biology

Review
The Gut Microbiome and Female Health
Ruqaiyyah Siddiqui 1,2 , Zinb Makhlouf 1, Ahmad M. Alharbi 3, Hasan Alfahemi 4 and Naveed Ahmed Khan 2,5,*

1 College of Arts and Sciences, American University of Sharjah, University City,

Sharjah 26666, United Arab Emirates
2 Department of Medical Biology, Faculty of Medicine, Istinye University, Istanbul 34010, Turkey
3 Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University,
Taif 21944, Saudi Arabia
4 Department of Medical Microbiology, Faculty of Medicine, Al-Baha University, Al-Baha 65799, Saudi Arabia
5 Department of Clinical Sciences, College of Medicine, University of Sharjah, University City,
Sharjah 27272, United Arab Emirates
* Correspondence: [email protected]

Simple Summary: A plethora of studies have highlighted the profound role of the gut microbiome
in human health. However, there is a lack of studies on female health. Given that females may
be more likely to be affected by some ailments such as osteoarthritis, heart disease, cancer, and
anxiety, it is imperative to study the effect of the gut microbiome and its role in female health. It is
evident that the presence/ratio of microbial species is altered in polycystic ovarian syndrome, cancer,
pregnancy, and menopause. Thus, potential probiotics should be developed and the administration of
certain bacterial species should be considered, as novel independent or adjunct therapies for various
female-related pathologies. Strategies such as the modulation of the gut microbiome via diet and
through supplementation with pre/pro/postbiotics in various female health-related issues should
be undertaken.

Abstract: The possession of two X chromosomes may come with the risk of various illnesses, females
are more likely to be affected by osteoarthritis, heart disease, and anxiety. Given the reported correla-
Citation: Siddiqui, R.; Makhlouf, Z.; tions between gut microbiome dysbiosis and various illnesses, the female gut microbiome is worthy
Alharbi, A.M.; Alfahemi, H.; Khan, of exploration. Herein, we discuss the composition of the female gut microbiota and its dysbiosis
N.A. The Gut Microbiome and in pathologies affecting the female population. Using PubMed, we performed a literature search,
Female Health. Biology 2022, 11, 1683.
using key terms, namely: “gut microbiome”, “estrogen”, “menopause”, “polycystic ovarian syn-
https://doi.org/10.3390/
drome”, “pregnancy”, and “menstruation”. In polycystic ovarian syndrome (PCOS), the abundance
biology11111683
of Bacteroides vulgatus, Firmicutes, Streptococcus, and the ratio of Escherichia/Shigella was found to be
Academic Editor: Thomas Caspari increased while that of Tenericutes ML615J-28, Tenericutes 124-7, Akkermansia, Ruminococcaceae, and
Bacteroidetes S24-7 was reduced. In breast cancer, the abundance of Clostridiales was enhanced, while
Received: 25 October 2022
Accepted: 16 November 2022
in cervical cancer, Prevotella, Porphyromonas, and Dialister were enhanced but Bacteroides, Alistipes, and
Published: 21 November 2022 members of Lachnospiracea, were decreased. In ovarian cancer, Prevotella abundance was increased.
Interestingly, the administration of Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus reuteri,
Publisher’s Note: MDPI stays neutral
and Lactobacillus fermentum ameliorated PCOS symptoms while that of a mix of Bifidobacterium lactis
with regard to jurisdictional claims in
W51, Bifidobacterium bifidum W23, Lactobacillus brevis W63, Bifidobacterium lactis W52, Lactobacillus sali-
published maps and institutional affil-
varius W24, Lactobacillus acidophilus W37, Lactococcus lactis W19, Lactobacillus casei W56, and Lactococcus
iations.
lactis W58 alleviated vascular malfunction and arterial stiffness in obese postmenopausal women,
and finally, while further research is needed, Prevotella maybe protective against postmenopausal
bone mass loss. As several studies report the therapeutic potential of probiotics and since the gut
Copyright: © 2022 by the authors. microbiota of certain female pathological states has been relatively characterized, we speculate that
Licensee MDPI, Basel, Switzerland. the administration of certain bacterial species as probiotics is warranted, as novel independent or
This article is an open access article adjunct therapies for various female pathologies.
distributed under the terms and
conditions of the Creative Commons
Keywords: gut microbiota; estrobolome; estrogen; probiotic; gut dysbiosis
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).

