The gut microbiota: emerging biomarkers and potential treatments for infertility-related diseases

The gut microbiota is a general term for all microorganisms colonizing the human gastrointestinal tract, with a wide variety of species, large numbers, and complex functions, known as the “second genome of the human body” ( Adak and Khan, 2019 ). The proportion of Firmicutes and Bacteroidetes in the gut microbiota in the human body is as high as 90%, followed by Actinomycetes, Proteobacteria, and Fusobacteria, which are involved in the maintenance of the microecological balance in the human body ( Zeng et al., 2019 ). The relationships between the gut microbiota and the host are divided into three major categories: beneficial bacteria, such as Lactobacillus and Bifidobacterium, which help the body digest and absorb toxins, reduce the release of toxins, improve the body’s immune system, alleviate inflammatory reactions, and decrease the incidence of tumors. Harmful bacteria, such as Salmonella and Staphylococcus, increase the toxin content, disrupt the internal environment of the intestine, and increase the incidence of cancer. Harmful bacteria, such as Salmonella and Staphylococcus, can increase the level of toxins and damage the internal environment of the intestine, leading to intestinal diseases and increasing the incidence of cancer; intermediate bacteria, such as Bacteroides and Escherichia coli ( Liu et al., 2017 ; McQuade et al., 2019 ). The species and number of microorganisms colonizing the gut vary within a certain range and are in dynamic equilibrium ( Zemel, 2017 ). The gut microbiota plays important roles in human growth and development, metabolism, immunity, and other pathophysiological processes, including the promotion of host immune system maturation, the inhibition of pathogen overgrowth, the regulation of intestinal endocrine function, neural signaling, and the synthesis of neurotransmitters ( He and Li, 2020 ). The gut microbiota not only exerts various effects on the intestinal environment but also regulates distal tissues and organs and is considered to be a mature endocrine organ ( Martin-Gallausiaux et al., 2021 ). With the development of gene sequencing technology, in-depth knowledge of the gut microbiota has increased, and many studies have confirmed that the gut microbiota composition and diversity are altered when dysbiosis occurs and that dysbiosis of the gut microbiota can promote the occurrence and development of diseases through various pathways, such as neuroendocrine and metabolic immunity pathways, in the human body ( Di Vincenzo et al., 2024 ) ( Figure 1 ). The gut microbiota has become one of the hotspots of research in medicine, microbiology, genetics, etc ( Yan and Charles, 2018 ). The gut microbiota plays a vital role in female reproductive health. It can be involved in the occurrence of diseases of the female reproductive system by directly or indirectly participating in the regulation of sex hormones, stimulating the production of inflammatory factors, and influencing immune function and metabolic homeostasis ( Escobar-Morreale, 2018 ). Factors determining intestinal barrier impairment and consequent systemic diseases ( Di Vincenzo et al., 2024 ).

Probiotic therapy to restore gut microbiota homeostasis has been used with some success in treating female reproductive disorders ( Karamali et al., 2018 ). Inulin and metformin can reduce the weight of mice, decrease the level of testosterone, and increase the level of E2 by altering the composition of the gut microbiota and inhibiting inflammation, altering the morphology of the ovaries ( Huang et al., 2022 ). Probiotics restored the diversity of the gut microbiota in rats with PCOS, further improving the reproductive function of the rats ( Cozzolino et al., 2020 ). Dietary improvements, as well as probiotic therapy, have been shown in clinical studies to positively impact the metabolic profile of women with PCOS, such as lower body weight and improved IR and lipid metabolism profiles ( Jakubowicz et al., 2013 ). However, the types and doses of probiotics used in these studies vary widely, and further standardization is needed for future clinical studies. By studying the phenotype of prenatal androgenized mice, it was found that the appearance of gut microbiota abnormalities preceded the appearance of a PCOS-like phenotype in prenatal mice compared with controls, suggesting that the early gut microbiota is a potential target for the prevention of PCOS. Fecal microbiota transplantation (FMT) technology is gradually improving disease quality. Both fecal microbe transplantation and Lactobacillus transplantation in mice were found to decrease serum androgen levels, increase serum estrogen levels, improve ovarian dysfunction, and improve the estrous cycle ( Yanjie et al., 2016 ). FMT has not been studied in the PCOS population. Further studies of FMT may provide novel alternative treatment options for PCOS. The gut microbiota structure and function are specific to patients with EMs, and treatments targeting the gut microbiota structure and metabolites, such as probiotics, antibiotics, and α-linolenic acid, have shown promising results ( Ni et al., 2021 ). The difference in the levels of IL-1 and IL-6 produced by peripheral blood mononuclear cells in EMs patients and healthy controls was statistically significant, and the application of Lactobacillus acidophilus induced the production of IL-1 and IL-6; therefore, probiotics can be used to treat EMs patients. Probiotics can improve neurotransmitter synthesis and signaling in the gut microbiota, modulate neurotransmitter levels, affect pain pathways, and reduce pain perception in patients with Ems ( Khodaverdi et al., 2019 ). Lactobacillus gasseri OLL2809 inhibits the development of ectopic endothelial cells by activating natural killer cells. The administration of Lactobacillus gasseri OLL2809 for three months significantly reduces dysmenorrhea ( Itoh et al., 2011 ). In animal models, broad-spectrum antibiotic treatment has been shown to be effective in the treatment of EMs. Chadchan et al. reported that the use of antibiotics to remove Bacteroidetes inhibited the growth of ectopic endometrial foci in mice, suggesting that antibiotics may have the potential to prevent the progression of EMs by altering the gut microbiota to improve the inflammatory microenvironment. When mice with reduced ectopic foci were transplanted with fecal bacteria from endometriosis model mice, the ectopic foci of the former mice were significantly enlarged, suggesting that specific gut microbiota can promote the development of EMs ( Chadchan et al., 2019 ). Exogenous supplementation with the bacterial metabolite unsaturated fatty acid α-linolenic acid improved the gut microbiota structure, dominant bacterial abundance, and intestinal wall barrier in EMs mice; regulated the intraperitoneal LPS content and inflammatory environment; and improved EMs. The use of gut microbiota preparations for diagnosing and treating EMs has broad research prospects ( Pascale et al., 2019 ). No studies have reported the use of FMT for the treatment of EMs, and further exploration is needed. The combination of antibiotic treatment with other conventional therapies may be a potential treatment option for combating EMs. Studies on POF and the gut microbiota are relatively limited. The diversity of the gut microbiota was significantly greater in POF mice than in normal mice, with a low abundance of Helicobacter, Odoribacter, and Alistipes and a high abundance of Clostridium XIVa, Barnesiella, and Bacteroides ( Cao et al., 2020 ). A comparison of the gut microbiota between POF patients and healthy women revealed that Firmicutes were more abundant in the intestines of healthy women. Moreover, Bacteroidetes, Butyricimonas, Dorea, and Lachnobacterium are more abundant in the intestines of POF patients ( Wu et al., 2021 ). Dysregulation of the gut microbiota plays a vital role in the pathogenesis of POF ( Wang et al., 2020 ). During cyclophosphamide-induced POF, the mouse gut microbiota is significantly altered, with a decrease in Akkermansia abundance and a marked increase in Lactobacillus abundance ( Lin et al., 2020 ). Fisetin attenuates cyclophosphamide-induced ovarian damage by modulating the gut microbiota in a manner that decreases CCR9+, CXCR3+, CD4+, T lymphocytes, and IL-12. The factors contributing to POF do not exist independently but interact with each other and synergistically contribute to the accelerated progression of ovarian senescence. The gut microbiota affects the occurrence and development of POF through various pathways and factors, and the underlying mechanism needs to be further explored. In the future, further exploration should be conducted to identify the characteristics of the gut microbiota profile in patients with POF, as well as to discover specific microbial spectra associated with the onset and progression of POF. These findings provide a deeper understanding of the pathogenesis of POF from metabolic, inflammatory, and other perspectives, ultimately leading to the development of effective treatment strategies.

