failure refers to ovarian failure occurring after chemotherapy treatment (Molina et al., 2005). The ovarian damage caused by chemotherapy is a common treatment complication among female cancer patients and affects their quality of life (Chen and Manson, 2006). Discovering ovarian protective agents with minimal side effects for clinical use could dramatically enhance the quality of life for female cancer patients undergoing chemotherapy, offering substantial social and academic advantages. Studies have indicated that GM influences the host’s responsiveness to chemotherapy drugs, enhancing efficacy and neutralizing drug toxicity. This suggests that GM will be a key aspect of individualized treatment for cancer patients (Zhang et al., 2016). Gori et al. (2019) found that antibiotics against Gram-positive bacteria can reduce the therapeutic effect of platinum-based chemotherapy drugs; Perales-Puchalt et al. (2018) discovered that fecal microbiota transplantation from healthy mice could improve Cis-platinum-induced intestinal mucosa damage. Research indicates that cyclophosphamide-induced POF in mice leads to notable alterations in gut microbiota, characterized by reduced Akkermansia abundance and increased Lactobacillus levels. Fisetin mitigates CTX-induced ovarian damage by modulating the GM to decrease CD4 + T lymphocytes and IL-12 levels (Lin et al., 2020). Targeting the GM could be a “breakthrough” in studying the pathogenesis of CIPOF and developing new preventive and therapeutic drugs.