Biology 2022, 11, 1683. https://doi.org/10.3390/biology11111683 https://www.mdpi.com/journal/biology

Biology 2022, 11, 1683 2 of 17

1. Introduction
An increasing body of research highlights the importance of gender differences in
the epidemiology, pathophysiology, and treatment of various diseases, especially non-
communicable diseases [1]. Furthermore, females are at a greater risk of suffering from
osteoarthritis, heart disease, urinary tract problems, stroke, depression, and anxiety [2].
However, although females comprise almost half of the human population, there is a
reported discrepancy in the presentation of the genders in health studies [3]. Moreover,
women are underrepresented, and their physical complaints are trivialized [4,5]. Hence,
many organizations call upon the inclusion of gender as a dimension in clinical trials [1].
Aside from obvious physical differences, the two genders are reported to have composi-
tional differences in their gut microbiome [6]. Namely, a study employing 348 male and
341 female mice from 89 matched strains reported marked abundance differences among
several taxa between the sexes, and a larger number of differences were observed at the
single strain level [7]. A bidirectional relationship is established between host hormones
and the host’s gut microbiome. Moreover, sex hormones can affect bacterial growth and vir-
ulence. Namely, the sex hormones estriol and estradiol inhibit bacterial virulence through
hindering quorum sensing while progesterone was shown to enhance the growth of oral
Bacteroides species and Prevotella intermedius [8]. Interestingly, some studies also imply that
commensal microbiota can influence and modulate sex hormone levels [7]. While we still
cannot define what a healthy gut microbiome is, gut microbial dysbiosis has been correlated
with various diseases ranging from irritable bowel syndrome to cancer [9–12]. In light of the
reported associations between the gut microbiome and overall human health, coupled with
the disproportionately higher risk females are under for various diseases, the female gut
microbiome is a topic worthy of investigation. Using PubMed as a database, we searched
the literature using key terms, namely “gut microbiome”, “estrogen”, “menopause”, “poly-
cystic ovarian syndrome”, “pregnancy”, and “menstruation” and a time interval ranging
from 2012 to 2022 with a focus on recent studies. Herein, we review and describe the
composition of the healthy female gut microbiome, the potential role of the gut microbiota
and its dysbiosis in female diseases such as polycystic ovaries syndrome (PCOS) and female
cancers, and otherwise, normal female physiology, namely, pregnancy, menstruation, and
menopause, and finally the importance of the gut microbiota in postmenopausal health
and postmenopausal illnesses.

2. Gut Microbiome in Healthy Females

Gender-dependent differences in the gut microbiome have been reported [9]. Women’s
gut microbiome composition markedly differs from men’s [13,14]. As depicted in Figure 1,
women are reported to have a lower Bacteroides abundance but higher α diversity, a measure
of diversity within an individual sample [13–15]. Female sex hormone levels affect the
microbiota composition [16]. However, this influence is bidirectional. This is because the
microbiome regulates steroid hormone levels including estrogens [17]. In a clinical trial
employing 25 men, 7 postmenopausal women, and 19 premenopausal women, results
imply that the intestinal microbiome indeed affects systemic estrogen levels [18]. Another
study reports that gut microbial diversity is positively correlated with estrogen metabolites
to parent estrogen ratio in a group of postmenopausal women [17]. However, further
studies with a larger and more inclusive population should be carried out to investigate
this linkage in women before menopause. Certain enteric bacteria, whose genome is called
the estrobolome, metabolize estrogens [17,19]. To be excreted, estrogens are hepatically
conjugated through glucuronidation or sulfonation [19]. These estrobolome bacterial
species with their ß-glucuronidase activity can deconjugate excreted estrogens in the bile
and prevent their excretion [17,19]. This may explain why fecal glucuronidase levels
were reported to be inversely associated with gut estrogen levels [18]. The human gut
also carries out various local and distant functions through hormonal metabolites and
intermediates [19]. Remarkably, gut microbes also carry out the synthesis of estrogen-
like compounds from nutrition [17]. In healthy females, probiotic administration has
Biology 2022, 11, 1683 3 of 17

shown promise. While probiotic administration fails to engender persistent gut microbiota
changes, it has been reported to improve vaginal lactobacilli concentration, female health
system bowel movement, and immune system responses in healthy adults [20]. Moreover,
probiotics help enhance local vaginal immunity and maintain female reproductive tract
health [21]. Notably, certain bacterial strains, namely, Lactobacillus strains have been shown
to prevent the recurrence of urinary tract infections and bacterial vaginosis [22,23].

