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Estrogen–gut microbiome axis: Physiological and clinical implications

  • Author Footnotes
    1 Present address: Department of Basic Medical Sciences, College of Medicine, University of Arizona, Phoenix, Arizona, USA.
    James M. Baker
    Footnotes
    1 Present address: Department of Basic Medical Sciences, College of Medicine, University of Arizona, Phoenix, Arizona, USA.
    Affiliations
    Department of Basic Medical Sciences, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA

    Department of Biology and Biochemistry, University of Bath, Bath, UK
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  • Layla Al-Nakkash
    Affiliations
    Department of Physiology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA
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  • Melissa M. Herbst-Kralovetz
    Correspondence
    Corresponding author at: The University of Arizona College of Medicine-Phoenix, Building ABC-1, Office 330, Lab 331E, 425 North 5th St., Phoenix, AZ 85004-2157, USA.
    Affiliations
    Department of Basic Medical Sciences, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA

    Department of Obstetrics and Gynecology, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ, USA
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  • Author Footnotes
    1 Present address: Department of Basic Medical Sciences, College of Medicine, University of Arizona, Phoenix, Arizona, USA.

      Highlights

      • One principal regulator of circulating estrogens is the gut microbiome.
      • Disruption in the gut microbiome results in decreased circulating estrogens.
      • Alterations in the estrobolome can drive estrogen-mediated pathologies.
      • Bariatric surgery, fecal-microbiome transplant and metformin alter gut microbiota composition.
      • Interventions that alter gut microbiome diversity impact estrogen-mediated disease.

      Abstract

      Low levels of gonadal circulating estrogen observed in post-menopausal women can adversely impact a diverse range of physiological factors, with clinical implications for brain cognition, gut health, the female reproductive tract and other aspects of women’s health. One of the principal regulators of circulating estrogens is the gut microbiome. This review aims to shed light on the role of the gut microbiota in estrogen-modulated disease. The gut microbiota regulates estrogens through secretion of β-glucuronidase, an enzyme that deconjugates estrogens into their active forms. When this process is impaired through dysbiosis of gut microbiota, characterized by lower microbial diversity, the decrease in deconjugation results in a reduction of circulating estrogens. The alteration in circulating estrogens may contribute to the development of conditions discussed herein: obesity, metabolic syndrome, cancer, endometrial hyperplasia, endometriosis, polycystic ovary syndrome, fertility, cardiovascular disease (CVD) and cognitive function. The bi-directional relationship between the metabolic profile (including estrogen levels) and gut microbiota in estrogen-driven disease will also be discussed. Promising therapeutic interventions manipulating the gut microbiome and the metabolic profile of estrogen-driven disease, such as bariatric surgery and metformin, will be detailed. Modulation of the microbiome composition subsequently impacts the metabolic profile, and vice versa, and has been shown to alleviate many of the estrogen-modulated disease states. Last, we highlight promising research interventions in the field, such as dietary therapeutics, and discuss areas that provide exciting unexplored topics of study.

      Keywords

      1. Introduction

      The impact of the gut microbiota, and bacteria that reside on other mucosal sites, on health has become a rapidly growing and exciting area of research over the last 10 years. The functional relevance of the bacteria that compose the gut microbiome has been demonstrated in probiotic, fecal-microbiome transplant (FMT) and bariatric surgery studies [
      • Forman D.
      Helicobacter pylori and gastric cancer.
      ,
      • Vrieze A.
      • Van Nood E.
      • Holleman F.
      • Salojarvi J.
      • Kootte R.S.
      • Bartelsman J.F.
      • Dallinga-Thie G.M.
      • Ackermans M.T.
      • Serlie M.J.
      • Oozeer R.
      • et al.
      Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome.
      ,
      • Wang J.
      • Tang H.
      • Zhang C.
      • Zhao Y.
      • Derrien M.
      • Rocher E.
      • van-Hylckama Vlieg J.E.
      • Strissel K.
      • Zhao L.
      • Obin M.
      • et al.
      Modulation of gut microbiota during probiotic-mediated attenuation of metabolic syndrome in high fat diet-fed mice.
      ]. The impact of the gut microbiome extends beyond the gut through the inflammatory and metabolic changes induced by the gut microbiome [
      • Guo Y.
      • Qi Y.
      • Yang X.
      • Zhao L.
      • Wen S.
      • Liu Y.
      • Tang L.
      Association between polycystic ovary syndrome and gut microbiota.
      ,
      • Markle J.G.
      • Frank D.N.
      • Mortin-Toth S.
      • Robertson C.E.
      • Feazel L.M.
      • Rolle-Kampczyk U.
      • von Bergen M.
      • McCoy K.D.
      • Macpherson A.J.
      • Danska J.S.
      Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity.
      ]. Similarly, the host microenvironment of the gut influences the gut microbiome [
      • Sommer F.
      • Backhed F.
      The gut microbiota − masters of host development and physiology.
      ]. The gut microbiome has been shown to be influenced by estrogen, however, the gut microbiome also significantly impacts estrogen levels [
      • Huang G.
      • Xu J.
      • Lefever D.E.
      • Glenn T.C.
      • Nagy T.
      • Guo T.L.
      Genistein prevention of hyperglycemia and improvement of glucose tolerance in adult non-obese diabetic mice are associated with alterations of gut microbiome and immune homeostasis.
      ,
      • Flores R.
      • Shi J.
      • Fuhrman B.
      • Xu X.
      • Veenstra T.D.
      • Gail M.H.
      • Gajer P.
      • Ravel J.
      • Goedert J.J.
      Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study.
      ]. The gut microbiome impacts estrogen levels in the host through the secretion of β-glucuronidase, an enzyme which deconjugates estrogen, enabling it to bind to estrogen receptors and leading to its subsequent physiological downstream effects [
      • Plottel C.S.
      • Blaser M.J.
      Microbiome and malignancy.
      ]. It is only the unbound, free estrogen that is biologically active. Most conjugated estrogen is bound via a glycoprotein sex hormone binding globulin (SHBG) produced by the liver [
      • Anderson D.C.
      Sex-hormone-binding globulin.
      ] with low SHBG levels being implicated in the development of metabolic syndrome [
      • Laaksonen D.E.
      • Niskanen L.
      • Punnonen K.
      • Nyyssonen K.
      • Tuomainen T.P.
      • Valkonen V.P.
      • Salonen R.
      • Salonen J.T.
      Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men.
      ]. It is widely accepted that estrogen plays a significant role in many disease states including gynecologic conditions and cancers in addition to less obvious estrogen-mediated diseases such as metabolic syndrome (Fig. 1) [
      • Grady D.
      • Gebretsadik T.
      • Kerlikowske K.
      • Ernster V.
      • Petitti D.
      Hormone replacement therapy and endometrial cancer risk: a meta-analysis.
      ,
      • Thomas H.V.
      • Reeves G.K.
      • Key T.J.A.
      Endogenous estrogen and postmenopausal breast cancer a quantitative review.
      ,
      • Fujishita A.
      • Nakane P.K.
      • Koji T.
      • Masuzaki H.
      • Chavez R.O.
      • Yamabe T.
      • Ishimaru T.
      Expression of estrogen and progesterone receptors in endometrium and peritoneal endometriosis: an immunohistochemical and in situ hybridization study.
      ,
      • Brusselaers N.
      • Maret-Ouda J.
      • Konings P.
      • El-Serag H.B.
      • Lagergren J.
      Menopausal hormone therapy and the risk of esophageal and gastric cancer.
      ,
      • Fu L.
      • Liu Y.
      • Wang J.
      • Sun Y.
      • Zhang L.
      • Wu T.
      • Li Y.
      • Wang B.
      • Huang S.
      • Bu H.
      • et al.
      Cardioprotection by low-dose of estrogen and testosterone at the physiological ratio on OVX rats during ischemia/reperfusion injury.
      ,
      • Jones H.E.
      • Conrad H.S.
      The growth and decline of intelligence: a study of a homogeneous group between the ages of ten and sixty.
      ]. This review will demonstrate the influence the gut microbiome has on estrogen, and therefore estrogen-mediated disease, and related health outcomes (Fig. 1).
      Fig. 1
      Fig. 1Estrogen-gut microbiome interactions exhibit physiological and clinical implications. Dysbiosis and a reduction of gut microbiota diversity impacts the estrobolome, which may lead to a wide range of disease states, illustrated. Reduction in gut microbiome diversity as result of dysbiosis and inflammation reduces the β-glucuronidase activity. This reduced β-glucuronidase activity results in decreased deconjugation of estrogen and phytoestrogen into their circulating and active forms. The subsequent decrease in circulating estrogens alters estrogen receptor activations which may lead to the hypoestrogenic pathologies: obesity, metabolic syndrome, CVD and cognitive decline. Hyperestrogenic pathologies can also be driven by the estrobolome through the increased abundance of β-glucuronidase-producing bacteria, which leads to elevates levels of circulating estrogens to drive diseases such as endometriosis and cancer. Obesity/metabolic syndrome can impact other disease states such including PCOS, EH and ultimately fertility. Intervention: Bariatric surgery, metformin and FMT provide therapeutic interventions that can mitigate the associated disease state through modulation of the gut microbiota composition. Solid arrows indicate the established interaction between estrobolome and disease states; dashed arrows indicate putative feedback mechanisms or interactions.

