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Enterohepatic recirculation of estrogens by the gut microbiome. Estrogens in the systemic circulation, produced by the ovaries, adrenal gland, and adipose or other tissues, undergo first-pass metabolism in the liver, and also may be conjugated with glucuronide or sulfate groups in the liver which facilitates biliary excretion. In the intestinal tract, conjugated estrogens are either excreted in feces, or deconjugated by gut microbiota with β-glucuronidase or sulfatase enzymes, termed the “estrobolome” – this allows estrogens to enter the enterohepatic circulation, and thus subsequently re-enter the systemic circulation and reach other tissues.
Source publication
The gut microbiome is an important contributor to human health, shaped by many endogenous and exogenous factors. The gut microbiome displays sexual dimorphism, suggesting influence of sex hormones, and also has been shown to change with aging. Yet, little is known regarding the influence of menopause – a pivotal event of reproductive aging in women...
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The immune system protects us from pathogens, such as viruses. Antiviral immune mechanisms aim to limit viral replication, and must maintain immunological homeostasis to avoid excessive inflammation and damage to the host. Sex differences in the manifestation and progression of immune-mediated disease point to sex-specific factors modulating antivi...
Citations
... Considering the importance of the gut-lung axis in this model and the association between respiratory diseases, including asthma, and intestinal disorders, we also investigated how acetate affects gut-specific gene expression and mucus production in our model of menopausal asthma. Furthermore, since menopausal women are more prone to experiencing intestinal imbalances (Chen and Madak-Erdogan, 2018;Peters et al., 2022), we explored whether acetate could influence these aspects as well. ...
... Considering that, the gut−;lung axis is important in this model, and respiratory diseases, including asthma, are associated with intestinal disorders. Furthermore, menopausal women are more prone to experiencing intestinal imbalances (Chen and Madak-Erdogan, 2018;Peters et al., 2022), thus we explored the effects of acetate on gut-specific gene expression and mucus production in our model of menopausal asthma. ...
Introduction
Asthma, an inflammatory lung disease, disproportionately affects women in adulthood and is associated with a decline in estrogen levels during the menstrual cycle and menopause. To study asthma symptoms during menopause, we used a mouse model of postmenopausal asthma via ovariectomy (OVx). Similar to human menopause, we previously discovered that re-exposure of allergic OVx mice to allergen exacerbates lung inflammation. Surprisingly, we found that probiotic treatment alleviates this inflammatory exacerbation and produces acetate as one of its metabolites. Here, we investigate whether exogenous acetate alone can inhibit the exacerbation of experimental asthma in menopause.
Methods
Mice received acetate administration before and during sensitization. After challenge and OVx the mice were subjected to a second challenge to test whether acetate protected against airway inflammation after menopause induction.
Results
Acetate administration reduced all lung T2 inflammatory responses, as well as the serum immunoglobulin (IgE) level. Early acetate treatment led to an increase in regulatory T cells, even 3 weeks after cessation of the treatment, suggesting that the increase in Treg percentage is associated with the reduction of type 2 inflammation in the airways after menopause induction, indicating its potential role in this process. Given the significant role of the lung-gut axis in asthma and the association of asthma and menopause with intestinal dysfunctions, this finding is particularly relevant; we also analyzed several markers of intestinal integrity. Compared with sham-operated mice, rechallenged allergic menopausal mice had a reduction in the intestinal epithelial genes, MUC2 and OCLN, and preventive supplementation with acetate returned their expression to normal. No change was found in menopausal mice without allergic inflammation.
Conclusion
In conclusion, treatment with acetate prior to estrogen level decline protects sensitized and challenged mice against later airway T2 inflammation and may restore gut homeostasis.
... Its composition is considered relatively stable during adult life, but changes may occur due to sex-and age-related conditions, such as menopause and post-menopause [2]. According to Peters et al. [3] post-menopausal women show lower gut microbial diversity, and a changed composition compared to pre-menopausal women. Zhao et al. [4] also reported lower microbial diversity and differences in the composition of the gut microbiome of ...