Figure 1. The role of gut microbiome in female health.

3. Gut Microbiome and PCOS

PCOS affects 8–13% of women worldwide in their reproductive age [24]. While the
clinical phenotype may vary, insulin resistance and hyperandrogenism are the hallmarks of
PCOS [25]. The gut microbiome of PCOS sufferers differs from that of controls [26]. As can
be seen in Table 1 and Figure 1, PCOS patients have a less diverse gut microbiome, which is
correlated with hyperandrogenism [25,27,28]. In a clinical trial, 43 healthy females and 50
PCOS patients were employed, taking into consideration the influence of body weight [26].
While Alpha (α) diversity was comparable in both groups, Beta (β) diversity, a measure
of diversity among different samples, was markedly decreased in the gut microbiota of
PCOS patients [15,26]. Conversely, a study reports that α diversity is altered in PCOS
patients’ guts [29]. Another study confirms the alteration by reporting a decrease in α
diversity in the guts of women with PCOS [30]. Notably, the abundance of a Bacteroides
species responsible for the deconjugation of conjugated bile acids synthesized in the liver,
Bacteroides vulgatus (B. vulgatus), was significantly higher in women with PCOS than in the
controls [26]. Firmicutes, a phylum correlated with obesity, is also more abundant in PCOS
patients while Tenericutes ML615J-28, Tenericutes 124-7, and Bacteroidetes S24-7 levels are
reduced [25,27,28]. An increase in streptococcus and the ratio of Escherichia/Shigella was also
reported in the gut of women with PCOS [25]. Opposingly, it was found that Akkermansia,
a species reported to modulate energy metabolism and glucose tolerance in humans, and
Ruminococcaceae, were less abundant in PCOS patients [25,31].
Biology 2022, 11, 1683 4 of 17

Table 1. The impact of gut microbiota on female health.

Condition Dysbiosis Strains Increased Strains Decreased References

Little is known about the
relationship between
Menstruation [32]
menstruation and the
gut microbiome.
Gut microbial changes Actinobacteria,
SCFA producers and in
Pregnancy mediated by gestational Proteobacteria, and [33–36]
overall species richness
hormonal changes opportunistic pathogens
positive immune
antibody-associated Unreported Blautia and Bacteroides None reported [37]
miscarriage
Lactobacillus and
Perimenopause Present Enterobacter [38]
Bifidobacteria
Grows in resemblance to
Postmenopause Conflicting results Conflicting results [38–40]
male gut microbiome
PrevotellaStudies report
Postmenopause-associated decreased bacterial unclassified Clostridia
conflicting results [41–44]
bone diseases richness and diversity and methanogenic archaea
on Bacteroides
Tenericutes ML615J-28,
Bacteroides vulgatus,
Tenericutes 124-7,
Present with Firmicutes, Streptococcus,
PCOS Akkermansia, [25–28,30,31]
decreased diversity and the ratio of
Ruminococcaceae, and
Escherichia/Shigella
Bacteroidetes S24-7
Present with a decrease
Breast cancer Clostridiales None reported [45]
in diversity
Prevotella, yet the effects
Ovarian cancer Present of chemotherapy have None reported [46]
not been accounted for.
Proteobacteria, Prevotella, Bacteroides, Alistipes,
Present with changes in
Cervical cancer Porphyromonas, and and members of the [47]
diversity
Dialister Lachnospiracea

Some clinical trials imply a lack of association between the disruption of the estrous cy-
cle and microbiome in PCOS [48]. However, studies have reported that the gut microbiome
is involved in the clinical manifestation of PCOS [28,49,50]. Murine studies report that gut
microbiome indeed alters female physiology. After oral–fecal transplantation from the gut
microbiota of PCOS individuals, mice exhibited insulin resistance, disrupted estrous cycle,
higher number of cyst-like follicles, fewer corpora lutea, and elevated testosterone and
luteinizing hormone than the controls [26]. Remarkably, these mice produced fewer pups
after the oral lavage [26]. In humans, it was reported that the serum insulin level in PCOS
patients was markedly correlated with various intestinal bacteria including Collinsella [25].
A disordered gut microbiome is correlated with obesity and more than half of PCOS pa-
tients are obese [28]. Consequently, correlations between obesity associated with PCOS
and the gut microbiome were described. In a recent clinical trial, [25] it was reported
that the abundance of Tenericutes in obese PCOS patients and control obese individuals
was comparable. However, β diversity differences have been reported in non-obese and
obese PCOS patients, which were not observed between obese and non-obese control
individuals [28]. Thus, gut microbiome disturbances may be a factor in obesity specifically
associated with PCOS.
There are various mechanisms behind the gut microbes’ participation in the clini-
cal course of PCOS. Bile acids endorse the digestion and absorption of fat-soluble sub-
stances [28]. However, bacteria are crucial to bile acid transformation [28]. The gut
Biology 2022, 11, 1683 5 of 17