      2. Methods

      A search of the scientific literature was conducted using PubMed/Medline or Google Scholar using the following search terms “estrobolome”, “estrogen and gut microbiome”, “phytoestrogen and gut microbiome”, “phytoestrogens and cancer”, “bariatric surgery and gut microbiome”, “gut microbiome and epithelial function” and “physiology and estrogen or phytoestrogen”. Further search terms included the disease states or aspects of health i.e. “cancer”, “obesity”, “metabolic syndrome”, “endometriosis”, “endometrial hyperplasia”, “polycystic ovary syndrome” “cardiovascular disease”, “infertility” and “cognition” which were combined with the terms “estrogen” and “gut microbiome”. Studies were manually examined and included for their relevance to the topic of this review. Pertinent original articles and reviews that were peer-reviewed, indexed in PubMed and written in English were included. The publication dates were not limited in order to fully review the literature available regarding gut microbiome and estrogen levels. The literature searches were performed between March 2017 and May 2017.

      3. Gut microbiome and homeostasis

      The gut epithelial barrier is maintained by a healthy, diverse gut microbiome composed primarily of 4 phyla: Bacteriodetes, Firmicutes, Actinobacteria and Proteobacteria. A balanced bacterial composition is key to maintaining intestinal immunity and homeostasis. A healthy gut microbiome consists of >90% of species within the Bacteroidetes and Firmicutes phyla [
      • Turnbaugh P.J.
      • Ley R.E.
      • Mahowald M.A.
      • Magrini V.
      • Mardis E.R.
      • Gordon J.I.
      An obesity-associated gut microbiome with increased capacity for energy harvest.
      ]. However, it is not only merely the combined abundance of Bacteroidetes and Firmicutes that have been associated with gut microbiome homeostasis. A lower Firmicutes/Bacteroidetes (F/B) ratio also correlates with health [
      • Turnbaugh P.J.
      • Ley R.E.
      • Mahowald M.A.
      • Magrini V.
      • Mardis E.R.
      • Gordon J.I.
      An obesity-associated gut microbiome with increased capacity for energy harvest.
      ], for example, lean humans and mice have a significantly lower F/B ratio compared to their obese counterparts [
      • Turnbaugh P.J.
      • Ley R.E.
      • Mahowald M.A.
      • Magrini V.
      • Mardis E.R.
      • Gordon J.I.
      An obesity-associated gut microbiome with increased capacity for energy harvest.
      ]. The metabolic profile also provides a key component of microbiota homeostasis in the gut microenvironment. Short chain fatty acids (SCFAs) such as butyrate provide a well-defined example of how the metabolites produced by a healthy microbiome confer with epithelial barrier integrity and immunological homeostasis (Fig. 2) [
      • Kau A.L.
      • Ahern P.P.
      • Griffin N.W.
      • Goodman A.L.
      • Gordon J.I.
      Human nutrition, the gut microbiome and the immune system.
      ]. Butyrate provides an energy source for colonic epithelial cells and exhibits immunmodulatory and anti-inflammatory properties that contribute to the maintenance of epithelial barrier integrity [
      • Riviere A.
      • Selak M.
      • Lantin D.
      • Leroy F.
      • De Vuyst L.
      Bifidobacteria and butyrate-Producing colon bacteria: importance and strategies for their stimulation in the human gut.
      ]. Gut microbiome diversity is important since a more diverse gut microbiome contains a greater diversity and abundance of enzymes capable of synthesizing metabolites such as butyrate that then contribute to gut homeostasis and health [
      • Xiao L.
      • Sonne S.B.
      • Feng Q.
      • Chen N.
      • Xia Z.K.
      • Li X.P.
      • Fang Z.W.
      • Zhang D.Y.
      • Fjaere E.
      • Midtbo L.K.
      • et al.
      High-fat feeding rather than obesity drives taxonomical and functional changes in the gut microbiota in mice.
      ].
      Fig. 2
      Fig. 2Estrogen and the gut microbiome maintain physiological health and homeostasis locally and at distal sites. A) Bile acid-secreted conjugated estrogen and phytoestrogens are deconjugated by the gut microbiome through bacterial secretion of β-glucuronidase. This enables the metabolized estrogen and phytoestrogens to be reabsorbed by the gut and translocate into the bloodstream B) Metabolized estrogen and phytoestrogen is then transported to distal mucosal sites through the circulatory system. C) Estrogen and phytoestrogen metabolites then act on estrogen receptors at distal sites (shown here using the vaginal epithelia as an example). D) Downstream effects of estrogen receptor binding in the vaginal epithelium which leads to physiological changes through downstream gene activation, epigenetic effects and triggering of intracellular signaling cascades. Dysbiosis in the gut microbiome potentially disrupts this homeostasis at this site through disruption of estrogen metabolism. A reduction in gut microbiota diversity leads to a decrease in the estrogen metabolism through a lack of estrogen metabolizing bacteria as well as other metabolic effects such as a reduction of short chain fatty acids. A lack of estrogen metabolizing bacteria leads to a decrease in circulating estrogens which may influence hypoestrogen-related disease.
      An imbalance of the gut microbiota is referred to as dysbiosis and has pathophysiological consequences. Dysbiosis disrupts homeostasis through a reduction of bacterial diversity and an increased F/B ratio that leads to an inflammatory response and metabolic profile that is detrimental to gut epithelial health [
      • Turnbaugh P.J.
      • Ley R.E.
      • Mahowald M.A.
      • Magrini V.
      • Mardis E.R.
      • Gordon J.I.
      An obesity-associated gut microbiome with increased capacity for energy harvest.
      ]. Gut epithelial barrier integrity has been shown to be influenced by dysbiosis through the reduction in cell–cell junctions leading to increased permeability and subsequently bacterial translocation [
      • Schwabe R.F.
      • Jobin C.
      The microbiome and cancer.
      ]. Bacterial translocation can lead to systemic inflammation leading to the exacerbation or induction of disease [
      • Deitch E.A.
      The role of intestinal barrier failure and bacterial translocation in the development of systemic infection and multiple organ failure.
      ]. The effects of dysbiosis have been shown to be alleviated through fecal microbiome transplant (FMT), bariatric surgery and pharmaceutical interventions (metformin), enabling the re-establishment of homeostasis by increasing gut microbiome diversity, decreasing inflammation and altering metabolite composition (Fig. 1) [
      • Markle J.G.
      • Frank D.N.
      • Mortin-Toth S.
      • Robertson C.E.
      • Feazel L.M.
      • Rolle-Kampczyk U.
      • von Bergen M.
      • McCoy K.D.
      • Macpherson A.J.
      • Danska J.S.
      Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity.
      ,
      • Damman C.J.
      • Miller S.I.
      • Surawicz C.M.
      • Zisman T.L.
      The microbiome and inflammatory bowel disease: is there a therapeutic role for fecal microbiota transplantation?.
      ].

