Endometriosis is an estrogen-dependent disease, that is characterized by the presence of endometrial glands and stromal cells outside the uterus (Ferrero et al., 2014). Estrogen plays an important role in maintaining female reproductive system development (Jeon et al., 2016). Estrogen can regulate the microenvironment of the female lower genital tract by increasing epithelial thickness, glycogen levels and mucus secretion, and indirectly reducing vaginal pH by increasing Lactobacillus abundance and lactic acid levels (Baker et al., 2017). Studies have found that estrogen can induce proliferative diseases such as endometriosis, endometrial cancer, and hysteromyoma by stimulating the proliferation of female genital epithelial cells (Buchanan et al., 1998; Merrheim et al., 2020). The metabolism of estrogen mainly occurs in the liver. The liver can produce sex hormone binding globulin, and the combination of sex hormone binding globulin and estrogen can lead to loss of estrogen biological activity (Phelps et al., 2019). The gut microbiota can secrete β-glucuronidase and β-glucosidase, and these products can promote the degradation of estrogen, thus increasing the reabsorption of free estrogen, and improving the level of estrogen in the circulation (Possemiers et al., 2011; Kwa et al., 2016). Analysis of the microbial genome shows that multiple bacterial genera in the gut microbiota can produce β-glucuronidase, including Bacteroid, Bifidobacterium, Escherichia coli and Lactobacillus (Beaud et al., 2005). Notably, in the feces of endometriosis patients, the Escherichia coli content is significantly increased (Leonardi et al., 2020). The above studies confirmed that the gut microbiota can lead to an increase in circulating estrogen levels, which is helpful in creating a high-estrogen environment for endometriosis progression (Qi et al., 2021). However, the factors that stimulate the production of β-glucuronidase by specific gut microbiota in the pathogenesis of endometriosis, the relationship between the gut microbiota and female upper reproductive tract microbiota, and whether they play a synergistic role in the pathogenesis of endometriosis still need further research.

Although endometriosis is an estrogen dependent disease, some studies have found that the growth of ectopic lesions continues even in ovariectomized animals, indicating that in addition to ovarian steroids, the innate immune system in the pelvic environment can also regulate the growth of ectopic lesions in endometriosis (Khan et al., 2009). The natural immune cells of mammals (such as macrophages and dendritic cells) can be activated by microbial components (non self), such as endotoxin or lipopolysaccharide from gram-negative bacteria (Ramirez-Pavez et al., 2021). Research shows that the inflammatory microenvironment is closely related to the occurrence of endometriosis (Bruner-Tran et al., 2013). The inflammatory response is the central process in the development of endometriosis, leading to pain, tissue remodeling, fibrosis, adhesion formation and infertility (Mu et al., 2018). A series of changes in inflammatory factors, cytokines and chemokines are observed in the focus and peritoneal fluid of patients with endometriosis, including both proinflammatory and anti-inflammatory components (Machairiotis et al., 2021). The levels of the proinflammatory factors IL-1β, IL-18, and TGF-β are increased in the peritoneal fluid. When the inflammatory activity decreases, the level of the anti-inflammatory factor IL-37 increases (Zhou et al., 2019). When the body is unable to remove inflammatory substances, an inflammatory state is induced, which may spread from the region of inflammation to the whole body and have a long-term impact on the immune system (Symons et al., 2018). One important factor in the pathogenesis of endometriosis is that deficiency of the immune system leads to difficulty in clearing ectopic endometrial tissue. The increase in the levels of proinflammatory factors, anti-inflammatory factors and immune cells reflects an imbalance in the regulation of inflammation and anti-inflammatory processes, as well as changes in intestinal microbiota, intestinal permeability and other immune regulatory processes (Laschke and Menger, 2016).

