Gut microbial β-glucuronidase (GUS) enzymes have been suggested to be involved in the estrobolome, the collection of microbial reactions involving estrogens. Furthermore, bacterial GUS enzymes within ...the gastrointestinal tract have been postulated to be a contributing factor in hormone-driven cancers. However, to date, there has been no experimental evidence to support these hypotheses. Here we provide the first in vitro analysis of the ability of 35 human gut microbial GUS enzymes to reactivate two distinct estrogen glucuronides, estrone-3-glucuronide and estradiol-17-glucuronide, to estrone and estradiol, respectively. We show that certain members within the Loop 1, mini-Loop 1, and FMN-binding classes of gut microbial GUS enzymes can reactivate estrogens from their inactive glucuronides. We provide molecular details of key interactions that facilitate these catalytic processes and present the structures of two novel human gut microbial GUS enzymes related to the estrobolome. Further, we demonstrate that estrogen reactivation by Loop 1 bacterial GUS enzymes can be inhibited both in purified enzymes and in fecal preparations of mixed murine fecal microbiota. Finally, however, despite these in vitro and ex vivo data, we show that a Loop 1 GUS-specific inhibitor is not capable of reducing the development of tumors in the PyMT mouse model of breast cancer. These findings validate that gut microbial GUS enzymes participate in the estrobolome but also suggest that the estrobolome is a multidimensional set of processes on-going within the mammalian gastrointestinal tract that likely involves many enzymes, including several distinct types of GUS proteins.
Abstract
BACKGROUND
Endometriosis is a chronic, burdensome condition that is historically understudied. Consequently, there is a lack of understanding of the etiology of the disease and its ...associated symptoms, including infertility and chronic pelvic pain (CPP). Endometriosis development is influenced by estrogen metabolism and inflammation, which are modulated by several factors including the microbiome and the estrobolome (the collection of genes encoding estrogen-metabolizing enzymes in the gut microbiome). Therefore, there is increasing interest in understanding the role of microbiota in endometriosis etiology.
OBJECTIVE AND RATIONALE
To date, there is no cure for endometriosis and treatment options often are ineffective. This manuscript will review the potential relationship between the microbiome and endometriosis, infertility and CPP and highlight the available data on the microbiome in relation to endometriosis and its related symptoms. The overarching goal of this manuscript is to inform future microbiome research that will lead to a deeper understanding of the etiology of the disease and possible diagnostic modalities and treatments. The potential impact of the microbiome on estrogen regulation modulated by the estrobolome, as well as inflammation and other endometriosis-promoting mechanisms within the genital tract, will be reviewed. The methodological limitations of microbiome-related studies will be critically assessed to provide improved guidelines for future microbiome and clinical studies.
SEARCH METHODS
PubMed databases were searched using the following keywords: endometriosis AND microbiome, infertility AND microbiome, pelvic pain AND microbiome, IVF (in-vitro fertilization) AND microbiome, endometriosis AND infertility. Clinical and preclinical animal trials that were eligible for review, and related to microbiome and endometriosis, infertility or CPP were included. All available manuscripts were published in 2002–2021.
OUTCOMES
In total, 28 clinical and 6 animal studies were included in the review. In both human and animal studies, bacteria were enriched in endometriosis groups, although there was no clear consensus on specific microbiota compositions that were associated with endometriosis, and no studies included infertility or CPP with endometriosis. However, bacterial vaginosis-associated bacteria and Lactobacillus depletion in the cervicovaginal microbiome were associated with endometriosis and infertility in the majority (23/28) of studies. Interpretation of endometrial studies is limited owing to a variety of methodological factors, discussed in this review. In addition, metadata outlining antibiotic usage, age, race/ethnicity, menopausal status and timing of sample collection in relation to diagnosis of endometriosis was not consistently reported. Animal studies (6/6) support a bidirectional relationship between the gut microbiota and endometriosis onset and progression.