microbiome influences host metabolism through interactions with host signaling path-
ways [26,29]. For instance, changes in the microbiome of PCOS patients affect bile acid
metabolism [26,29]. Specifically, levels of the bile acids: glycodeoxycholic acid (GDCA)
and tauroursodeoxycholic acid (TUDCA) were decreased in the stool and serum of PCOS
patients [26]. Remarkably, the abundance of B. vulgatus was negatively correlated with that
of GDCA and TUDCA [26]. Furthermore, B. vulgatus species in PCOS patients exhibited a
higher abundance of bile salt hydrolase genes than controls [26]. Hence, the gut microbiome
influences its host metabolism.
Through the decomposition of organic material, gut microbes produce short-chain
fatty acids (SCFA) and other metabolites to supply the host with energy [28]. SCFAs
regulate glucose uptake and fatty acid oxidation through activating peroxisome proliferator-
activated receptor gamma (PPAR-γ) in the liver and muscles [28]. Notably, SCFAs bind to
free fatty acid receptors FFAR-2 and FFAR-3 leading to the inhibition of appetite stimulating
hormone [28]. This inhibition hinders the secretion and transformation of sex hormones,
specifically the transformation of androgen to estrogen [28]. Secondly, gut microbes can
affect insulin sensitivity through branched short amino acids (BCAA). An increase in
BCAAs has been associated with the development of diabetes type 2 [24,28]. Gut bacteria
from the genus provotella are BCAAs synthesizers [28]. Thus, an increase in these bacteria
may lead to insulin resistance. In [25] it is reported that the gut microbiome of obese PCOS
patients employed in their clinical trial harbored Paraprevotella and Alloprevotella.
Lipopolysaccharides (LPS) are a cell wall constituent in Gram-negative bacteria such
as Bacteroides [28]. After their absorbance to the blood, LPS can bind to Toll-like re-
ceptor 4 and activate signaling pathways that affect insulin sensitivity and, ultimately,
lead to insulin resistance [28]. After being fermented by the gut microbiota to trimethy-
lamine, the nutrient choline is hepatically metabolized to trimethylamine oxide (TMAO),
an osmotic substance involved in regulating insulin resistance [28]. Thus, an increase in
trimethylamine-producing bacteria leads to higher TMAO levels, which may aggravate
PCOS [28]. Further work is warranted to elucidate the precise role of the gut microbiome
in PCOS. Future studies should be carried out to develop therapies that modulate the gut
microbiome in order to alleviate or prevent PCOS.

4. Gut Microbiome and Cancer

Disturbances in the gut microbiome have been associated with and observed in vari-
ous cancers including gastric, colorectal, hepatic, pancreatic, and prostate cancer [51–53].
Interestingly, in pancreatic cancer and melanoma murine models, a significant decrease
in subcutaneous tumor burden was observed after depleting the gut microbiome through
antibiotic administration [51]. Dysbiosis of the gut microbiota is also observed in various
cancers affecting the female population including breast, cervical, and ovarian cancer as
depicted in Table 1 and Figure 1 [45–47]. Furthermore, some studies imply a decrease
in the diversity of the gut microbiota and an increase in the abundance of Clostridiales in
breast cancer patients [45]. An analysis of the gut microbiota of postmenopausal women
with breast cancer reveals that while the differences in relative species abundance in gut
microbiota between premenopausal breast cancer patients and premenopausal controls
was negligible, 45 species differed significantly in their relative abundance between post-
menopausal patients and postmenopausal controls [54]. Moreover, in postmenopausal
cancer patients, 38 species were overrepresented such as Escherichia coli, Actinomyces sp.
HPA0247, Klebsiella sp_1_1_55, Prevotella amnii, and Shewanella. A study revealed that α and
β diversity differed significantly between employed cervical cancer patients and cancer-free
women [47]. Additionally, the study disclosed that cervical cancer patients had higher
levels of Prevotella, Porphyromonas, and Dialister while cancer-free individuals had greater
levels of Bacteroides, Alistipes, and members of the Lachnospiracea than controls [47]. In ovar-
ian cancer patients, a shared increase in Prevotella regardless of platinum sensitivity was
observed, but the study was unable to count for the potential effects of chemotherapy [46].
Biology 2022, 11, 1683 6 of 17

