Gut Microbiome and Estrogen.

Basically, GM and their metabolites linked to the onset and advancement of bone disorders due to their essential function in nutrient absorption. The GM plays a crucial role in fermenting non-digestible substances like dietary fiber and intestinal mucus, synthesizing vitamins, transforming bile acids, and producing amino acids. These functions can impact bone health either positively or negatively by influencing the composition and activities of the GM [ 18 ]. For example, osteoporosis is a prevalent bone metabolic disorder observed in postmenopausal females, with a significant contribution from dysbiosis in the GM in the pathogenesis of metabolic bone ailments [ 10 19 ]. It has been revealed that short chain fatty acids may have an indirect impact on bone mineral density (BMD) by notably influencing the activity of host endocrine factors linked to bone metabolism, including peptide YY and glucagon-like peptide 1. Peptide YY, a gastrointestinal hormone produced by endocrine L cells, has been found to have a negative correlation with total body and hip BMD in premenopausal women [ 20 ]. In animal study, mice that underwent ovariectomy showed increased concentrations of lipopolysaccharide in both their bloodstream and experienced an imbalance in GM composition, as evidenced by a rise in the Firmicutes/Bacteroidetes ratio within the intestinal lumen. By depleting the GM using antibiotic intervention, enhancements in bone mass, microstructure, and strength were observed in ovariectomized mice. Conversely, transplantation of GM adapted to ovariectomy resulted in bone loss [ 21 ]. Although further research is required to explore the complex mechanisms underlying the effects of the GM, it is currently recognized that restoring the balance of intestinal flora is more important than its richness. Also, this approach is considered therapeutic for a variety of diseases.

The process of skin aging is experienced by all individuals at differing rates, which can be influenced by genetic, environmental, and hormonal factors [ 22 23 ]. As mentioned above, estrogen can regulate various systems, including the skin. It not only prevents a decrease in skin collagen, maintaining skin thickness but also enhances skin moisture by increasing acid mucopolysaccharides and hyaluronic acid levels, possibly preserving stratum corneum barrier function. Additionally, estrogen affects elastic fibers and collagen, potentially reducing skin wrinkling [ 22 ]. Numerous studies and analyses have been conducted on the gut-skin axis, with a particular focus on elucidating the interactions between the skin and GMs and their implications for various dermatological conditions [ 24 25 ]. Recent studies find that because human skin harbors a diverse array of microorganisms such as fungi, bacteria, and viruses, the imbalance in the skin microbiome can activate the pathogenic characteristics of various dermal conditions and illnesses, including acne, atopic dermatitis, and psoriasis [ 25 26 27 28 ]. Interestingly, scientists have found evidence that estrogens have a beneficial impact on the GM by enhancing microbial diversity and increasing the activity of enzymes involved in estrogen metabolism [ 29 ]. Among the GM, certain bacterial species produce β-glucuronidase activity, which plays a role in estrogen metabolism [ 30 ]. This enzyme showed negative correlation with total estrogen levels in the circulation [ 31 ]. In other word, estrogens promote diversity within the GM, leading to reduced availability of β-glucuronidase and increased excretion of estrogen.

In postmenopausal women, a decrease in cognition, particularly in memory function, is observed due to declining estrogen levels [ 12 ]. This may be caused by estrogen depletion, can also affect fine motor coordination, as well as contribute to symptoms of depression and anxiety. Recent studies suggest that the gut microbiome (GM) may influence the development of neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease, which are leading causes of dementia [ 13 14 15 ]. According to these studies, people who have AD showed that higher level of pro-inflammatory cytokines (e.g., interleukin (IL)-6, CXCL2, NLRP3, and IL-1β), higher ratio of Escherichia/Shigella and decreased GM diversity than health control [ 13 ]. Numerous studies conducted on animals have shown cognitive effects, such as impaired memory task performance in subjects that have undergone ovariectomy, which may be associated with decreased spinal neuron densities. Additionally, the provision of different antibiotics via drinking water has been found to impede object recognition behavior in mice [ 16 17 ]. The findings indicate that imbalance of GM results in decreased levels of estrogen, potentially leading to cognitive decline due to reduced bioactive estrogen.