WIDER IMPLICATIONS
There is evidence that a dysbiotic gut or genital microbiota is associated with multiple gynecologic conditions, with mounting data supporting an association between the microbiome and endometriosis and infertility. These microbiomes likely play a role in the gut-brain axis, which further supports a putative association with the spectrum of symptoms associated with endometriosis, including infertility and CPP. Collectively, this review highlights the demand for more rigorous and transparent methodology and controls, consistency across the field, and inclusion of key demographic and clinical characteristics of disease and comparison participants. Rigorous study designs will allow for a better understanding of the potential role of the microbiome in endometriosis etiology and the relationship to other disorders of the female reproductive tract.
Imbalances in gut and reproductive tract microbiota composition, known as dysbiosis, disrupt normal immune function, leading to the elevation of proinflammatory cytokines, compromised ...immunosurveillance and altered immune cell profiles, all of which may contribute to the pathogenesis of endometriosis. Over time, this immune dysregulation can progress into a chronic state of inflammation, creating an environment conducive to increased adhesion and angiogenesis, which may drive the vicious cycle of endometriosis onset and progression. Recent studies have demonstrated both the ability of endometriosis to induce microbiota changes, and the ability of antibiotics to treat endometriosis. Endometriotic microbiotas have been consistently associated with diminished Lactobacillus dominance, as well as the elevated abundance of bacterial vaginosis-related bacteria and other opportunistic pathogens. Possible explanations for the implications of dysbiosis in endometriosis include the Bacterial Contamination Theory and immune activation, cytokine-impaired gut function, altered estrogen metabolism and signaling, and aberrant progenitor and stem-cell homeostasis. Although preliminary, antibiotic and probiotic treatments have demonstrated efficacy in treating endometriosis, and female reproductive tract (FRT) microbiota sampling has successfully predicted disease risk and stage. Future research should aim to characterize the “core” upper FRT microbiota and elucidate mechanisms behind the relationship between the microbiota and endometriosis.
Breast Cancer and Its Relationship with the Microbiota Fernández, Mariana F; Reina-Pérez, Iris; Astorga, Juan Manuel ...
International journal of environmental research and public health,
08/2018, Volume:
15, Issue:
8
Journal Article
Peer reviewed
Open access
The microorganisms that live symbiotically in human beings are increasingly recognized as important players in health and disease. The largest collection of these microorganisms is found in the ...gastrointestinal tract. Microbial composition reflects both genetic and lifestyle variables of the host. This microbiota is in a dynamic balance with the host, exerting local and distant effects. Microbial perturbation (dysbiosis) could contribute to the risk of developing health problems. Various bacterial genes capable of producing estrogen-metabolizing enzymes have been identified. Accordingly, gut microbiota is capable of modulating estrogen serum levels. Conversely, estrogen-like compounds may promote the proliferation of certain species of bacteria. Therefore, a crosstalk between microbiota and both endogenous hormones and estrogen-like compounds might synergize to provide protection from disease but also to increase the risk of developing hormone-related diseases. Recent research suggests that the microbiota of women with breast cancer differs from that of healthy women, indicating that certain bacteria may be associated with cancer development and with different responses to therapy. In this review, we discuss recent knowledge about the microbiome and breast cancer, identifying specific characteristics of the human microbiome that may serve to develop novel approaches for risk assessment, prevention and treatment for this disease.
In breast cancer (BC) the employment of sequencing technologies for metagenomic analyses has allowed not only the description of the overall metagenomic landscape but also the specific microbial ...changes and their functional implications. Most of the available data suggest that BC is related to bacterial dysbiosis in both the gut microenvironment and breast tissue. It is hypothesized that changes in the composition and functions of several breast and gut bacterial taxa may contribute to BC development and progression through several pathways. One of the most prominent roles of gut microbiota is the regulation of steroid-hormone metabolism, such as estrogens, a component playing an important role as risk factor in BC development, especially in postmenopausal women. On the other hand, breast and gut resident microbiota are the link in the reciprocal interactions between cancer cells and their local environment, since microbiota are capable of modulating mucosal and systemic immune responses. Several in vivo and in vitro studies show remarkable evidence that diet, probiotics and prebiotics could exert important anticarcinogenic effects in BC. Moreover, gut microbiota have an important role in the metabolism of chemotherapeutic drugs and in the activity of immunogenic chemotherapies since they are a potential dominant mediator in the response to cancer therapy. Then, the microbiome impact in BC is multi-factorial, and the gut and breast tissue bacteria population could be important in regulating the local immune system, in tumor formation and progression and in therapy response and/or resistance.