      3.1 Physiological role of estrogen

      The role of estrogens in female reproductive development and maintenance is well defined [
      • Eyster K.M.
      The estrogen receptors: an overview from different perspectives.
      ]. In the lower female reproductive tract estrogen regulates this microenvironment through mechanisms involving increasing epithelial thickness, increasing glycogen levels, increasing mucus secretion and indirectly by decreasing vaginal pH through promotion of lactobacilli abundance and lactic acid production [
      • Muhleisen A.L.
      • Herbst-Kralovetz M.M.
      Menopause and the vaginal microbiome.
      ]. Phytoestrogens have been shown to have the opposite effect on the female reproductive tract compared to estrogen. Mice able to produce the phytoestrogen, equol, have significantly thinner vaginal epithelia as well as lower uterine weight [
      • Dewi F.N.
      • Wood C.E.
      • Lampe J.W.
      • Hullar M.A.J.
      • Franke A.A.
      • Golden D.L.
      • Adams M.R.
      • Cline J.M.
      Endogenous and exogenous equol are antiestrogenic in reproductive tissues of apolipoprotein E-null mice.
      ]. However, the action of estrogen is not limited to reproductive tissues [
      • Eyster K.M.
      The estrogen receptors: an overview from different perspectives.
      ]. Gut epithelial barrier integrity can also be modified by estrogen (Fig. 2) [
      • Homma H.
      • Hoy E.
      • Xu D.Z.
      • Lu Q.
      • Feinman R.
      • Deitch E.A.
      The female intestine is more resistant than the male intestine to gut injury and inflammation when subjected to conditions associated with shock states.
      ]. The dichotomy of gut epithelial integrity is illustrated through murine studies demonstrating that females are more resistant to gut injury compared to their male counterparts [
      • Homma H.
      • Hoy E.
      • Xu D.Z.
      • Lu Q.
      • Feinman R.
      • Deitch E.A.
      The female intestine is more resistant than the male intestine to gut injury and inflammation when subjected to conditions associated with shock states.
      ]. Furthermore, it has been shown that inhibition of androgens in male mice with flutamide results in reduced gut injury [
      • Homma H.
      • Hoy E.
      • Xu D.Z.
      • Lu Q.
      • Feinman R.
      • Deitch E.A.
      The female intestine is more resistant than the male intestine to gut injury and inflammation when subjected to conditions associated with shock states.
      ]. A variety of tissues express estrogen receptors, including, intestine, brain, bone and adipose tissue [
      • Eyster K.M.
      The estrogen receptors: an overview from different perspectives.
      ]. As a result of this global expression, estrogen has been shown to influence a variety of physiological responses including neural development [
      • Toranallerand C.D.
      • Miranda R.C.
      • Bentham W.D.L.
      • Sohrabji F.
      • Brown T.J.
      • Hochberg R.B.
      • Maclusky N.J.
      Estrogen-receptors colocalize with low-affinity nerve growth-factor receptors in cholinergic neurons of the basal forebrain.
      ], cardiovascular health [
      • Fu L.
      • Liu Y.
      • Wang J.
      • Sun Y.
      • Zhang L.
      • Wu T.
      • Li Y.
      • Wang B.
      • Huang S.
      • Bu H.
      • et al.
      Cardioprotection by low-dose of estrogen and testosterone at the physiological ratio on OVX rats during ischemia/reperfusion injury.
      ], bone density [
      • Felson D.T.
      • Zhang Y.Q.
      • Hannan M.T.
      • Kiel D.P.
      • Wilson P.W.F.
      • Anderson J.J.
      The effect of postmenopausal estrogen therapy on bone-Density in elderly women.
      ] and neoplastic diseases including cancers [
      • Grady D.
      • Gebretsadik T.
      • Kerlikowske K.
      • Ernster V.
      • Petitti D.
      Hormone replacement therapy and endometrial cancer risk: a meta-analysis.
      ,
      • Thomas H.V.
      • Reeves G.K.
      • Key T.J.A.
      Endogenous estrogen and postmenopausal breast cancer a quantitative review.
      ,
      • Brusselaers N.
      • Maret-Ouda J.
      • Konings P.
      • El-Serag H.B.
      • Lagergren J.
      Menopausal hormone therapy and the risk of esophageal and gastric cancer.
      ,
      • Kitawaki J.
      • Kado N.
      • Ishihara H.
      • Koshiba H.
      • Kitaoka Y.
      • Honjo H.
      Endometriosis: the pathophysiology as an estrogen-dependent disease.
      ]. During menopause a variety of negative health outcomes may occur from the depletion of circulating estrogen. This is a particularly important health issue as life expectancy continues to increase and the number of women ≥50 years old will increase by 60% between 2000 and 2025 [
      • Day J.C.
      Population Projections of the United States by Age, Sex, Race, and Hispanic Origin 1995–2050.
      ].

      3.2 Estrobolome: complex interplay between estrogen, the gut microbiome and distal mucosal sites

      The estrobolome is defined as the gene repertoire of the microbiota of the gut that are capable of metabolizing estrogens [
      • Plottel C.S.
      • Blaser M.J.
      Microbiome and malignancy.
      ]. Estrogens are metabolized by microbial secreted β-glucuronidase from their conjugate forms to their deconjugated forms [
      • Plottel C.S.
      • Blaser M.J.
      Microbiome and malignancy.
      ]. It is these “active” deconjugated and unbound estrogens that enter the bloodstream and subsequently act on estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) (Fig. 2) [
      • Plottel C.S.
      • Blaser M.J.
      Microbiome and malignancy.
      ]. Phytoestrogens are also metabolized in this manner, enabling their ability to act via mechanisms involving ERα and ERβ [
      • Rietjens I.M.
      • Louisse J.
      • Beekmann K.
      The potential health effects of dietary phytoestrogens.
      ]. Both estrogens and phytoestrogens can act genomically by binding to estrogen receptors, eliciting downstream gene activation and epigenetic effects and triggering of intracellular signaling cascades [
      • Rietjens I.M.
      • Louisse J.
      • Beekmann K.
      The potential health effects of dietary phytoestrogens.
      ]. This interaction leads to physiological changes across a variety of tissues ranging from neural development to reproductive health (Fig. 2) [
      • Muhleisen A.L.
      • Herbst-Kralovetz M.M.
      Menopause and the vaginal microbiome.
      ,
      • Toranallerand C.D.
      • Miranda R.C.
      • Bentham W.D.L.
      • Sohrabji F.
      • Brown T.J.
      • Hochberg R.B.
      • Maclusky N.J.
      Estrogen-receptors colocalize with low-affinity nerve growth-factor receptors in cholinergic neurons of the basal forebrain.
      ]. Therefore the gut microbiota regulates homeostasis at intestinal and distal mucosal sites [
      • Sommer F.
      • Backhed F.
      The gut microbiota − masters of host development and physiology.
      ]. When dysbiosis occurs, these physiological responses are altered and contribute to disease states described below and highlighted in Fig. 1.