Estrogens, a class of steroid hormones, regulate the growth, development, and physiology of the human reproductive system. They also play a role in the neuroendocrine, skeletal, adipogenesis, and cardiovascular systems [ 1 ]. Estrogen is introduced into the systemic circulation in two forms: either as a free hormone or bound to proteins such as sex hormone-binding globulin or albumin. Unbound estrogen, which is not attached to proteins, possesses the ability to permeate cell membranes unhindered, without any regulatory constraints [ 2 ]. Microbiome, can be described as a specific microbial community residing in a clearly defined habitat with unique physio-chemical characteristics, exists in a mutually beneficial relationship with the host, aiding in maintaining internal balance and modulating immune responses [ 3 4 ]. Over the past decades, the significance of microbiome in maintaining health and causing diseases has been emphasized in various research studies and found that an imbalance in microbiome, known as dysbiosis, can disrupt body functions and contribute to the development of conditions such as cardiovascular diseases, cancers, and respiratory illnesses. Especially, the intestinal microbiome plays a significant role in maintaining human health [ 5 ]. The balance of the intestinal microecological system is influenced by a variety of factors. These factors include food, drugs and pathogens, and internal factors such as endocrine factors [ 6 ]. Recent research has shown that there is a gender disparity in the prevalence of certain diseases associated with the microbiome, with specific conditions being influenced by sex hormones [ 7 ]. Post-menopausal women may experience negative effects on various physiological factors due to decreased levels of circulating estrogen, which can have clinical implications on brain cognition, gut health, the female reproductive tract, and other aspects of women’s health [ 8 ]. Many researches have demonstrated that estrogen can affect the composition of the microbiome. Also, microbiome plays a substantial role in modulating estrogen levels [ 8 9 10 11 ]. Despite these facts, there is a limited number of review articles discussing the clinical effects of estrogen and microbiome. Thus, this review will discuss diseases resulting from dysbiosis of the microbiome and estrogen deficiency.

The microbiome has been recognized as a promising hallmark of cancer. For example, elevated levels of Fusobacterium nucleatum are associated with the incidence and progression of head and neck cancer [ 60 ]. According to recent research, GM and its metabolites can promote and inhibit gastrointestinal cancer [ 61 ]. Among various cancers, GM affects breast cancer and ovarian cancer, which is influenced by sex hormones like estrogen. Breast cancer is the most heterogeneous cancer type. Types of breast cancer that are hormone receptor-positive and-negative can be broadly classified [ 62 ]. The risk factors for breast cancer are related to the levels and duration of exposure to estrogen and progesterone [ 63 ]. Gut microbial β-glucuronidase (GUS) enzymes may be involved in the estrobolome, a group of microbial processes involving estrogens. Furthermore, bacterial GUS enzymes within the gastrointestinal tract have been postulated to be a contributing factor in hormone-driven cancers [ 29 ]. The activity of phytoestrogens is strongly dependent on the microbiome [ 64 ]. The GM’s activity is affected by menstruation. The effects of progesterone on transcellular, paracellular, and vascular pathways (leaky gut) may cause menstrual cycle-associated changes in IgA directed against lipopolysaccharides and, by extension, bacterial translocation. This could exacerbate physio-somatic and anxiety symptoms as well as fatigue, breast swelling, and food cravings [ 65 ]. Ovarian cancer is also associated with GM for diagnosis and treatment. Previous studies have suggested that gut microbiota-derived bile acids are involved in inflammation [ 66 ]. Inflammatory cytokines have been implicated in ovarian cancer [ 67 68 ]. IL-6 may promote the development of high-grade ovarian cancer [ 67 ]. GM is linked to endometriosis Shigella and Escherichia predominated in the gut microbiota of endometriosis patients [ 69 ]. Actinobacteria, Firmicutes, Proteobacteria, and Verrucomicrobia were more prevalent in the GMs of endometriosis patients than in healthy individuals [ 70 ]. Conversely, the abundance of lactobacilli was lower in individuals with endometriosis. The precise mechanism linking endometriosis and the GM remains unknown. Estrogen can be an answer to this connection because estrogen associated with the development of endometriosis [ 71 ].

The human gut is densely populated with bacterial cells called GM, exceeding the number of host cells by a factor of 10 [ 32 ]. In general, Firmicutes, Bacteroidetes, Fusobacteria, Actinobacteria, Tenericutes, Proteobacteria, Verrucomicrobia, and Lentisphaerae are the major phyla; whereas, Lactobacillus , Faecalibacterium , Streptococcus , Eubacterium , Peptococcus , Ruminococcus , Peptostreptococcus , and Bifidobacterium are the predominant genera in the gut microbiota [ 33 ]. This intricate microbial community profoundly influences human health and disease. Imbalances in this microbial ecosystem have been linked to gastrointestinal conditions like inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) [ 34 35 ]. Over recent years, there has been substantial progress in unraveling the pathogenesis of both IBD and IBS. A pivotal breakthrough has been the identification of the gut microbiota as a critical inflammatory factor, carrying significant clinical implications [ 32 36 ]. In the past, IBD was most prevalent in western countries. However, its incidence is swiftly increasing in newly industrialized regions across Asia, the Middle East, Africa, and South America [ 37 ]. Most studies have shown that reduced gut microbial diversity in patients with IBD results in abnormal mucosal immune responses, resulting in various intestinal and extraintestinal diseases [ 32 35 38 ]. It is well known that estrogen can alter the composition of the GM [ 8 39 40 ]. It can also have a direct effect on the intestine. Previous researches have demonstrated that estrogen peaks during the menstrual cycle leads to reduced gut motility, increased gut permeability, and heightened sensitivity to pain. In contrast, hormonal changes during menopause, particularly estrogen fluctuations, occur more gradually compared to premenopausal women [ 36 38 41 ]. IBS, no less prevalent than IBD, is a digestive disorder marked by abdominal discomfort or pain linked with alterations in bowel habits [ 36 ]. Numerous studies have demonstrated that sex hormones impact both peripheral and central regulatory mechanisms of the braingut axis, which play a crucial role in the development of IBS. These hormones contribute to changes in visceral sensitivity, gut motility, intestinal permeability, and immune activation [ 36 ]. Interestingly, recent studies have reported that not only sex hormones but also the microbiome are important factors. The concept of an imbalanced gut-brain axis has been widely accepted as a suitable model for understanding this disorder [ 42 ].