... A diet high in protein and low in complex carbohydrates (typical of the Western diet), increases levels of BCFAs in vitro [51], both in animal and human intervention studies [52,53]. Conversely, supplementation with complex carbohydrates, capable of reaching the colon, tends to lower fecal BCFAs levels [3]. In our experimental work, the BCFAs content differed significantly from the control samples. ...
... Only the addition of probiotics (with the exception of BC4) led to an increase in the relative abundance of the genus Bacteroides compared to the control. Regarding the scientific literature on the gut microbiota of post-menopausal women, it is important to emphasize the heterogeneity of results between studies, which could be related to different sample sizes and different study populations, as the gut microbiome is known to vary according to geography and lifestyle [3]. Although various gut bacterial taxa were reported to differ by menopause status, some consistent results were observed across studies. ...
The gut microbiome of women can change after menopause, and during this phase women can also be more susceptible to vaginal dysbiosis. Recent studies have explored the probiotic potential of Lactobacillus crispatus BC4 and Lactobacillus gasseri BC9 against various pathogens and their use as co-starters in foods. However, their effects on the gut microbiota of post-menopausal women, who are more prone to dysbiosis, have not been examined. This study investigated the effects of predigested soy beverages (INFOGEST) containing BC4 and BC9 (encapsulated or not) on the composition and metabolic activity of the gut microbiota in post-menopausal women, using a fecal batch culture model. Parameters such as pH, gas, SCFAs, and microbiota composition (targeted qPCR and 16S rRNA gene sequencing) were assessed. The study, while highlighting a strong variability among donors, showed differences in gut microbiota response to the tested products. For instance, donor 2 showed a significant increase in bifidobacteria with BC4 + BC9 and E-BC9, while BC4 increased Ruminococcaceae in donors 1 and 3, and E-BC4 and E-BC9 enhanced Akkermansia in donor 1. BC4, E-BC4, E-BC9, and E-BC4 + BC9 significantly impacted metabolic activity, as measured by SCFAs, compared to other samples. However, no significant differences in gas production were observed.
... Estrogens rapidly affect neuronal and pituitary cell excitability, activate cyclic adenosine monophosphate and mitogen-activated protein kinase (MAPK) pathways for kainite and IGF-1 receptors, modulate G-protein coupling, calcium currents, calcium channels, and calcium ion entry, and protect neurons from excitotoxins and free radical cells. 18,19 By genetically regulating neuropeptide, neuroactive transmitter, and receptor production, release, and metabolism, steroids affect neurons. Nongenomic estrogen action and novel intracellular signaling cascades may be enabled by the high-affinity membrane-associated Gprotein coupled ER GPR30/GPER1. ...
... Hypoestrogenism affects basic forebrain cholinergic, dopaminergic, and mitochondrial bioenergetics and cognitive aging. 19 Clinical studies suggest that glucose metabolism failure may drop estrogen levels and impair cognition. Low-grade inflammation may impair cognition. ...
... Sex HT may reduce inflammation by reducing inflammatory markers. 18,19 Estrogen may help us think sharply as we age. Estrogens protect the brain by regulating neuropeptides, neurotransmitters, and neurosteroid hormones, reducing cell death, promoting neuron development, regulating mitochondrial function, having antioxidant properties, modulating the immune system, and reducing β-amyloid production. ...
The World Health Organization (WHO)
defines menopause as the permanent
cessation of menstruation due to a decrease
in ovarian activity without physiological or
pathological causes. Twelve months of
amenorrhea signal menopause. Menopause
usually begins around 50 but can occur at
41, 45, or 40. Menopause between 45 and
55 is different from early menopause.
Women are more likely to have
cardiovascular illness, parkinsonism,
melancholy, osteoporosis, hypertension,
weight gain, midlife diabetes, cognitive
impairments, and dementia, including
Alzheimer's disease (AD). When estrogen
levels drop prematurely, women are more
likely to acquire certain disorders.