      4. Clinical implications

      4.1 Obesity and metabolic syndrome

      Obesity, as well as other hallmarks of metabolic syndrome, are significantly more prevalent in postmenopausal women [
      • Mauvais-Jarvis F.
      • Clegg D.J.
      • Hevener A.L.
      The role of estrogens in control of energy balance and glucose homeostasis.
      ]. As such, a main driver of obesity could be related to the low circulating estrogen levels observed in postmenopausal women. However, estrogen levels are not solely mediated through their level of endogenous secretion. As described above metabolism of circulating estrogen and phytoestrogens, are mediated by the gut microbiome [
      • Fuhrman B.J.
      • Feigelson H.S.
      • Flores R.
      • Gail M.H.
      • Xu X.
      • Ravel J.
      • Goedert J.J.
      Associations of the fecal microbiome with urinary estrogens and estrogen metabolites in postmenopausal women.
      ]. Modulation of the gut microbiota through FMT and probiotics has been shown to reduce the effects of metabolic syndrome (diabetes, obesity and heart disease) [
      • Vrieze A.
      • Van Nood E.
      • Holleman F.
      • Salojarvi J.
      • Kootte R.S.
      • Bartelsman J.F.
      • Dallinga-Thie G.M.
      • Ackermans M.T.
      • Serlie M.J.
      • Oozeer R.
      • et al.
      Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome.
      ,
      • Wang J.
      • Tang H.
      • Zhang C.
      • Zhao Y.
      • Derrien M.
      • Rocher E.
      • van-Hylckama Vlieg J.E.
      • Strissel K.
      • Zhao L.
      • Obin M.
      • et al.
      Modulation of gut microbiota during probiotic-mediated attenuation of metabolic syndrome in high fat diet-fed mice.
      ,
      • Markle J.G.
      • Frank D.N.
      • Mortin-Toth S.
      • Robertson C.E.
      • Feazel L.M.
      • Rolle-Kampczyk U.
      • von Bergen M.
      • McCoy K.D.
      • Macpherson A.J.
      • Danska J.S.
      Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity.
      ,
      • Li J.
      • Zhao F.
      • Wang Y.
      • Chen J.
      • Tao J.
      • Tian G.
      • Wu S.
      • Liu W.
      • Cui Q.
      • Geng B.
      • et al.
      Gut microbiota dysbiosis contributes to the development of hypertension.
      ]. A recent study in mice investigated the metabolic function of the gut microbiota and demonstrated that diet drives the gut microbiota composition more dramatically than obesity alone [
      • Xiao L.
      • Sonne S.B.
      • Feng Q.
      • Chen N.
      • Xia Z.K.
      • Li X.P.
      • Fang Z.W.
      • Zhang D.Y.
      • Fjaere E.
      • Midtbo L.K.
      • et al.
      High-fat feeding rather than obesity drives taxonomical and functional changes in the gut microbiota in mice.
      ]. Butyrate, an essential nutrient in the gut, plays an important role in epithelial barrier health and function [
      • Riviere A.
      • Selak M.
      • Lantin D.
      • Leroy F.
      • De Vuyst L.
      Bifidobacteria and butyrate-Producing colon bacteria: importance and strategies for their stimulation in the human gut.
      ]. The role of butyrate was investigated in a mouse study aimed at identifying the impact of diet on the gut microbiome in two mouse models: one obesity prone and the other obesity resistant [
      • Xiao L.
      • Sonne S.B.
      • Feng Q.
      • Chen N.
      • Xia Z.K.
      • Li X.P.
      • Fang Z.W.
      • Zhang D.Y.
      • Fjaere E.
      • Midtbo L.K.
      • et al.
      High-fat feeding rather than obesity drives taxonomical and functional changes in the gut microbiota in mice.
      ]. The number of genes capable of metabolizing converting products into butyrate in the gut microbiota (butyryl-CoA transferase related-genes) was assessed to investigate the role of microbial metabolism of butyrate [
      • Xiao L.
      • Sonne S.B.
      • Feng Q.
      • Chen N.
      • Xia Z.K.
      • Li X.P.
      • Fang Z.W.
      • Zhang D.Y.
      • Fjaere E.
      • Midtbo L.K.
      • et al.
      High-fat feeding rather than obesity drives taxonomical and functional changes in the gut microbiota in mice.
      ]. Xiao et al., also hypothesized that obesity resistant mice are less prone to obesity because they have a higher level of butyryl-CoA transferase related-genes in the gut microbiota compared to the obesity prone mouse strain of the same diet [
      • Xiao L.
      • Sonne S.B.
      • Feng Q.
      • Chen N.
      • Xia Z.K.
      • Li X.P.
      • Fang Z.W.
      • Zhang D.Y.
      • Fjaere E.
      • Midtbo L.K.
      • et al.
      High-fat feeding rather than obesity drives taxonomical and functional changes in the gut microbiota in mice.
      ]. Furthermore, Greiner et al. provided evidence indicating that the gut microbiota is a regulator of diabetic autoimmunity and glucose metabolism, suggesting that changes in microbial metabolism can influence the pathogenesis of type I diabetes [
      • Greiner T.U.
      • Hyotylainen T.
      • Knip M.
      • Backhed F.
      • Oresic M.
      The gut microbiota modulates glycaemic control and serum metabolite profiles in non-obese diabetic mice.
      ].
      Alteration of the gut microbiota through bariatric surgery has been shown to alter many of the negative metabolic signatures indicative of metabolic syndrome such as hyperlipidemia and hypertension [
      • Buchwald H.
      • Avidor Y.
      • Braunwald E.
      • Jensen M.D.
      • Pories W.
      • Fahrbach K.
      • Schoelles K.
      Bariatric surgery: a systematic review and meta-analysis.
      ]. Many of the conditions illustrated in Fig. 1 such as metabolic syndrome, infertility, polycystic ovary syndrome (PCOS) and cancer have been shown to be alleviated via bariatric surgery [
      • Charalampakis V.
      • Tahrani A.A.
      • Helmy A.
      • Gupta J.K.
      • Singhal R.
      Polycystic ovary syndrome and endometrial hyperplasia: an overview of the role of bariatric surgery in female fertility.
      ,
      • Christou N.V.
      • Lieberman M.
      • Sampalis F.
      • Sampalis J.S.
      Bariatric surgery reduces cancer risk in morbidly obese patients.
      ]. The pleiotropic benefits of bariatric surgery demonstrates the interrelatedness of the diseases illustrated in Fig. 1 and also highlights the therapeutic power of gut microbiota modulation in treatment of these disease states.
      Phytoestrogens have also shown to be promising therapeutic molecules in combating metabolic syndrome through their interaction with estrogen receptors. Panneerselvam et al., found that soy based phytoestrogen consumption effectively restored lipid metabolism in their mouse model of obesity and estrogen deficiency [
      • Panneerselvam S.
      • Packirisamy R.M.
      • Bobby Z.
      • Elizabeth Jacob S.
      • Sridhar M.G.
      Soy isoflavones (Glycine max) ameliorate hypertriglyceridemia and hepatic steatosis in high fat-fed ovariectomized Wistar rats (an experimental model of postmenopausal obesity).
      ]. Furthermore, obese individuals were more likely to be N/a incapable of producing the phytoestrogen O-desmethylangolensin (ODMA) from its soy isoflavone precursor daidzein [
      • Frankenfeld C.L.
      • Atkinson C.
      • Wahala K.
      • Lampe J.W.
      Obesity prevalence in relation to gut microbial environments capable of producing equol or O-desmethylangolensin from the isoflavone daidzein.
      ]. Similarly, another study found that individuals able to produce the phytoestrogen metabolite S-equol were significantly less likely to be obese [
      • Usui T.
      • Tochiya M.
      • Sasaki Y.
      • Muranaka K.
      • Yamakage H.
      • Himeno A.
      • Shimatsu A.
      • Inaguma A.
      • Ueno T.
      • Uchiyama S.
      • et al.
      Effects of natural S-equol supplements on overweight or obesity and metabolic syndrome in the Japanese, based on sex and equol status.
      ]. This demonstrates that it is not only phytoestrogen consumption that influences the potential health benefits; the appropriate gut microbiota composition capable of metabolizing phytoestrogens also plays a crucial role. Dietary supplementation with soy isoflavone phytoestrogens has been shown to significantly decrease insulin levels as well as insulin resistance in a recent meta-analysis of over 1500 postmenopausal women [
      • Fang K.
      • Dong H.
      • Wang D.
      • Gong J.
      • Huang W.
      • Lu F.
      Soy isoflavones and glucose metabolism in menopausal women: a systematic review and meta-analysis of randomized controlled trials.
      ]. Additionally, in a separate meta-analysis it was found that soy isoflavone consumption significantly correlated with reduced body weight, glucose and insulin levels in non-Asian postmenopausal women [
      • Zhang Y.B.
      • Chen W.H.
      • Guo J.J.
      • Fu Z.H.
      • Yi C.
      • Zhang M.
      • Na X.L.
      Soy isoflavone supplementation could reduce body weight and improve glucose metabolism in non-Asian postmenopausal women–a meta-analysis.
      ]. High levels of dietary phytoestrogen consumption in Asian populations may explain the reduced incidence of metabolic syndrome [
      • Chan J.L.
      • Kar S.
      • Vanky E.
      • Morin-Papunen L.
      • Piltonen T.
      • Puurunen J.
      • Tapaniennen J.S.
      • Rosa Maciel G.A.
      • Hayashida S.A.
      • Saores Jr., J.M.
      • et al.
      Racial and ethnic differences in the prevalence of metabolic syndrome and its components of metabolic syndrome in women with polycystic ovary syndrome (PCOS): a regional cross-sectional study.
      ]. Further characterization of this consequence may prove to be a useful therapeutic tool in combating postmenopausal-induced metabolic syndrome.

      4.2 Endometriosis

      Estrogen stimulates epithelial proliferation throughout the female reproductive tract and has been shown to drive proliferative diseases such as endometrial cancer, endometriosis and uterine fibroids [
      • Zhang Q.
      • Shen Q.
      • Celestino J.
      • Milam M.R.
      • Westin S.N.
      • Lacour R.A.
      • Meyer L.A.
      • Shipley G.L.
      • Davies P.J.A.
      • Deng L.
      • et al.
      Enhanced estrogen-induced proliferation in obese rat endometrium.
      ]. Endometriosis is common in premenopausal women, and coupled with its hyper-proliferative condition advocates that the disease may be mediated by high estrogen levels [
      • Laschke M.W.
      • Menger M.D.
      The gut microbiota: a puppet master in the pathogenesis of endometriosis?.
      ]. Proliferation of endometrial tissue outside the uterus resulting in pelvic pain and infertility are hallmarks of endometriosis [
      • Goenka L.
      • George M.
      • Sen M.
      A peek into the drug development scenario of endometriosis − A systematic review.
      ]. Moreover, endometriosis can also result in menstrual disorders including menorrhagia [
      • Tietjen G.E.
      • Conway A.
      • Utley C.
      • Gunning W.T.
      • Herial N.A.
      Migraine is associated with menorrhagia and endometriosis.
      ]. It is therefore promising that mediation of estrogen levels may alleviate hyper-proliferation associated with endometriosis. One caveat however is that other conditions can cause pelvic pain or ovarian cysts, thereby resulting in diagnostic dilemmas. For example, it may be confused with irritable bowel syndrome (IBS), since it too causes diarrhea, constipation and abdominal cramping. Furthermore IBS can accompany endometriosis, making it even more complex to diagnose [
      • Seaman H.E.
      • Ballard K.D.
      • Wright J.T.
      • de Vries C.S.
      Endometriosis and its coexistence with irritable bowel syndrome and pelvic inflammatory disease: findings from a national case-control study − Part 2.
      ]. Gut microbiota shifts (lower lactobacilli concentrations and higher Gram-negative bacteria levels) have been demonstrated in a primate study of endometriosis, although the mechanisms linking these remain unclear [
      • Bailey M.T.
      • Coe C.L.
      Endometriosis is associated with an altered profile of intestinal microflora in female rhesus monkeys.
      ]. Gonadotropin releasing hormone agonist (GnRHa) stimulates the production of follicle-stimulating hormone and luteinizing hormone thereby suppressing estrogen production making it a common treatment for the estrogen-driven disease, endometriosis. Interestingly, GnRHa has been shown to impact the local microbiota of the uterus demonstrating the ability of hormonal regulation to modulate microbiota composition [
      • Khan K.N.
      • Fujishita A.
      • Masumoto H.
      • Muto H.
      • Kitajima M.
      • Masuzaki H.
      • Kitawaki J.
      Molecular detection of intrauterine microbial colonization in women with endometriosis.
      ]. Data elucidating β-glucuronidase activity in the gut microbiota of endometriosis patients may provide mechanistic insights into the role the estrobolome plays in endometriosis. The gut microbiome in patients with endometriosis may have a large number of β-glucuronidase producing bacteria which may lead to increased levels of estrogen metabolites and therefore drive endometriosis.