The sex steroid hormone estrogen plays a number of regulatory roles in female development. During menopause, estrogen synthesis in the ovaries decreases, which results in adverse physiological ...remodeling and increased risk of disease. Reduced bone density, changes in the community composition profiles of the gut and vaginal microbiome, mood swings and changes in the vaginal environment are to be expected during this time. To alleviate these changes, postmenopausal women can be prescribed hormone replacement therapy (HRT) through the use of exogenous estradiol, often in conjunction with progestin treatment, which re-induces estrogenic action throughout the body. The microbiome and estrogen have a bidirectional, regulatory relationship in the gut, while in the vaginal environment estrogen works indirectly on the microbiome through restoring the vaginal tissue environment that leads to microbial homeostasis. This review discusses what is known about how the gut and vaginal microbiomes of postmenopausal women are responding to HRT, and the potential future of microbe-based therapeutics for symptoms of menopause.
A growing amount of evidence has supported that gut microbiota plays a vital role in the reproductive endocrine system throughout a woman's whole life, and gut microbial β-glucuronidase (gmGUS) is a ...key factor in regulating host estrogen metabolism. Moreover, estrogen levels also influence the composition as well as the diversity of gut microbiota. In normal condition, the gmGUS-estrogen crosstalk maintains body homeostasis of physiological estrogen level. Once this homeostasis is broken, the estrogen metabolism will be disturbed, resulting in estrogen-related diseases, such as gynecological cancers, menopausal syndrome, etc. together with gut microbial dysbiosis, which may accelerate these pathological processes. In this review, we highlight the regulatory role of gmGUS on the physical estrogen metabolism and estrogen-related diseases, summarize the present evidence of the interaction between gmGUS and estrogen metabolism, and unwrap the potential mechanisms behind them. Finally, gmGUS may become a potential biomarker for early diagnosis of estrogen-induced diseases. Regulating gmGUS activity or transplanting gmGUS-producing microbes shows promise for treating estrogen-related diseases.
Endometriosis and dysbiosis: State of art Zizolfi, Brunella; Foreste, Virginia; Gallo, Alessandra ...
Frontiers in endocrinology,
02/2023, Volume:
14
Journal Article
Peer reviewed
Open access
Endometriosis is a complex and heterogeneous disease affecting approximately 10% of reproductive age women. The hypothesis that alterations in the microbiota are involved in the pathogenesis of ...endometriosis has been postulated. Possible explanations for the implications of dysbiosis in endometriosis include the Bacterial Contamination hypothesis and immune activation, cytokine-impaired gut function, altered estrogen metabolism and signaling. Thus, dysbiosis, disrupt normal immune function, leading to the elevation of proinflammatory cytokines, compromised immunosurveillance and altered immune cell profiles, all of which may contribute to the pathogenesis of endometriosis. The aim of this review is to summarize the available literature data about the relationship between microbiota and endometriosis.
The gut microbiome is a key regulator of metabolism and influences the metabolism of estrogens, however, the microbiome's role in the changes in body composition and metabolic risk factors ...experienced by menopausal women remains largely unexplored. Menopause has been shown to alter the gut microbiome, and rodent studies suggest that microbiome changes postovariectomy are associated with increased adiposity, decreased metabolic rate, and insulin resistance, changes attenuated by estrogen administration. Given these data, a deeper understanding of the gut microbiome's relationship to menopause-induced changes in body composition and metabolism is warranted and may offer opportunity for novel therapeutic interventions.The microbiome is central to both systemic and estrogen metabolism, and is altered by the menopausal transition, suggesting an important role of the microbiome in the increased metabolic risk faced by menopausal women. Although additional research is needed to establish a causal link, the interrelationship between menopause and the gut microbiome may represent a new frontier to address menopause-related metabolic risk.
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