Experimental and epidemiological studies
suggests that female sex hormones have
neuroprotective and anti-aging effects over
time. According to new research, estrogen
protects and promotes the CNS. Working
memory, attention, processing speed, and
verbal memory are lower in menopausal
women. Age-related estrogen may protect
cognition. Estrogens improve brain health
by regulating neuropeptides,
neurotransmitters, and neurosteroid
production, affecting cell death, neuronal
development, synaptic plasticity,
mitochondrial function, antioxidants,
immune system modulation, and β-amyloid
reduction. Sex hormone prescriptions ease
cognitive impairments in early menopause
when estradiol and estrogen receptor levels
diminish. The selective estrogen receptor
modulators tamoxifen and raloxifene
interact with ERα, ERβ, and GPR30 to
protect the brain.
... One further relationship between SF and menopausal changes relates to the capacity of SF to influence gut health (the microbiome) [17]. The microbiome has been documented to have an important impact upon the progression and quality of life in menopause [55]. Thus, the incorporation of SF as a dietary intervention offers significant promise for improving health outcomes in menopausal women. ...
Featured Application
The phytochemical sulforaphane has been safely consumed in cruciferous vegetables, wild and cultivated, for centuries. There are multiple applications and copious mechanistic documentation supporting its use in both female- and male-specific conditions, syndromes, diseases, and cancers. All of these relate to the body’s hormonal axes in one way or another. More awareness of the specific benefits of sulforaphane on female and male healthspan is warranted for both scientists and the general public.
Abstract
The health-promoting, preventive, protective, and therapeutic applications of the natural compound sulforaphane (SF) produced from its biogenic precursor in broccoli, glucoraphanin, are extremely well established. SF has been the subject of thousands of studies and over 125 clinical trials. The many mechanisms of action of SF in mammalian systems have been extensively documented. SF is the most potent naturally occurring inducer of the Keap1/Nrf2 pathway, which is most well-known for its upregulation of antioxidant and detoxification mechanisms and activation of pathways resulting in the inhibition of inflammation. Much of this regulation involves the various hormonal axes of the body. However, the influence of SF on hormone-mediated health conditions remains unexplored in recent scholarly reviews. This review aims to address this gap by exploring many of these interactions, with a focus on the health and wellness issues specific to both females and males.
... Diet-induced changes in gut microbiota also include seasonal variability as observed in hunter-gatherer 84 and industrialized populations 85 as well upon interventions such as fasting 86 . Microbiota variation has also been linked to non-pathological changes in host phenotype throughout life 87,88 , including times of major hormonal changes 89,90 , and has even been associated with circadian rhythm 91 , which may be mediated by physiological processes occurring during short-term fasting. To the gut microbiota, both the host and the world are environments that can change, and it is beneficial for the gut ecosystem to be able to adapt to those changes. ...
The disruptive effect of antibiotics on the composition and function of the human microbiota is well established. However, the hypothesis that probiotics can help restore the antibiotic-disrupted microbiota has been advanced, with little consideration of the strength of evidence supporting it. Some clinical data suggest that probiotics can reduce antibiotic-related side effects, including Clostridioides difficile-associated diarrhoea, but there are no data that causally link these clinical effects to microbiota protection or recovery. Substantial challenges hinder attempts to address this hypothesis, including the absence of consensus on the composition of a 'normal' microbiota, non-standardized and evolving microbiome measurement methods, and substantial inter-individual microbiota variation. In this Review, we explore these complexities. First, we review the known benefits and risks of antibiotics, the effect of antibiotics on the human microbiota, the resilience and adaptability of the microbiota, and how microbiota restoration might be defined and measured. Subsequently, we explore the evidence for the efficacy of probiotics in preventing disruption or aiding microbiota recovery post-antibiotic treatment. Finally, we offer insights into the current state of research and suggest directions for future research.
... The risk of osteoporosis in women increases in menopause due to a decrease in estrogen levels, and estrogen-independent mechanisms, including secondary hyperparathyroidism, chronic inflammation, and senility, can add to the development of osteoporosis [25][26][27][28][29]. Moreover, decreased diversity of the gut microbiome in menopause, known as dysbiosis, has been linked to metabolic syndrome, as well as behavioral and physiological deficits (Figure 1) [30][31][32][33]. Metabolic syndrome is a multiplex modifiable risk factor involving several health outcomes, including T2DM, which is normally associated with high body mass index, that share common biological and societal pathways [34][35][36][37][38][39]. ...