      4.3 Polycystic ovary syndrome

      Polycystic Ovary Syndrome (PCOS) patients have an increased incidence of metabolic syndrome, however, this incidence is not uniform across women from different countries and of varying ethnicity [
      • Chan J.L.
      • Kar S.
      • Vanky E.
      • Morin-Papunen L.
      • Piltonen T.
      • Puurunen J.
      • Tapaniennen J.S.
      • Rosa Maciel G.A.
      • Hayashida S.A.
      • Saores Jr., J.M.
      • et al.
      Racial and ethnic differences in the prevalence of metabolic syndrome and its components of metabolic syndrome in women with polycystic ovary syndrome (PCOS): a regional cross-sectional study.
      ]. PCOS is a hyperandrogen and low estrogen driven disease, and patients suffering from PCOS have significantly lower gut microbiota diversity compared to healthy controls [
      • Charalampakis V.
      • Tahrani A.A.
      • Helmy A.
      • Gupta J.K.
      • Singhal R.
      Polycystic ovary syndrome and endometrial hyperplasia: an overview of the role of bariatric surgery in female fertility.
      ,
      • Lindheim L.
      • Bashir M.
      • Munzker J.
      • Trummer C.
      • Zachhuber V.
      • Leber B.
      • Horvath A.
      • Pieber T.R.
      • Gorkiewicz G.
      • Stadlbauer V.
      • et al.
      Alterations in gut microbiome composition and barrier function are associated with reproductive and metabolic defects in women with polycystic ovary syndrome (PCOS): a pilot study.
      ]. These variations in gut microbiome compositions highlight the interaction between microbiome composition, sex hormone levels and PCOS. Gut microbiome transfer from adult male mice to immature female mice has been shown to alter the microbiota resulting in increased levels of testosterone and to provide protection against type I diabetes [
      • Markle J.G.
      • Frank D.N.
      • Mortin-Toth S.
      • Robertson C.E.
      • Feazel L.M.
      • Rolle-Kampczyk U.
      • von Bergen M.
      • McCoy K.D.
      • Macpherson A.J.
      • Danska J.S.
      Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity.
      ]. Testosterone has been shown to be produced in the gut by Clostridium scindens [
      • Ridlon J.M.
      • Ikegawa S.
      • Alves J.M.P.
      • Zhou B.
      • Kobayashi A.
      • Iida T.
      • Mitamura K.
      • Tanabe G.
      • Serrano M.
      • De Guzman A.
      • et al.
      Clostridium scindens: a human gut microbe with a high potential to convert glucocorticoids into androgens.
      ]. Evidence of an increase in testosterone levels due to gut microbiome transfer coupled with direct evidence of testosterone synthesis from bacteria that inhabit the gut alludes to the existence of the “testrobolome”. Similar to the estrobolome, the testrobolome may influence sex hormone driven disease states that lack a clear link to estrogen such as PCOS.

      4.4 Endometrial hyperplasia

      High levels of estrogen relative to progesterone can be found as a result of diseases such as PCOS and obesity [
      • Charalampakis V.
      • Tahrani A.A.
      • Helmy A.
      • Gupta J.K.
      • Singhal R.
      Polycystic ovary syndrome and endometrial hyperplasia: an overview of the role of bariatric surgery in female fertility.
      ]. For example, the increased amount of adipose tissue in obesity results in the increased level of estrone conversion [
      • Charalampakis V.
      • Tahrani A.A.
      • Helmy A.
      • Gupta J.K.
      • Singhal R.
      Polycystic ovary syndrome and endometrial hyperplasia: an overview of the role of bariatric surgery in female fertility.
      ]. This is particularly relevant in obese postmenopausal women for whom their major source of estrogen is adipose tissue [
      • Siiteri P.K.
      Adipose-tissue as a source of hormones.
      ]. Increased estrogen production due to the high levels of adipose tissue is thought to be a key driver in female reproductive cancers and therefore hyperplasia [
      • Siiteri P.K.
      Adipose-tissue as a source of hormones.
      ]. This idea is supported by the fact that female reproductive tract cancers are more prevalent in obese women [
      • Siiteri P.K.
      Adipose-tissue as a source of hormones.
      ]. It is the reduction of progesterone levels relative to estrogen levels that is the principal driver of endometrial hyperplasia (EH) due to the lack of progesterone to oppose estrogen [
      • Charalampakis V.
      • Tahrani A.A.
      • Helmy A.
      • Gupta J.K.
      • Singhal R.
      Polycystic ovary syndrome and endometrial hyperplasia: an overview of the role of bariatric surgery in female fertility.
      ]. Increased estrogen levels as a result of estrogen-only hormone therapy results in an increased risk of developing EH [
      • Epplein M.
      • Reed S.D.
      • Voigt L.F.
      • Newton K.M.
      • Holt V.L.
      • Weiss N.S.
      Risk of complex and atypical endometrial hyperplasia in relation to anthropometric measures and reproductive history.
      ]. Much like PCOS, the risk of developing EH has been shown to be reduced following bariatric surgery [
      • Upala S.
      • Sanguankeo A.
      Bariatric surgery and risk of postoperative endometrial cancer: a systematic review and meta-analysis.
      ]. As previously alluded to in this review, bariatric surgery significantly alters both the microbiome composition and metabolic profile of obese women [
      • Kaska L.
      • Sledzinski T.
      • Chomiczewska A.
      • Dettlaff-Pokora A.
      • Swierczynski J.
      Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome.
      ]. Therefore it may be the shift in the microbiome and metabolome composition as a result of bariatric surgery that plays a role in the reduced incidence of EH. The modulation of the estrobolome composition following bariatric surgery is a plausible driver in reduced risk of developing EH considering the critical role estrogen plays in driving the disease.