From the past, many studies found that vaginal health is important in female reproduction and health [ 43 ]. Recent studies suggest that microbiome is one of the key factors [ 44 45 ]. The vaginal environment hosts a vast microecosystem comprising billions of microorganisms. According to a study, reproductive age indicated that the vagina harbors approximately 10 10 to 10 11 bacteria [ 46 ]. In healthy state, host offers a suitable condition that is humid-warm, and nutrient-rich, for the microbes, while the resident microbiome makes antimicrobial and anti-inflammatory substances. However, this balance can be disrupted by an imbalance of microbial environment [ 47 ]. During pregnancy, a woman undergoes profound physiological adaptations including increased levels of estrogen and progesterone, modulation of immune responses to maintain fetal tolerance [ 48 ], and significant alterations in the gut, vaginal, and oral microbiomes [ 49 ]. These microbiome shifts, such as increased abundance of Proteobacteria and Actinobacteria and reduced microbial diversity [ 50 ], support enhanced energy storage, immune regulation, and nutrient absorption, ultimately creating optimal conditions for fetal development [ 51 ]. Alterations in the maternal microbiome are among the changes that can lead to various pregnancy-related diseases [ 52 ]. Preeclampsia is a significant concern within the field of obstetrics, impacting approximately 2%–15% of pregnancies globally. It stands as a prevalent contributor to morbidity and mortality during the perinatal phase for both mothers and their offspring [ 53 54 ]. While the exact cause of preeclampsia is not fully understood, certain research indicates a potential connection between the maternal GM and the development of preeclampsia. Jin et al. [ 55 ] reported that the intestinal microbiome of individuals with preeclampsia notably worsened the pathologies and symptoms observed in preeclamptic rats, while the intestinal microbiome of pregnant women without preeclampsia exhibited substantial protective properties. In a healthy condition, an adequate supply of estrogen maintains the optimal level and structure of the vaginal mucosa. Furthermore, this hormone may also induce proliferation of layers of vaginal wall epithelium as well as smooth muscle fibers and collagen [ 56 ]. During menopause, however, a reduction in estrogen levels in the bloodstream causes the vaginal mucus to shrink and resulting in a range of symptoms including hot flashes, night sweats, cognitive decline, and mood changes that are commonly reported [ 57 ]. Especially, Vaginal atrophy, which involves changes in the genitourinary tract, is common in at least 50% of menopausal women. This disease also shows decreased in vaginal mucus production, they suffer symptoms such as dryness, redness, itching, painful intercourse, and occasionally, discharge or bleeding [ 58 ]. Many researches indicate the critical role of the vaginal microbiota in maintaining vaginal homeostasis. Lactobacillus is identified as the predominant component of the vaginal microbiota. Through their metabolic processes, these bacteria produce lactic acid, which plays a crucial role in sustaining the optimal acidic pH level of the vaginal fluid. This acidic environment serves as a protective barrier against urogenital infections. Additionally, the vaginal epithelium contributes to the maintenance of the low pH through active proton transport facilitated by anaerobic glucose metabolism [ 59 ].

In conclusion, the reciprocal relationship between estrogen and the microbiome underscores their profound impact on human health across multiple physiological systems. Estrogen, essential for the regulation of reproductive functions and beyond, intricately influences the composition and function of the microbiome. Conversely, the microbiome plays a crucial role in modulating estrogen metabolism and availability within the body. Various health conditions, such as cognitive decline, bone disorders like osteoporosis, skin aging processes, and gastrointestinal ailments like IBDs, have implicated disruptions in estrogen levels or microbiome composition. Understanding these complex interactions offers opportunities for targeted therapeutic interventions. Strategies aimed at restoring microbiome balance or modulating estrogen levels have the potential to mitigate the onset or progression of diseases associated with dysbiosis or estrogen deficiency. Future research should focus on elucidating the bidirectional mechanisms between estrogen and the microbiome across different life stages and organ systems. Longitudinal and multiomics studies, particularly in diverse populations, are needed to understand causality and population-specific responses. Furthermore, exploring the effects of diet, probiotics, and hormone therapies on the estrogen-microbiome axis may open new avenues for personalized medicine. Clinically, these insights could contribute to the development of predictive biomarkers and microbiome-based interventions, ultimately enhancing disease prevention, diagnosis, and treatment in women’s health.