... The risk of osteoporosis in women increases in menopause due to a decrease in estrogen levels, and estrogen-independent mechanisms, including secondary hyperparathyroidism, chronic inflammation, and senility, can add to the development of osteoporosis [25][26][27][28][29]. Moreover, decreased diversity of the gut microbiome in menopause, known as dysbiosis, has been linked to metabolic syndrome, as well as behavioral and physiological deficits ( Figure 1) [30][31][32][33]. Metabolic syndrome is a multiplex modifiable risk factor involving several health outcomes, including T2DM, which is normally associated with high body mass index, that share common biological and societal pathways [34][35][36][37][38][39]. ...
Background/objectives:
Correction of decreased diversity of the gut microbiome, which is characteristic of menopause, by supplementation with a synbiotic may attenuate or prevent dysbiosis processes and preserve bone mass. We describe the rationale and design of the OsteoPreP trial aimed at evaluating the effects of 12 months of supplementation with a synbiotic on bone and metabolic health in postmenopausal Caucasian women.
Methods:
This is a randomized, double-blinded, placebo-controlled trial among 160 Caucasian, postmenopausal women with no current diagnosis of osteoporosis or supplementation with pro- or prebiotics, and no medical treatment affecting bone turnover. Dual-energy X-ray absorptiometry scans will be conducted at screening to confirm absence of osteoporosis. The primary outcome is the relative change (%) in total bone mineral density of the distal tibia at 12 months post-treatment between the active and placebo groups, as determined via high-resolution peripheral quantitative computed tomography. Secondary outcomes are the effects on immune system modulation and cognition, gut microbiota composition, and musculoskeletal and metabolic functions, with particular emphasis on blood glucose regulation.
Conclusions:
The trial will inform on the efficacy and safety of a synbiotic containing both aerobic and anerobic bacterial strains and a prebiotic fiber on reduction in bone loss and on indices of blood glucose regulation. This trial may pave the way for an exciting field of translational research and be the underpinnings of the prevention strategy of osteoporosis and the management of metabolic dysfunction in postmenopausal women. The trial is registered with clinicaltrials.gov (NCT05348694).
... The presence of estrogen receptors (ERα, ERβ, and the G-protein-coupled receptor GPER) and androgen receptors in the intestinal epithelium [124] explains the effects of hormone therapy on the diversity of the gut microbiota and intestinal barrier function in experimental studies [54,59,125,126]. In postmenopausal women treated with estrogens, the abundance of Proteobacteria and Bacteroidetes in the duodenum reached premenopausal levels [127]. ...
Purpose of the Review
The purpose of this Review was to summarize the evidence on the associations among estrogen status, cellular senescence, the gut microbiome and osteoporosis.
Recent Findings
Indicate that osteoporosis is a global public health problem that impacts individuals and society. In postmenopausal women, a decrease in estrogen levels is associated with a decrease in gut microbial diversity and richness, as well as increased permeability of the gut barrier, which allows for low-grade inflammation. The direct effects of estrogen status on the association between bone and the gut microbiome were observed in untreated and treated ovariectomized women. In addition to the direct effects of estrogens on bone remodeling, estrogen therapy could reduce the risk of postmenopausal osteoporosis by preventing increased gut epithelial permeability, bacterial translocation and inflammaging. However, in studies comparing the gut microbiota of older women, there were no changes at the phylum level, suggesting that age-related comorbidities may have a greater impact on changes in the gut microbiota than menopausal status does.
Summary
Estrogens modify bone health not only by directly influencing bone remodeling, but also indirectly by influencing the gut microbiota, gut barrier function and the resulting changes in immune system reactivity.