      4.5 Infertility

      Obesity has been shown to reduce spontaneous pregnancy rates and is associated with other obstetric complications such as preterm birth [
      • Charalampakis V.
      • Tahrani A.A.
      • Helmy A.
      • Gupta J.K.
      • Singhal R.
      Polycystic ovary syndrome and endometrial hyperplasia: an overview of the role of bariatric surgery in female fertility.
      ,
      • McDonald S.D.
      • Han Z.
      • Mulla S.
      • Beyene J.
      • Grp K.S.
      Overweight and obesity in mothers and risk of preterm birth and low birth weight infants: systematic review and meta-analyses.
      ]. Following bariatric surgery in obese women, fertility is improved and women with PCOS, a disease strongly associated with infertility, exhibit reduced symptoms [
      • Butterworth J.
      • Deguara J.
      • Borg C.M.
      Bariatric surgery polycystic ovary syndrome, and infertility.
      ]. However, the metabolic aspects of PCOS are not restricted to obese women. Non-obese women with PCOS retain several hallmarks of metabolic syndrome such as insulin resistance, hypertension and increased risk of cardiovascular disease (CVD) [
      • Charalampakis V.
      • Tahrani A.A.
      • Helmy A.
      • Gupta J.K.
      • Singhal R.
      Polycystic ovary syndrome and endometrial hyperplasia: an overview of the role of bariatric surgery in female fertility.
      ]. This demonstrates that the alleviation of hallmark symptoms of PCOS is not simply mediated through weight loss, but rather through the modulation of the metabolic, including hormonal, aspects of PCOS perhaps through alterations in gut microbiota composition. PCOS patients have an altered hormonal profile, which results in a dysfunctional menstrual cycle that ultimately leads to infertility [
      • Lobo R.A.
      • Carmina E.
      The importance of diagnosing the polycystic ovary syndrome.
      ]. The gut microbiome composition is altered following bariatric surgery and that may be the driving factor that increases fertility and resolution of PCOS [
      • Kaska L.
      • Sledzinski T.
      • Chomiczewska A.
      • Dettlaff-Pokora A.
      • Swierczynski J.
      Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome.
      ]. There is an increase in circulating bile acids following bariatric surgery, which may be a direct consequence of the shift in microbiota composition [
      • Kaska L.
      • Sledzinski T.
      • Chomiczewska A.
      • Dettlaff-Pokora A.
      • Swierczynski J.
      Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome.
      ]. It is possible that a shift in microbiota composition that resolves PCOS also reduces a women’s risk of developing another infertility-linked pathology: endometrial hyperplasia (EH), following bariatric surgery. Fecal transplantation from healthy rats to a rat PCOS model as well as lactobacilli transplantation has been shown to improve estrous cycles and decrease androgen biosynthesis (a key component of PCOS) [
      • Guo Y.
      • Qi Y.
      • Yang X.
      • Zhao L.
      • Wen S.
      • Liu Y.
      • Tang L.
      Association between polycystic ovary syndrome and gut microbiota.
      ]. PCOS has also been shown to be resolved through administration of metformin and clomiphene [
      • Zhang J.
      • Si Q.
      • Li J.
      Therapeutic effects of metformin and clomiphene in combination with lifestyle intervention on infertility in women with obese polycystic ovary syndrome.
      ]. Metformin and clomiphene are used in treatment of type II diabetes and in regulation of estrogen respectively [
      • Hostalek U.
      • Gwilt M.
      • Hildemann S.
      Therapeutic use of metformin in prediabetes and diabetes prevention.
      ,
      • Kousta E.
      • White D.M.
      • Franks S.
      Modern use of clomiphene citrate in induction of ovulation.
      ]. Metformin is now used to help treat the lack of glycemic control found in PCOS patients, which subsequently improves PCOS-associated infertility [
      • Legro R.S.
      • Barnhart H.X.
      • Schlaff W.D.
      • Carr B.R.
      • Diamond M.P.
      • Carson S.A.
      • Steinkampf M.P.
      • Coutifaris C.
      • McGovern P.G.
      • Cataldo N.A.
      • et al.
      Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome.
      ]. Metformin has been shown to alter the gut microbiome composition, increasing Akkermansia spp. abundance [
      • Shin N.R.
      • Lee J.C.
      • Lee H.Y.
      • Kim M.S.
      • Whon T.W.
      • Lee M.S.
      • Bae J.W.
      An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice.
      ]. Clearly, a complex interaction exists between the disease states which impact fertility illustrated in Fig. 1 and gut microbiota composition that requires further investigation.

      4.6 Cancer and phytoestrogens

      Estrogen has been associated with a variety of sex-hormone driven cancers including: endometrial [
      • Grady D.
      • Gebretsadik T.
      • Kerlikowske K.
      • Ernster V.
      • Petitti D.
      Hormone replacement therapy and endometrial cancer risk: a meta-analysis.
      ], cervical [
      • Brake T.
      • Lambert P.F.
      Estrogen contributes to the onset, persistence, and malignant progression of cervical cancer in a human papillomavirus-transgenic mouse model.
      ], ovarian [
      • Lacey J.V.
      • Mink P.J.
      • Lubin J.H.
      • Sherman M.E.
      • Troisi R.
      • Hartge P.
      • Schatzkin A.
      • Schairer C.
      Menopausal hormone replacement therapy and risk of ovarian cancer.
      ], prostate [
      • Nelles J.L.
      • Hu W.Y.
      • Prins G.S.
      Estrogen action and prostate cancer.
      ] and breast cancer [
      • Pike M.C.
      • Spicer D.V.
      • Dahmoush L.
      • Press M.F.
      Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk.
      ]. Gut microbiota composition is altered in many of these cancers and could play a role in promoting carcinogenesis by impacting the hallmarks of cancer (e.g. genomic instability, cell proliferation and apoptosis, etc.) [
      • Schwabe R.F.
      • Jobin C.
      The microbiome and cancer.
      ]. Therefore it has been postulated that alteration of the estrobolome may be a key driver in many of these cancers (Fig. 1) [
      • Plottel C.S.
      • Blaser M.J.
      Microbiome and malignancy.
      ]. The gut microbiota deconjugates estrogens through bacterial secretion of β-glucuronidase enabling them to bind to estrogen receptors [
      • Plottel C.S.
      • Blaser M.J.
      Microbiome and malignancy.
      ]. Estrogen receptor activation increases the number of G0/G1 cells entering the cell cycle promoting cell proliferation, which is particularly well defined in breast cancer [
      • Doisneau-Sixou S.F.
      • Sergio C.M.
      • Carroll J.S.
      • Hui R.
      • Musgrove E.A.
      • Sutherland R.L.
      Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells.
      ].
      Estrogen receptor positive breast cancer is the most common subtype of breast cancer [
      • Reinert T.
      • Saad E.D.
      • Barrios C.H.
      • Bines J.
      Clinical implications of ESR1 mutations in hormone receptor-positive advanced breast cancer.
      ]. This particular cancer subtype is significantly mediated by estrogen [
      • Pike M.C.
      • Spicer D.V.
      • Dahmoush L.
      • Press M.F.
      Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk.
      ]. Goedert et al. found that breast cancer patients had a significantly altered gut microbiota composition in terms of alpha and beta diversity, however there was no difference in fecal estrogens between cancer patients and controls [
      • Goedert J.J.
      • Jones G.
      • Hua X.
      • Xu X.
      • Yu G.
      • Flores R.
      • Falk R.T.
      • Gail M.H.
      • Shi J.
      • Ravel J.
      • et al.
      Investigation of the association between the fecal microbiota and breast cancer in postmenopausal women: a population-based case-control pilot study.
      ]. This is contrary to the previous literature, which consistently found higher levels of circulating estrogens in breast cancer patients [
      • Key T.
      • Appleby P.
      • Barnes I.
      • Reeves G.
      • Endogenous H.
      • Breast Cancer Collaborative G.
      Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies.
      ]. However is it worth noting that fecal estrogens are exclusively conjugated whereas urinary estrogens can be either conjugated or deconjugated [
      • Plottel C.S.
      • Blaser M.J.
      Microbiome and malignancy.
      ]. A previous study by Flores et al. found that Clostridia taxa, as well as three genera in the Ruminococcaceae family were significantly associated with urinary estrogen and microbiome richness [
      • Flores R.
      • Shi J.
      • Fuhrman B.
      • Xu X.
      • Veenstra T.D.
      • Gail M.H.
      • Gajer P.
      • Ravel J.
      • Goedert J.J.
      Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study.
      ]. Overall these data suggest that there is a relationship between gut microbiota, the estrobolome, estrogen levels and breast cancer.
      Elevated estrogen levels are also indicative of other cancer types, particularly female-specific cancers such as endometrial cancer [
      • Grady D.
      • Gebretsadik T.
      • Kerlikowske K.
      • Ernster V.
      • Petitti D.
      Hormone replacement therapy and endometrial cancer risk: a meta-analysis.
      ]. Endometrial cancer is also linked to the gut microbiota in obesity, as obese women who undergo bariatric surgery have a reduced risk of developing EH and subsequently endometrial cancer [
      • Charalampakis V.
      • Tahrani A.A.
      • Helmy A.
      • Gupta J.K.
      • Singhal R.
      Polycystic ovary syndrome and endometrial hyperplasia: an overview of the role of bariatric surgery in female fertility.
      ]. It may be that the microbiome composition or diversity favors bacteria capable of metabolizing estrogens, enabling increased reabsorption and increased estrogen receptor binding which contribute to the development of EH [
      • Chase D.
      • Goulder A.
      • Zenhausern F.
      • Monk B.
      • Herbst-Kralovetz M.
      The vaginal and gastrointestinal microbiomes in gynecologic cancers: a review of applications in etiology, symptoms and treatment.
      ].
      Phytoestrogens can be estrogenic or anti-estrogenic [
      • Rietjens I.M.
      • Louisse J.
      • Beekmann K.
      The potential health effects of dietary phytoestrogens.
      ]. Much like estrone, phytoestrogens only bind weakly to estrogen receptors, preventing estrogens with higher affinity (estradiol) from binding [
      • Eyster K.M.
      The estrogen receptors: an overview from different perspectives.
      ,
      • Rietjens I.M.
      • Louisse J.
      • Beekmann K.
      The potential health effects of dietary phytoestrogens.
      ]. Thus phytoestrogens can be considered to have estrogenic and anti-estrogenic activity. This dual activity may explain why phytoestrogens can be therapeutic in both hyper- and hypo-estrogen diseases [
      • Rietjens I.M.
      • Louisse J.
      • Beekmann K.
      The potential health effects of dietary phytoestrogens.
      ]. Phytoestrogen consumption has been shown to reduce cancer incidence in reproductive and non-reproductive tissue [
      • Rietjens I.M.
      • Louisse J.
      • Beekmann K.
      The potential health effects of dietary phytoestrogens.
      ]. Consumption of soy-based food, which is high in phytoestrogens, has been shown to reduce lung cancer risk in a meta-analysis by Yang et al. [
      • Yang W.S.
      • Va P.
      • Wong M.Y.
      • Zhang H.L.
      • Xiang Y.B.
      Soy intake is associated with lower lung cancer risk: results from a meta-analysis of epidemiologic studies.
      ]. Increased serum phytoestrogen concentrations have also been shown to be inversely correlated to risk of gastric cancer in a study of male and female Korean individuals [
      • Ko K.P.
      • Park S.K.
      • Park B.
      • Yang J.J.
      • Cho L.Y.
      • Kang C.
      • Kim C.S.
      • Gwack J.
      • Shin A.
      • Kim Y.
      • et al.
      Isoflavones from phytoestrogens and gastric cancer risk: a nested case-control study within the korean multicenter cancer cohort.
      ]. Furthermore, Chinese ERα positive gastric cancer patients, had a significantly worse prognosis compared to those that were ERβ positive [
      • Tang W.
      • Liu R.
      • Yan Y.
      • Pan X.
      • Wang M.
      • Han X.
      • Ren H.
      • Zhang Z.
      Expression of estrogen receptors and androgen receptor and their clinical significance in gastric cancer.
      ]. The most well characterized correlation between cancer incidence and phytoestrogen consumption is found in breast cancer. Numerous meta-analyses have reported a decreased risk in breast cancer with increased consumption of phytoestrogens [
      • Trock B.J.
      • Hilakivi-Clarke L.
      • Clarke R.
      Meta-analysis of soy intake and breast cancer risk.
      ,
      • Wu A.H.
      • Yu M.C.
      • Tseng C.C.
      • Pike M.C.
      Epidemiology of soy exposures and breast cancer risk.
      ,
      • Dong J.Y.
      • Qin L.Q.
      Soy isoflavones consumption and risk of breast cancer incidence or recurrence: a meta-analysis of prospective studies.
      ]. Decreased risk of breast cancer may be mediated through an anti-estrogenic action of phytoestrogen and subsequent reduction in estrogen receptor mediated proliferation of cancer. However, the interaction between the gut microbiome and phytoestrogens may not be unidirectional. Non-obese diabetic mice fed with the phytoestrogen genistein, have been shown to have significantly different gut microbial beta-diversity linked to immune homeostasis [
      • Huang G.
      • Xu J.
      • Lefever D.E.
      • Glenn T.C.
      • Nagy T.
      • Guo T.L.
      Genistein prevention of hyperglycemia and improvement of glucose tolerance in adult non-obese diabetic mice are associated with alterations of gut microbiome and immune homeostasis.
      ]. Gut microbiota alteration following phytoestrogen consumption may be a factor in the alleviation or causation of cancer.

