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Menopause: The Journal of The North American Menopause Society
Vol. 28, No. 3, pp. 000-000
DOI: 10.1097/GME.0000000000001702
ß 2020 by The North American Menopause Society
PERSONAL PERSPECTIVE
Menopause, the gut microbiome, and weight gain: correlation
or causation?
Sarah L. Becker, BA,1 and JoAnn E. Manson, MD, DrPH, NCMP 2
Abstract
The gut microbiome is a key regulator of metabolism and influences the metabolism of estrogens, however, the
microbiome’s role in the changes in body composition and metabolic risk factors experienced by menopausal
women remains largely unexplored. Menopause has been shown to alter the gut microbiome, and rodent studies
suggest that microbiome changes postovariectomy are associated with increased adiposity, decreased metabolic
rate, and insulin resistance, changes attenuated by estrogen administration. Given these data, a deeper understanding
of the gut microbiome’s relationship to menopause-induced changes in body composition and metabolism is
warranted and may offer opportunity for novel therapeutic interventions.
The microbiome is central to both systemic and estrogen metabolism, and is altered by the menopausal transition,
suggesting an important role of the microbiome in the increased metabolic risk faced by menopausal women.
Although additional research is needed to establish a causal link, the interrelationship between menopause and the
gut microbiome may represent a new frontier to address menopause-related metabolic risk.
Key Words: Enterohepatic – Estrobolome – Menopause – Metabolic syndrome – Metabolism –
Microbiome.
E
strogens are essential hormones in regulating meta- shown to alter the gut microbiome as well, leading to
bolic status in premenopausal women. The decline in decreased microbial richness and diversity.10-12 In obese
estrogen levels during and after the menopausal postmenopausal women, several bacterial species have been
transition is often accompanied by a reduction in the meta- identified which are associated with metabolic risk factors
bolic rate, an increase in central adiposity, and a higher even after covariate adjustment for age, body fat, and diet,
prevalence of metabolic syndrome risk factors.1,2 Higher suggesting a causal role of the microbiome in the development
body mass index and adiposity are also associated with of obesity-related metabolic disease.13 Furthermore, estrogen
increased prevalence of vasomotor symptoms, one of the has been shown to increase gut epithelial integrity, and
primary menopause-related reasons women seek care.1,2 With menopause-induced estrogen deficiency may lead to an
the number of women over 50 years of age continuing to rise increase in epithelial permeability and bacterial translocation,
due to increased life expectancy, understanding how to treat, contributing to systemic inflammation, implicated in the
manage, and prevent adverse consequences of the menopausal development of obesity and metabolic syndrome.14-17
transition is increasingly important.3,4 Rodent studies provide additional insights into the potential
The microbiome is known to contribute to obesity and role of the microbiome in menopausal weight gain and meta-
metabolic syndrome, and transfer of microbial content from a bolic syndrome. Ovariectomized rats tend to eat more and
healthy donor to an obese recipient is able to abrogate these gain more weight than sham controls,18-20 an effect which is
conditions in both mice and humans.5-9 Menopause has been attenuated by estrogen receptor agonists.21 Ovariectomy in
rodents is also associated with a shift in the microbiota, with
an increased ratio of the phyla Firmicutes and Bacteroidetes
Received August 24, 2020; revised and accepted September 29, 2020.
From the 1Division of Gastroenterology, Brigham and Women’s Hospi-
in ovariectomized rats compared to sham nonovariectomized
tal, Harvard Medical School, Boston, MA; and 2Department of Medicine, controls.22,23 In particular, menopause-induced obesity produ-
Brigham and Women’s Hospital, Harvard Medical School, and Depart- ces unique changes to the composition of the gut microbiome
ment of Epidemiology, Harvard T.H. Chan School of Public Health, with differential changes in gene expression of estrogen signal-
Boston, MA.