Aside from regulating the host’s immune system, the gut microbiome is involved
in both oncogenesis and the suppression of malignant transformation [51,55]. Further-
more, bacterial metabolites produced by the gut microbiome also regulate cancer cell
metabolism [45,56]. These secreted bacterial metabolites act like hormones since they can
enter the circulation, reach far targets, and carry out important functions such as impacting
mitochondrial metabolism and modulating the behavior of breast cancer cells, lithocholic
acid (LCA), SCFAs, cadaverine, and deconjugated estrogens [45,56]. As mentioned in the
previous section, the gut microbiome is an important player in estrogen metabolism. Since
80% of breast cancer cases are estrogen receptor-positive, the deconjugation of estrogens
by the gut microbiome is of relevance [19,57–61]. Aside from being more abundant in the
gut of breast cancer patients, Clostridiales reactivates estrogens and increases their serum
levels [45]. Estrogen receptors play a direct role in the expression of nuclear-coded mito-
chondrial proteins [45]. An increase in oxidative phosphorylation promotes metastasis [45].
The gut microbiome also synthesizes estrogen-like compounds from dietary sources [17].
The gut microbiome generates the SCFAs: formate, acetate, propionate, butyrate, and
lactate, through the fermentation of non-digestible carbohydrates and in minute amounts
through amino acid degradation [45]. With receptors on cancer and stromal cells, SCFAs
regulate various cancer hallmarks such as cell proliferation, gene expression, cell invasion,
apoptosis, and metabolism in breast cancer [45]. SCFAs in general can serve as energy
substrates for cancer cells [45]. Interestingly, sodium butyrate drives oxygen consumption
in breast cancer cell lines and inhibits lactate metabolism, markedly decreasing breast
cancer cell viability [45]. The anaerobic bacteria Clostridiales are mainly responsible for
bile acid transformation [45]. At the serum level, the secondary bile acid LCA exhibits
an antineoplastic effect on breast cancer cells, regulates oxidative phosphorylation, and
inhibits proliferation [45]. Remarkably, the gut microbiota of breast cancer patients dis-
played a reduced ability to synthesize LCA [45]. Gut bacteria including Shigella flexneri,
Shigella sonnei, Escherichia coli, and Streptococci carry out the biosynthesis of cadaverine
from lysine [45]. Cadaverine is important because it hinders cell proliferation and tumor
infiltration [45]. Interestingly, cadaverine was ineffective on primary untransformed cells
and the microbiome’s capacity to synthesize cadaverine is decreased in breast cancer pa-
tients [45]. The link between the gut microbiota and gynecological cancers requires further
study [62] However, just like breast cancer, ovarian cancer is correlated with estrogen ab-
normalities [62]. In cervical cancer patients, gut microbiota profiles and β diversity differed
markedly from cancer-free women [63]. Namely, the Proteobacteria phylum was significantly
more abundant in cervical cancer patients [63]. Thus, gut microbial modulation should be
considered as a therapeutic option or at the very least an additional therapeutic strategy in
tandem with traditional cancer therapies.

5. Gut Microbiome and Pregnancy

Aside from infant health, evidence indicates that maternal microbiome niches influ-
ence maternal well-being and post-partum recovery [64]. Furthermore, gut microbiome
disturbances have been linked with the clinical characteristics of preeclampsia, a pregnancy
complication characterized by high blood pressure, and some even hypothesize that there
is a link between the maternal gut microbiome and postpartum depression [64,65]. In fact,
a Chinese herbal medicine has been shown to ameliorate postpartum depression through
modulating the gut microbiota [66]. A study also indicates that the maternal gut micro-
biome may play a part in the immunological adaptations accompanying pregnancy, as
shown in Table 1 and Figure 1 [67]. Interestingly, an investigation of gut microbiota changes
in patients with positive immune antibody-associated recurrent miscarriage reveals that
some highly abundant genera, such as Blautia and Bacteroides, may be incriminated in
recurrent miscarriage [37]. Bidirectional interactions between the gut microbiome and
pregnancy have been reported. For instance, bacterial growth can be influenced by hor-
monal changes [68,69]. Moreover, gut microbial changes during pregnancy are mediated
by hormonal changes accompanying gestation [33,34]. Namely, it has been reported that
Biology 2022, 11, 1683 7 of 17