      4.7 Cardiovascular disease

      Premenopausal women have a decreased risk of cardiovascular disease (CVD) compared to their age-matched male counterparts [
      • Rosenthal T.
      • Oparil S.
      Hypertension in women.
      ]. However, once women reach the age of 55 years old, they have an increased risk of CVD compared to men [
      • Rosenthal T.
      • Oparil S.
      Hypertension in women.
      ], which may be due to the reduction of circulating estrogen levels found in postmenopausal women. Estrogen has been shown to promote beneficial physiological responses that promote cardiovascular health and lessen CVD risk including enhancing endothelial function and decreasing vascular resistance, promoting attenuation of proinflammatory mediator pathways such as the NFκB pathway, and decreasing levels of plasma low-density lipoprotein cholesterol [
      • Faulds M.H.
      • Zhao C.Y.
      • Dahlman-Wright K.
      • Gustafsson J.A.
      The diversity of sex steroid action: regulation of metabolism by estrogen signaling.
      ]. The protective role of estrogen in CVD is further evidenced by the decreased risk of CVD in women on hormone replacement therapy [
      • Mosca L.
      • Collins P.
      • Herrington D.M.
      • Mendelsohn M.E.
      • Pasternak R.C.
      • Robertson R.M.
      • Schenck-Gustafsson K.
      • Smith S.C.
      • Taubert K.A.
      • Wenger N.K.
      Hormone replacement therapy and cardiovascular disease − a statement for healthcare professionals from the American Heart Association.
      ].
      Interestingly, the metabolic risk factors in men and women differ [
      • Rosano G.M.C.
      • Vitale C.
      • Marazzi G.
      • Volterrani M.
      Menopause and cardiovascular disease: the evidence.
      ]. For example, high cholesterol is an effective predictor of CVD in men, however, in women lipoprotein(a) levels provides a much more powerful predictor of CVD incidence [
      • Rosano G.M.C.
      • Vitale C.
      • Marazzi G.
      • Volterrani M.
      Menopause and cardiovascular disease: the evidence.
      ]. Gut microbiome composition has been shown to impact levels of metabolites strongly associated with CVD, such as equol [
      • Wang Z.N.
      • Klipfell E.
      • Bennett B.J.
      • Koeth R.
      • Levison B.S.
      • Dugar B.
      • Feldstein A.E.
      • Britt E.B.
      • Fu X.M.
      • Chung Y.M.
      • et al.
      Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.
      ]. Postmenopausal women able to produce equol, a phytoestrogen metabolite, have been shown to have better cardiometabolic health (decreased arterial stiffness and improved endothelial function) [
      • Tormala R.
      • Appt S.
      • Clarkson T.B.
      • Groop P.H.
      • Ronnback M.
      • Ylikorkala O.
      • Mikkola T.S.
      Equol production capability is associated with favorable vascular function in postmenopausal women using tibolone; no effect with soy supplementation.
      ]. However, in a prospective study of equol and non-equol producing men, the cardiometabolic benefit of equol producing gut microbiota was limited to a decrease in arterial stiffness, and reduced CVD risk to 11–12% for middle aged men at moderate risk of CVD [
      • Hazim S.
      • Curtis P.J.
      • Schar M.Y.
      • Ostertag L.M.
      • Kay C.D.
      • Minihane A.M.
      • Cassidy A.
      Acute benefits of the microbial-derived isoflavone metabolite equol on arterial stiffness in men prospectively recruited according to equol producer phenotype: a double-blind randomized controlled trial.
      ]. The low estrogen levels in postmenopausal women may explain why women capable of producing equol had both decreased arterial stiffness and endothelial function, whereas men solely had decreased arterial stiffness. The restoration of normal estrogen signaling through phytoestrogens may mitigate the negative CVD health implications of low estrogen levels in postmenopausal women.
      Using a spontaneously hypertensive rat (SHR) model it has been shown that gut microbiome diversity is decreased in SHR relative to controls [
      • Yang T.
      • Santisteban M.M.
      • Rodriguez V.
      • Li E.
      • Ahmari N.
      • Carvajal J.M.
      • Zadeh M.
      • Gong M.H.
      • Qi Y.F.
      • Zubcevic J.
      • et al.
      Gut dysbiosis is linked to hypertension.
      ]. In addition SHR have an increased Firmicutes/Bacteroidetes (F/B) ratio relative to controls [
      • Yang T.
      • Santisteban M.M.
      • Rodriguez V.
      • Li E.
      • Ahmari N.
      • Carvajal J.M.
      • Zadeh M.
      • Gong M.H.
      • Qi Y.F.
      • Zubcevic J.
      • et al.
      Gut dysbiosis is linked to hypertension.
      ]. Treatment with the antibiotic minocycline reduced hypertension in chronic angiotensin II infusion rat model as well as decreased the F/B ratio and increased gut microbiome diversity [
      • Yang T.
      • Santisteban M.M.
      • Rodriguez V.
      • Li E.
      • Ahmari N.
      • Carvajal J.M.
      • Zadeh M.
      • Gong M.H.
      • Qi Y.F.
      • Zubcevic J.
      • et al.
      Gut dysbiosis is linked to hypertension.
      ]. In the same study researchers performed fecal transplantation from hypertensive humans to germ free mice, which resulted in increased blood pressure, compared to mice that underwent fecal transplantation from healthy controls [
      • Li J.
      • Zhao F.
      • Wang Y.
      • Chen J.
      • Tao J.
      • Tian G.
      • Wu S.
      • Liu W.
      • Cui Q.
      • Geng B.
      • et al.
      Gut microbiota dysbiosis contributes to the development of hypertension.
      ]. Furthermore, clinical studies have revealed gut dysbiosis and reduced gut microbiome diversity in both pre-hypertensive and hypertensive individuals [
      • Li J.
      • Zhao F.
      • Wang Y.
      • Chen J.
      • Tao J.
      • Tian G.
      • Wu S.
      • Liu W.
      • Cui Q.
      • Geng B.
      • et al.
      Gut microbiota dysbiosis contributes to the development of hypertension.
      ].
      The reduction in diversity of the gut microbiome in CVD patients and the putative reduction in estrogen and phytoestrogen levels through reduced β-glucuronidase activity may be a key aspect of the gut microbiome-CVD interaction, considering the important protective role estrogen plays against CVD. Gut microbiome diversity impacts the metabolic profile modulating metabolites such as short chain fatty acids, which subsequently modulate cholesterol metabolism [
      • Puertollano E.
      • Kolida S.
      • Yaqoob P.
      Biological significance of short-chain fatty acid metabolism by the intestinal microbiome.
      ]. Given the numerous physiological facets of estrogen on cardiovascular health, there could be a link between reduced gut microbiome diversity, reduced estrogen levels and hallmarks of CVD such as increased arterial stiffness and impaired endothelial function. It is also important to consider other factors associated with gut microbiome dysbiosis and hypertension including environmental, nutritional and genetic factors [
      • Yang T.
      • Santisteban M.M.
      • Rodriguez V.
      • Li E.
      • Ahmari N.
      • Carvajal J.M.
      • Zadeh M.
      • Gong M.H.
      • Qi Y.F.
      • Zubcevic J.
      • et al.
      Gut dysbiosis is linked to hypertension.
      ]. Lastly, dietary interventions may serve as an innovative strategy to reinstate gut homeostasis to alleviate hypertension.