... The gut microbiota may also be influenced by brain function through the "brain-gut" axis (Sasso et al., 2023), and current research has found that flora plays a vital role in the development of depression Parker et al., 2020). Vice versa, the disorder can also affect the function of neurons in the brain (Peters et al., 2022). With regard the specific traits of menopause transition and sex hormone importance, the tridirection cross-talk between sex hormones, brain behavior changes, and gut flora needs further study as a whole, which refers to "E2-brain-gut-microbiota axis." ...
Object
Perimenopause depression disorder (PDD) is a very common problem in clinical practice and is characterized by depression and autonomic nervous symptoms, including hot flashes, palpitation, and night sweating. In addition, the comorbidity of menopause depression has long been an integral component of the estradiol (E2) shortage. Previous studies have suggested that the mechanisms underlying this comorbidity involved overlap of endocrine and cerebellar networks. Emerging evidence has shown that the endocrine–brain–gut–microbiota axis plays a key role in the regulation of affective disorders. Yangyin-ningshen formula (YYNS) is a traditional Chinese decoction tailored by Yijintang for menopausal depression intervention. Thus, we hypothesized that the YYNS may be involved in the menopause depression alleviation through the endocrine–brain–gut–microbiota axis.
Methods
To verify this, we constructed a bilateral ovariectomy (OVX) mouse model to simulate menopausal-related depression. Subsequently, behavioral tests including the open field test (OFT) and the forced swimming test (FST) were conducted to examine the depression state post-OVX. With YYNS or E2 intervention, enzyme-linked immunosorbent assay (ELISA) was used to determine the serum sex hormones level. 16S rRNA gene sequencing and liquid chromatography-mass spectrometry (LC-MS) were used to analyze the microbiome of the colon samples collected from mice in the sham surgery group (CSH), the OVX model group (CMD), the OVX with E2 hormone intervention group (CHM), and the OVX with YYNS intervention group (CYYNS). One week after OVX, CMD, CHM, and CYYNS showed depression in OFT, FST. Three weeks post-OVX, CHM and CYYNS showed a notable relief of depression; CMD shaped the OTUs shrinkage; and OTUs were raised in the sham, CHM, and CYYNS group. The CMD group showed that the abundance of Actinobiota decreased but that of Bacteriodia increased. The relative abundance of the genus varied in each group. Moreover, functional correlation of changes in sex hormone and gut microbes between different groups showed that the PRL level was negatively correlated with Odoribacter. T level was positively correlated with Lachnospiraceae NK4A136 group and Odoribacter abundance (p < 0.05).
Conclusion
Our results not only offer novel insights into the sex hormones and depression with OVX mice but also build an important basis for E2 or YYNS therapeutic efficacy on PDD, which provide for future research on this etiology through the endocrine–brain–gut–microbiota network.
... This could be explained by the decline in estrogens levels shown by women in the menopausal phase (Scavello et al., 2019), generally occurring between 45 and 55 years for women worldwide (World Health Organization, 2022). In fact, a recent review on the effect of menopause or female sex hormones on the gut microbiota (Peters et al., 2022b) found decreased α-diversity in post-vs. pre-menopausal women (Flores et al., 2012;Zhao et al., 2019;Peters et al., 2022a) and higher similarity to the male gut microbiota for postmenopausal women (Santos-Marcos et al., 2018;Mayneris-Perxachs et al., 2020;Peters et al., 2022a), which might also explain why, in our study, higher gut α-diversity in females compared to males was no longer observed in adults over the age of 45. ...
Introduction
Although the oral cavity and the gut are anatomically continuous regions of the gastrointestinal tract, research on the relationship between oral and gut microbiota remains sparse. Oral-gut bacterial translocation is mostly studied in pathological contexts, thus evidence of translocation in healthy conditions is still scarce. Studying the oral-gut microbiota relationship in humans in different life stages is necessary in order to understand how these microbial communities might relate throughout life.
Methods
In this study, saliva and fecal samples were collected from healthy participants (39 children, 97 adults). Microbiota analysis was carried out by sequencing the V4 region of the 16S ribosomal RNA gene, followed by amplicon sequence variant (ASV) analysis.