Funding/support: None reported. ing pathways and metabolic pathways in mice who undergo
Financial disclosure/conflicts of interest: None reported. ovariectomy.10 In this study, which compared the effect of diet-
Address correspondence to: JoAnn E. Manson, MD, DrPH, Chief, induced versus ovariectomy-induced obesity on the gut micro-
Division of Preventive Medicine, Brigham and Women’s Hospital, biota, ovariectomized mice displayed a decrease in the number
Professor of Medicine and the Michael and Lee Bell Professor of
Women’s Health, Harvard Medical School, 900 Commonwealth Ave- of bacteria and in alpha diversity compared to control animals
nue, 3rd fl, Boston, MA 02215. E-mail: jmanson@rics.bwh.harvard.edu who underwent a sham procedure.10 High-fat diet feeding
Menopause, Vol. 28, No. 3, 2021 1
Copyright ß 2021 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.BECKER AND MANSON
resulted in a similar microbiota composition to that of animals metabolic syndrome.23 Taken together, this suggests estrogen
who underwent ovariectomy with the exception of an increased exerts an effect on the gut microbiome concurrent with a
abundance of Bifidobacterium animalis solely in ovariecto- reduction in the metabolic and vasomotor changes associated
mized animals, a species correlated with the expression of with declining estrogens during menopause.
female hormone metabolism genes.10 Is the interplay between estrogen and the microbiome bidi-
Similarly, gut microbiome diversity is protected by low- rectional, with the microbiome itself regulating estrogen
dose estrogen supplementation in ovariectomized rats and metabolism? Estrogen is primarily metabolized in the liver
prevents the onset of menopause-associated weight gain, where it is hydroxylated and conjugated before being excreted
decreased daily energy expenditure, impaired glucose toler- in the bile to enter the enterohepatic circulation.25-27 Once in the
ance, and insulin resistance.24 In a study by Park and Kim distal gut, estrogens in the bile are deconjugated by bacterial
et al, ovariectomized rats displayed a decrease in microbial enzymes allowing for reabsorption through the mucosa
richness which was prevented by low-dose intracerebroven- and subsequent re-entry into the systemic circulation.28-32
tricular estrogen administration. Comparisons of bacterial The primary deconjugators of enteric estrogens are bacterial
distribution by principle coordinate analysis showed ovariec- b-D-glucuronidases, which decrease fecal estrogen excretion.
tomized animals clustered separately from those who received It has been estimated that between 33% and 50% of circulating
estrogen (17b-estradiol or conjugated equine estrogens), or estrogens are incorporated into the bile, with up to 80% of these
controls who underwent sham ovariectomy surgery, suggest- estrogens then reabsorbed into the intestinal tract.30,33 Such
ing a difference in the diversity of ovariectomized animals reabsorption is thought to extend the activity of these estrogens
compared to those who received hormone therapies or who in the body, leading to increased serum levels of estrogen
were not menopausal.24 No major differences in effect on metabolites.34
microbial diversity were observed between estrogen formu- The gut microbiome modulates this system through the
lations. Additionally, estrogen supplementation was shown to estrobolome, the specific intestinal microbes in the gut that
reduce vasomotor changes including a reduction in tail vein encode for enzymes capable of deconjugating estrogens28
temperature, a proxy for hot flashes, and conferred a nonsig- (Figure 1). Dietary compounds may also bind directly to
nificant benefit to memory function.24 Other rodent studies estrogen receptors in the gut lumen, regulating target genes
support this work, finding that estrogen supplementation through transcriptional activation or repression, and influenc-
in the form of 17b-estradiol modifies the gut microbiome, ing intracellular signaling pathways as well as nongenomic
with changes associated with a decreased susceptibility to activity through receptor binding in the plasma membrane and
Eubiosis
↑ Bacterial diversity
↑ Short-chain fatty acid
production
↑ Gut epithelial integrity ↓ Inflammation
↑ Deconjugated ↓ Risk of adiposity
Menopause and metabolic
estrogens
↑ Intestinal reabsorption syndrome
↓Serum Estrobolome
of estrogens
estrogens
↑ β-D-glucuronidase
↑Risk of adiposity
activity
and metabolic
syndrome
Dysbiosis
Factors influencing gut
microbiota: ↓Bacterial diversity
↓Short-chain fatty acid ↑ Inflammation
Diet production ↑ Risk of adiposity
Xenoestrogens ↑ Gut permeability and metabolic
Antibiotics ↓ Glucose tolerance syndrome
Host genetics ↓β-D-glucuronidase
Probiotics activity
Fecal Microbiota Transfer (FMT) ↑Fecal hormone excretion
FIG. 1. Relationship between menopause and gut microbiome. Menopause decreases serum estrogens produced in the ovaries, adrenal glands, and
adipose tissues. These estrogens circulate in the body and are excreted in their conjugated form or can be deconjugated by bacteria in the intestinal tract
and reabsorbed. Known as the ‘‘estrobolome,’’ the gut bacteria which facilitate deconjugation and reabsorption are influenced by numerous host factors
and their activity is central to the regulation of systemic hormone levels and risk of menopause-related metabolic changes. Causal relationships are
denoted with black arrows, correlative relationships are denoted with red arrows.