      4.8 Gut-brain axis

      The gut microbiota regulates neurophysiological behaviors by altering neural, endocrine and immune pathways [
      • Collins S.M.
      • Surette M.
      • Bercik P.
      The interplay between the intestinal microbiota and the brain.
      ]. Postmenopausal women show a decline in cognition, most notably in memory, as a result of declining estrogen levels [
      • Jones H.E.
      • Conrad H.S.
      The growth and decline of intelligence: a study of a homogeneous group between the ages of ten and sixty.
      ]. Estrogen depletion can also impact fine motor coordination as well as depression and anxiety [
      • Mcewen B.S.
      Alves SE: Estrogen actions in the central nervous system.
      ]. Animal studies have replicated these cognitive effects through observing the decline in performance in memory tasks in ovariectomized perhaps linked to significantly lower densities of spinal neurons [
      • Wallace M.
      • Luine V.
      • Arellanos A.
      • Frankfurt M.
      Ovariectomized rats show decreased recognition memory and spine density in the hippocampus and prefrontal cortex.
      ]. While beyond the scope of this review, numerous fecal microbiome transplant and antibiotic studies have been performed illustrating the role of the gut microbiome in cognitive conditions such as anxiety, depression and memory impairment [
      • Vuong H.E.
      • Yano J.M.
      • Fung T.C.
      • Hsiao E.Y.
      The microbiome and host behavior.
      ]. Studies have shown that estrogen stimulates neural growth in both in vitro [
      • Ferreira A.
      • Caceres A.
      Estrogen-enhanced neurite growth − evidence for a selective induction of tau and stable microtubules.
      ,
      • Murphy D.D.
      • Segal M.
      Morphological plasticity of dendritic spines in central neurons is mediated by activation of cAMP response element binding protein.
      ] and in animal studies [
      • Toranallerand C.D.
      • Miranda R.C.
      • Bentham W.D.L.
      • Sohrabji F.
      • Brown T.J.
      • Hochberg R.B.
      • Maclusky N.J.
      Estrogen-receptors colocalize with low-affinity nerve growth-factor receptors in cholinergic neurons of the basal forebrain.
      ]. Furthermore, endogenous estrogen levels have been shown to be positively associated with verbal memory in both postmenopausal women and older men [
      • Wolf O.T.
      • Kirschbaum C.
      Endogenous estradiol and testosterone levels are associated with cognitive performance in older women and men.
      ].
      The interplay of the gut microbiome and the brain is a rapidly growing area of research. Germ free mice have been shown to have reduced working memory compared to conventionally colonized controls [
      • Gareau M.G.
      • Wine E.
      • Rodrigues D.M.
      • Cho J.H.
      • Whary M.T.
      • Philpott D.J.
      • MacQueen G.
      • Sherman P.M.
      Bacterial infection causes stress-induced memory dysfunction in mice.
      ]. Administration of a variety of antibiotics through drinking water has also been shown to impair object recognition behavior in mice [
      • Mohle L.
      • Mattei D.
      • Heimesaat M.M.
      • Bereswill S.
      • Fischer A.
      • Alutis M.
      • French T.
      • Hambardzumyan D.
      • Matzinger P.
      • Dunay I.R.
      • et al.
      Ly6C(hi) monocytes provide a link between antibiotic-induced changes in gut microbiota and adult hippocampal neurogenesis.
      ]. As previously described in this review, a reduction in gut microbiota diversity reduces the estrobolome and therefore the deconjugative ability of the gut microbiome [
      • Flores R.
      • Shi J.
      • Fuhrman B.
      • Xu X.
      • Veenstra T.D.
      • Gail M.H.
      • Gajer P.
      • Ravel J.
      • Goedert J.J.
      Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study.
      ]. Reduction of estrogen deconjugation by the gut microbiome could be driving the cognitive decline in germ free mice through reduction of bioactive estrogen.

      5. Future areas of study

      Phytoestrogens have a range of affinities to estrogen receptors making certain phytoestrogens more appropriate for putative treatment of particular disease [
      • Rietjens I.M.
      • Louisse J.
      • Beekmann K.
      The potential health effects of dietary phytoestrogens.
      ]. Similarly, some phytoestrogens have been shown to have antiestrogenic effects which could be utilized as a therapeutic treatment of hyperestrogenic disease [
      • Rietjens I.M.
      • Louisse J.
      • Beekmann K.
      The potential health effects of dietary phytoestrogens.
      ]. Therefore an important future area of study will be to assess the most effective phytoestrogens for particular diseases in terms of estrogen receptor affinity and their interaction with estrogen receptors. The role of the gut microbiome in modulating estrogen levels also promises to have exciting therapeutic applications. Randomized control studies are needed to better define the therapeutic efficacy of treatment of estrogen-modulated disease. Characterization of the microbiota and metabolome composition before and after bariatric surgery may help elucidate microbial and metabolic components of healthy and disease states which could have further therapeutic and diagnostic applications. Gut microbiota could also be used to diagnostically in unison with serum, urinary and fecal estrogen levels to determine risk factors for disease or as a biomarker. Profiling of the gut microbiome could be taken a step further by metagenomic analysis to assess the levels of genes encoding β-glucuronidase and other genes that influence estrogen metabolism in the context of these diseases outlined herein.

      6. Conclusion

      The number of postmenopausal women is increasing; therefore diseases resulting from low estrogen levels will become an increasing public health burden. Modulating the gut microbiome to subsequently impact estrogen levels provides an exciting future therapeutic application. Novel estrogen modulation methods through microbiome alteration and/or phytoestrogen consumption may have greater efficacy and provide an alternative to current treatment of estrogen-mediated conditions and disease. Modulation of the gut microbiome and metabolic profile as a means of treating estrogen-driven disease through surgical (bariatric surgery), fecal microbiome transfer, nutraceutical (genistein) and pharmaceutical (metformin) methods also shows promise for combating the metabolic aspects of disease states, which subsequently aids in resolving the associated disease (Fig. 1). The impact of bacterial therapeutics on the estrobolome should also be taken into consideration when developing probiotics especially in diseases prevalent in women. However, the impact of the estrobolome is not exclusive to women. More broadly, the impact of particular microbiota composition on the metabolic profile is an emerging area of research. These studies could prove to have particularly pertinent health applications extending to a vast number of major public health concerns. Overall, the estrobolome is an important component of the gut microbiota as demonstrated by the range of putative estrobolome-mediated diseases illustrated in this review and may provide an attractive diagnostic and therapeutic target for future research to enhance women’s health.

      Contributors

      MMH-K designed the scope and organization of the review.
      JMB, LA-N and MMH-K conducted literature reviews, figure construction and contributed to the writing of the manuscript.
      MMH-K supervised the writing and critically edited and reviewed the complete manuscript, and figures.
      All authors approved the final manuscript for submission.

      Conflict of interest

      The authors declare that they have no conflict of interest.

      Funding

      This work was supported by the University of Arizona.

      Provenance and peer review

      This article has undergone peer review.

      Acknowledgements

      The authors would like to thank the members of the Herbst-Kralovetz research team for thoughtful discussions on this topic and Dr. Rayna Gonzales for critical review of the manuscript. The authors would also like to acknowledge the University of Bath Placement Program.

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