Recently, studies have demonstrated that the gut microbiota may interact with cytokines abnormally expressed in endometriosis lesions, peritoneal fluid and peripheral blood (Yuan et al., 2018). Increased Escherichia coli and Shigella in the gut were observed in patients with endometriosis (Quaranta et al., 2019). Additionally, the level of LPS in the gut and serum is also increased in patients with endometriosis (Ni et al., 2020). Studies have shown that both initial inflammatory mediators (lipopolysaccharide) and secondary inflammatory mediators (cytokines/growth factors) participate in the development of endometriosis, and that TLR are expressed in macrophages and other dendritic cells (Azuma et al., 2017). Other studies have shown that macrophages can promote the release of inflammatory mediators under lipopolysaccharide stimulation, thereby promoting the inflammatory infiltration, proliferation and angiogenesis observed in endometriosis (Rana et al., 1996; Jeljeli et al., 2020).

Endometriosis is a chronic disease with a recurrence rate of 10%-15% one year after conservative surgery. At the 5-year follow-up, the recurrence rate was 40%-50% (Berlanda et al., 2010). Women with endometriosis will experience severe pain during menstruation and sexual intercourse, which can not only cause health problems, but also interfere with normal activities during work and leisure time (Huntington and Gilmour, 2005). In addition to pain and infertility, endometriosis has a huge negative impact on women’s social functions, work and employment (Facchin et al., 2015). Treatment of endometriosis involves conservative or radical surgery, or medical therapies. Therefore, finding a safe and effective way to prevent and treat endometriosis has become a global problem, especially for women of reproductive age with endometriosis. Gut microbiota imbalance has many adverse effects on the body, and correcting the gut microbiota imbalance to restore its normal functional state provides another option for the treatment of many diseases, including endometriosis. Regulation of gut microbiota by means of antibiotics, fecal bacteria transplantation, probiotics, nutrients, etc., may provide new ideas for the clinical treatment of endometriosis (Xu et al., 2015).

Gut microbiota imbalance has been found to be closely related to a reduction in short-chain fatty acid production (Macfabe, 2012; Melbye et al., 2019). Butyric acid is a short-chain fatty acid that plays an important role in maintaining the intestinal barrier, inhibiting immune function and optimizing mitochondrial function (Zhao Z. H. et al., 2021; Rekha et al., 2022). In addition, butyrate can also inhibit the immune response caused by intestinal biological imbalance (Ma et al., 2020). Some scholars have found that the gut microbiota can cause depression by reducing the short-chain fatty acid butyrate; patients with endometriosis have a relatively high risk of depression, and women with chronic pelvic pain usually have a higher degree of depression than those without pain (Silva et al., 2020). Furthermore, a recent study showed that gut microbiota-derived butyrate can protect mice against endometriosis by regulating G-protein-coupled receptors (Chadchan et al., 2021).

A study on the correlation between fecal metabonomics and gut microbiota in mice with endometriosis found that chenodeoxycholic acid (CDCA) and ursodeoxyl content increased and the abundance of linolenic acid (ALA) decreased (Ni et al., 2020). Meanwhile, another study demonstrated that ALA reduced the inflammatory response by inhibiting the accumulation of nitrite and prostaglandin E2 (PGE2) (Ni et al., 2021). In addition, ALA can inhibit the inflammatory response of M1 macrophages (Pauls et al., 2018). Moreover, ALA can improve the abdominal inflammatory environment and reduce the level of LPS in mice with endometriosis (Ni et al., 2021). The above two studies suggest that metabolic changes may play an important role in the pathogenesis of endometriosis and that some metabolites of gut microbiota may have the potential to treat endometriosis.

Gut microbiota can be divided into symbiotic bacteria, probiotics and pathogenic bacteria. Gut microbiota disorder is considered to be a decrease in the number of probiotics in the body (Barengolts, 2016; Feng et al., 2018). Therefore, many scholars have carried out studies on the addition of probiotics. Karamali et al. conducted a randomized, double-blind controlled trial in women with polycystic ovary syndrome (Karamali and Gholizadeh, 2022). They found that probiotic supplementation in women with polycystic ovary syndrome could significantly improve serum sex hormone binding globulin and plasma total antioxidant capacity, significantly reduce total testosterone level, and benefit the body (Karamali and Gholizadeh, 2022). Vitellio et al. found that adding Bifidobacterium longum alleviated the symptoms of lactose intolerance patients (Vitellio et al., 2019). Furthermore, probiotics have also been used for the treatment of endometriosis (Chenoll et al., 2019). Lactobacillus gasseri has protective effects against endometriosis by inhibiting inflammation and the development of ectopic endometrial cells (Itoh et al., 2011; Uchida and Kobayashi, 2013).