Results and discussion
Although the oral and gut microbiota are vastly different, a subset of 61 ASVs were present in both the oral cavity and gut of the same individual, and represented 1.6% of all ASVs detected. From these, 26 ASVs (classified into 18 genera: Actinomyces, Rothia, Bacteroides, Porphyromonas, Prevotella, Alistipes, Fusobacterium, Neisseria, Haemophilus, Akkermansia, Solobacterium, Granulicatella, Streptococcus, Gemella, Mogibacterium, Dialister, Veillonella, Christensenellaceae R-7 group) were present in both children and adults, suggesting the possibility of persistent colonization of both habitats by these microorganisms, initiating in childhood. Additionally, 62% of shared ASVs were more abundant in the oral cavity, indicating that oral-to-gut translocation may be the main route of translocation between environments, and highlighting that this phenomenon might be more common than previously thought in healthy individuals of all ages.
... A few studies have investigated the impact of aging on the gut microbiome, especially with regard to women's health and menopause. As women go through the menopausal transition, they are more likely to gain weight, and their gut microbiome composition shifts, implicating a pivotal role of sex hormones in shaping the gut microbiome [12]. This is further supported by the absence of sex differences in the gut microbiome before puberty [13]. ...
Background
Obesity, and in particular abdominal obesity, is associated with an increased risk of developing a variety of chronic diseases. Obesity, aging, and menopause are each associated with differential shifts in the gut microbiome. Obesity causes chronic low-grade inflammation due to increased lipopolysaccharide (LPS) levels which is termed “metabolic endotoxemia.” We examined the association of visceral adiposity tissue (VAT) area, circulating endotoxemia markers, and the gut bacterial microbiome in a cohort of aged postmenopausal women.
Methods
Fifty postmenopausal women (mean age 78.8 ± 5.3 years) who had existing adipose measurements via dual x-ray absorptiometry (DXA) were selected from the extremes of VAT: n = 25 with low VAT area (45.6 ± 12.5 cm²) and n = 25 with high VAT area (177.5 ± 31.3 cm²). Dietary intake used to estimate the Healthy Eating Index (HEI) score was assessed with a food frequency questionnaire. Plasma LPS, LPS-binding protein (LBP), anti-LPS antibodies, anti-flagellin antibodies, and anti-lipoteichoic acid (LTA) antibodies were measured by ELISA. Metagenomic sequencing was performed on fecal DNA. Female C57BL/6 mice consuming a high-fat or low-fat diet were treated with 0.4 mg/kg diet-derived fecal isolated LPS modeling metabolic endotoxemia, and metabolic outcomes were measured after 6 weeks.
Results
Women in the high VAT group showed increased Proteobacteria abundance and a lower Firmicutes/Bacteroidetes ratio. Plasma LBP concentration was positively associated with VAT area. Plasma anti-LPS, anti-LTA, and anti-flagellin IgA antibodies were significantly correlated with adiposity measurements. Women with high VAT showed significantly elevated LPS-expressing bacteria compared to low VAT women. Gut bacterial species that showed significant associations with both adiposity and inflammation (anti-LPS IgA and LBP) were Proteobacteria (Escherichia coli, Shigella spp., and Klebsiella spp.) and Veillonella atypica. Healthy eating index (HEI) scores negatively correlated with % body fat and anti-LPS IgA antibodies levels. Preclinical murine model showed that high-fat diet-fed mice administered a low-fat diet fecal-derived LPS displayed reduced body weight, decreased % body fat, and improved glucose tolerance test parameters when compared with saline-injected or high-fat diet fecal-derived LPS-treated groups consuming a high-fat diet.
Conclusions
Increased VAT in postmenopausal women is associated with elevated gut Proteobacteria abundance and immunogenic metabolic endotoxemia markers. Low-fat diet-derived fecal-isolated LPS improved metabolic parameters in high-fat diet-fed mice giving mechanistic insights into potential pro-health signaling mediated by under-acylated LPS isoforms.
7yVbQmTTfsF9b4Af3tznWNVideo Abstract