The aging process of female ovaries is accelerating, and the incidence of infertility is significantly increasing at a younger age ( Inhorn and Patrizio, 2015 ). Delayed childbearing has become a global problem. The WHO predicts that infertility will become the third most important disease of the 21st century after tumors and cardiovascular disease ( Carson and Kallen, 2021 ). Clinical conditions that lead to female infertility include PCOS, EMs, and POF ( American College of Obstetricians and Gynecologists Committee on Gynecologic Practice and Practice Committee, 2014 ; Gu et al., 2022 ; Salmeri et al., 2024 ). Reduced human fertility is not simply a reproductive health issue but also raises a variety of social, economic, and family issues. Approximately 100 trillion microorganisms colonize the human gastrointestinal tract, and gut microorganisms form interdependent symbioses with their hosts, affecting normal physiology and susceptibility to disease ( Illiano et al., 2020 ). James et al. proposed that the gut microbiota plays a vital role in the pathogenesis of various estrogen-dependent diseases and proposed the concept of the “estrogen-gut microbiota axis.” The gut microbiota regulates estrogen by secreting β-glucuronidase ( Flores et al., 2012 ). Disruption of this process by dysbiosis of the gut microbiota results in a decrease in circulating estrogen. Alterations in circulating estrogen can lead to the development of diseases such as obesity, metabolic syndrome, PCOS, EMs, and decreased fertility ( Saunders and Horne, 2021 ). With the increasing development and improvement of microbiome research, the involvement of the gut microbiota in the curative mechanism of female infertility diseases such as PCOS, EMs, and POF deserves further investigation, which is highly important in guiding the improvement of female infertility and fertility ( Dinsdale and Crespi, 2021 ).

Infertility is a public health problem that has a significant effect on women’s quality of life and reproductive health, as well as on economic and social development and population security. The gut microbiota can affect the development of infertility in various ways. Dysregulation of the gut microbiota leads to an increase in intestinal permeability, resulting in an increase in lipopolysaccharide levels in the body, triggering inflammatory and immune responses in the body, resulting in disruption of glucose metabolism in the body and disruption of the gut microbiota, which ultimately leads to the development of infertility symptoms in the patient ( Table 1 ). Intervening in infertility by regulating the gut microbiota through probiotics, nutrients, antibiotics, and FTM supplementation provides new ideas for treating infertility. The many roles of the gut microbiota in the pathogenesis of infertility disorders are well documented, but certain limitations remain: (1) studies on the relationship between the gut microbiota and infertility are focused primarily on the correlation level, and there are still few studies on its specific mechanism of action; (2) the influence of regional, dietary, ethnic, and cultural differences on the structural composition of the gut microbiota is a significant interfering factor in related studies; and (3) there are individual differences in the number and types of human gut microbiota, and individualized application is an important issue that needs to be explored in further research in the future. Future exploration of the potential mechanisms by which gut microbiota alterations mediate infertility is needed to provide new strategies for the prevention, diagnosis, and treatment of infertility. Changes in the gut microbiota associated with infertility-related diseases.