fecal progesterone levels were negatively correlated with diversity during pregnancy [34].
Notably, profound alterations in the microbial profile of the gut microbiome have been
observed during the progression of pregnancy such as an increase in Actinobacteria, Pro-
teobacteria, and opportunistic pathogens, and a decrease in SCFA producers and in overall
species richness [35,36].
In humans, an analysis of the gut microbiome of thirty-five women in their first
and third trimesters of pregnancy reveals that Bifidobacterium, Blautia, unclassified Ru-
minococcaceae, Bacteroides, unclassified Lachnospiraceae, unclassified Clostridiales, Akkermansia,
Faecalibacterium, Ruminococcus, and Prevotella were the generally dominant bacterial species.
Interestingly, Bifidobacterium is crucial for human milk oligosaccharide degradation and
Prevotella metabolizes estradiol and progesterone [36]. Differences were also observed
between the two semesters. Furthermore, Bifidobacterium, Neisseria, Blautia, and Collinsella
increased most significantly in the third semester while Dehalobacterium, Clostridium, and
Bacteroidales were markedly higher in the first [36]. Another report disclosed that maternal
microbiome biodiversity changes with the progression of pregnancy and is associated
with gestational weight gain [70]. While studies imply that gut microbiota changes dra-
matically such as an increase in lactic acid-producing bacteria coupled with a decrease
in butyrate-producing bacteria, a recent analysis conducted on Japanese women during
early and late pregnancy negates differences between late and early pregnancy microbial
composition and reveals that the recruited women did not show notable differences in
gut microbiota related to pregnancy, except for the phylum TM7, which decreased in late
pregnancy [71,72]. Similarly, another study confirms a lack of difference and mentions that
the study carried out by [35], which reported significant changes associated with pregnancy,
recruited women who were consuming probiotic supplementation [73]. Interestingly, stud-
ies imply that pregnancy-induced changes in the female gut microbiome occurring at the
onset of pregnancy may be vulnerable to modulation by diet while being independent
of maternal weight gain and even the number of successive pregnancies [74,75]. Thus,
in late pregnancy, the microbiota readjusts carbohydrate-related functions expression in
consistency with the high glucose availability [76]. Notably, the microbiome of pregnant
women can also bring about metabolic alterations in germ-free hosts. Furthermore, a
study disclosed that fecal transplantation from pregnant women to germ-free mice induced
greater adiposity and insulin insensitivity [35]. Given the plethora of studies indicative of
the effect of the gut microbiome in pregnancy, further work is warranted to comprehend a
more detailed mechanistic understanding as well as work to develop pre/pro/postbiotics
for pregnant women.
Similarly, animal studies reported changes in gut microbiota accompanying pregnancy.
In pigs, different stages of pregnancy brought about distinct changes in the abundance of
Tenericutes, Fibrobacteres, and Cyanobacteria [33]. Overall, the α diversity values of the gut
microbiota and the abundance of Clostridiales, Desulfovibrio, Mogibacteriaceae, and Prevotella
increased over the course of pregnancy only to decrease at weaning [33]. The progression
of pregnancy markedly affected the beta diversity of the gut microbiota and modified the
abundance of multiple carbohydrate-degradation bacteria: Bacteroides, Prevotella, Parabac-
teroides, and Succinivibrio [33]. Another study conducted on sows reveals changes in the gut
microbiota across the perinatal period with variance in microbial function and abundance
between the prenatal and postnatal periods where the alpha diversity was higher in the
latter [77]. Furthermore, Akkermansia, Desulfovibrio, Methanobrevibacter, and Turicibacter were
enriched in the prenatal period while Actinobacillus, Acidaminococcus, Megasphaera, Eubac-
terium, Butyricimonas, Paludibacter, Rummeliibacillus, and Succiniclasticum were enriched in
the postnatal period. The changes in gut microbiota accompanying cow parturition were
investigated through 16S rRNA and metagenomic sequencing, revealing notable changes
in the gut microbiome throughout the late pregnancy to the postpartum stage [78]. During
late pregnancy, Lactobacillus, Streptococcus, and Clostridium were enriched while Bacteroides,
Escherichia, and Campylobacter were more abundant at postpartum [78]. Similarly, a study
reports substantial remodeling of sow gut microbiota during the late stages of pregnancy
Biology 2022, 11, 1683 8 of 17