In recent years, increasing attention has been given to botanical drugs, which include not only traditional Chinese medicine, but also various plant extracts (Li, 2002; Liu and Wang, 2008). Botanical drugs have been widely studied for their role in the treatment of endometriosis, and are considered as a good strategy with few side effects and the benefit of fertility retention (Flower et al., 2011; Bina et al., 2019). At present, the most commonly studied botanical drug types include plant extracts, plant-derived bioactive compounds and Chinese herbal medicine (Farnsworth, 1990). Plant extracts, including pueraria lobata and black garlic extracts, have been widely confirmed to play an anti-inflammatory, antiangiogenic and antioxidant roles in endometrial cells. Bioactive substances, including resveratrol, catechin, and curcumin, are believed to modulate a variety of signaling pathways and have therapeutic effects in endometriosis (Kamal et al., 2021; Hipolito-Reis et al., 2022; Madanes et al., 2022). Although botanical drugs have shown good “potential” in vitro and in animal experiments, the data from clinical double-blind randomized controlled trials are still insufficient. The clinical effects and safety of these drugs need to be further evaluated and verified.

Different dietary components deliver different carbohydrates and phytonutrients to the colon, causing different microbial changes (Yalcin Bahat et al., 2022). Wheat bran free foods, such as fruits, vegetables, meat, eggs, and milk can change the distribution of the gut microbiota and regulate intestinal permeability (Lazar et al., 2019; Campmans-Kuijpers and Dijkstra, 2021). The addition of probiotics can inhibit the immune inflammatory cascade reaction in patients with depression and improve their mental state. A large body of studies have demonstrated that dietary factors are associated with endometriosis risk (Parazzini et al., 2013; Jurkiewicz-Przondziono et al., 2017). Trans-unsaturated fatty acids and red meat can increase the risk of endometriosis (Missmer et al., 2010). Women who consume a large amount of fruits, vegetables, dairy products, and omega-3 fatty acids have an attenuated risk of endometriosis (Samaneh et al., 2019). The intake of antioxidants and a combination of vitamins and minerals may have protective effects against endometriosis (Guney et al., 2007). Recent studies have demonstrated that ω-3 polyunsaturated fatty acids can change the composition of gut microbiota (Watson et al., 2018). Adding ω-3 polyunsaturated fatty acids and probiotics can effectively prevent osteoporosis, obesity and diabetes (Bi et al., 2017; Wang et al., 2022). ω-3 polyunsaturated fatty acids were found to attenuate the inflammation in a mouse model of endometriosis (Pereira et al., 2019). In addition, women who consume a large amount of ω-3 polyunsaturated fatty acids have a lower risk of developing endometriosis (Brasky et al., 2015). It is speculated that regulation of the gut microbiota through diet may help prevent endometriosis.

Fecal microbiota transplantation (FMT) refers to a standardized treatment in which the feces of healthy people, and therefore the acquired functional flora, is transplanted into the gastrointestinal tract of patients with dysbacteriosis to rebuild the gut microbiota of patients and treat disease (Kelly et al., 2015; Nigam et al., 2022). At present, FMT has been applied for the treatment of gastrointestinal diseases, blood diseases, neuropsychiatric diseases, chronic hepatitis B, metabolic syndrome, drug-resistant bacterial infections and other diseases (Brandt and Aroniadis, 2013; Kim and Gluck, 2019). In 2013, FMT was written into the clinical guidelines of the United States for the treatment of recurrent Clostridium difficile infection (Cammarota et al., 2014). The clinical efficacy of FMT has been verified in many diseases (Bowman et al., 2015). Recently, studies have shown that FMT can be used for the treatment of female reproductive tract diseases (Quaranta et al., 2019; Huang J. et al., 2021). Due to the role of gut microbiota in the development of endometriosis, FMT could be an innovative treatment option for the treatment of endometriosis.