2 Menopause, Vol. 28, No. 3, 2021 ß 2021 The North American Menopause Society
Copyright ß 2021 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.MENOPAUSE, THE GUT MICROBIOME, AND ADIPOSITY
second messenger signaling.35,36 Gut microbial diversity is inter-individual variation of such effects.52 Between 25% and
correlated with high levels of urinary estrogen metabo- 60% of individuals are known to produce equol from isoflavones,
lites37,38 (Figure 1). Perturbing the gut microbiota through a variance hypothesized to be influenced by diet leading to
administration of antibiotics has been shown to decrease the presence or absence of equol-producing bacteria.53-55 In
urinary estrogen metabolites and increase fecal estrogen postmenopausal women, equol phenotype has been inconsis-
excretion by 18 fold, indicating a reduced capacity of a tently associated with serum estrogen levels and adiposity,56-58
dysbiotic gut microbiota for deconjugation and resulting in however, it does appear to be associated with a diverse micro-
conjugated estrogens being excreted in the feces instead of biome in postmenopausal women.55 Additional research is needed
being reabsorbed into enterohepatic circulation.34 This study in postmenopausal women to understand the determinants of
was performed in pregnant women, suggesting a need for the equol production and validate the benefits of such production
study of this process in menopause and other life stages. to inform the use of isoflavones as a potential therapeutic.
However, changes to the microbiome due to menopause are Another approach to harnessing the microbiome to improve
supported by observations of decreased enterohepatic estrogen metabolic health in menopausal women and warranting fur-
recycling among women who are infertile due to endocrine ther investigation is the use of oral pre- or probiotic treat-
causes and who excrete lower urinary levels of estrogen ments. Specific strains of probiotics have been shown to
metabolites compared to fertile women.39 Additional research modulate b-D-glucuronidase activity, and prebiotics high
is needed to understand the effect of menopause-related endo- in fermentable fibers are able to improve some markers of
crine deficiencies specifically on enterohepatic circulation and metabolic health.59-61 Prebiotic administration in rats has
on the estrobolome’s capacity for deconjugation. Moreover, been shown to reduce weight gain after ovariectomy, decrease
there is likely substantial interindividual variation in the activ- fat oxidation, and improve glucose tolerance, as well as
ity of bacterial enzymes responsible for deconjugation,40 which reduce vasomotor changes.62,63 Such studies are promising,
combined with differences in diet, body weight, and other but additional research is needed to optimize enzyme activity,
factors affecting the microbiome, may contribute to differences determine appropriate dosing, and to identify the gut microbes
in menopause-associated changes in body composition, that must be present to elicit such a response.
adiposity, and risk of metabolic syndrome between individuals.
Given emerging evidence for a role of the microbiome in CONCLUSION
regulating both adiposity and systemic estrogen levels, under- We propose that the interrelationship between menopause,
standing how the microbiome can be utilized in a therapeutic the gut microbiome, adiposity, and metabolic health is an
capacity during and after the menopausal transition is of great exciting new frontier that warrants further study. The inter-
clinical interest. A start may be what we feed our bodies and thus, play of these systems suggest an opportunity for future
our microbiomes. Diet has been shown to be a stronger driver of clinical interventions such as pre- or probiotic therapy or
microbiome composition than adiposity or estrogen levels and dietary modifications to support and enhance the gut micro-
can be easily modified through food choices. An example is biota during and after the menopausal transition, although
higher intake of dietary fiber, which has been shown to exert a additional research into the estrogen-gut axis is needed to
protective effect on intestinal mucosal integrity and risk of establish causality. We encourage further research to better
obesity in rodent models.41-43 In addition to its effects on gut understand the role of the microbiome in the menopausal
and metabolic health, diet can also serve as a source of phytoes- transition and as an untapped resource that may have preven-
trogens, such as the naturally occurring isoflavones found in soy tive and therapeutic potential.
products, as well as the lignans and coumestans found in
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