to the postpartum stage [69]. Furthermore, the gut bacterial richness of both pregnant
and delivery sows decreased markedly while the β-diversity notably expanded [69]. The
relative abundance of Lactobacillus notably increased from the late pregnancy to the post-
partum stage while the Bacteroidetes to Firmicutes ratio and the relative Prevotella abundance
decreased [69]. An investigation of gut microbiota composition alterations across different
reproductive periods of Tibetan macaques wild females revealed nonnegligible deviations
in taxonomic structure, composition, and potential functions of gut microbes [79]. The
study revealed an increase in the relative abundance of Proteobacteria during pregnancy
and lactation, and an overrepresentation of the relative abundance of Succinivibrionaceae
and Bifidobacteriaceae in pregnant and lactating females, respectively [79].

6. Changes in Gut Microbiome during the Menstrual Cycle

The menstrual cycle extends 28 ± 4 days and is comprised of the follicular, luteal, and
menstrual phases [80,81]. The menstrual cycle is accompanied by significant hormonal
fluctuations. Moreover, the level of the steroid hormone estrogen soars in the middle
of the follicular phase, drops after ovulation, and rises back again in the early luteal
phase [80]. The early luteal phase is also characterized by an increase in the progesterone
level [81]. The sudden drop in these two hormones in the late luteal phase brings about
menses [81]. Many healthy females report variations in gastrointestinal (GI) symptoms
during their menstrual cycle, which may be deduced to the presence of sex hormone
receptors along the GI tract [81]. For instance, a study investigating the relationship
between menstrual cycle phase, daily stool number, and consistency reveals looser stool
consistency in the early menstrual period in comparison to midcycle in six out of the seven
employed participants [82]. However, studies investigating GI transit throughout the
menstrual cycle produce contradicting results. Furthermore, some disclose an increase in
transit time during the luteal phase, accompanying the increased progesterone levels while
others negate any change [13,83,84].
Hormonal fluctuations may impose pressures on the function and composition of the
human microbiome [85]. Namely, the gut microbiome is reported to be influenced by estro-
gen [86]. Furthermore, estrogen levels are associated with gut microbiome alpha diversity
and fecal Clostrdia taxa [13]. Given the influence estrogen has on the gut microbiome, the
potential link between the GI disturbances and menstruation may potentially be mediated
by the gut microbiome. The gut microbiota is also reported to be affected by the steroid
hormone progesterone. A study reports the amelioration of depression and anxiety-like
behaviors accompanying the premenstrual, post-partum, and premenopausal periods by
progesterone in mice [84]. However, that effect was undermined by antibiotic treatment,
indicating that this improvement is mediated through progesterone’s enhancing effect on
Lactobacillus reuteri growth [84].
The influence between sex hormones and the gut microbiome is bidirectional. More-
over, bacteria can metabolize sex hormones through various enzymes such as hydroxys-
teroid dehydrogenase, regulating the balance between active and inactive steroids [80].
Namely, fecal bacteria carry out hydrolytic reductive and oxidative reactions of androgens
and estrogen [80]. Furthermore, the gut microbiome markedly influences estrogen lev-
els [86]. This is through the gut microbiome’s secretion of β-glucuronidase, which is the
enzyme responsible for estrogen deconjugation [86]. A decrease in the gut microbiome
diversity affects β-glucuronidase activity adversely, lowering estrogen levels [13]. Since
estrogen is only biologically active if deconjugated, this deconjugation enables estrogen to
bind to its receptors: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) [86,87].
Estrogen is crucial for homeostasis in healthy premenopausal women and its decrease
accompanying menopause drives metabolic rate reduction and weight gain, yet it also
stimulates epithelial proliferation within the female reproductive tract, driving various
proliferative diseases such as uterine fibroids and endometriosis [86,87]. This engendered
the hypothesis that the gut microbiome of endometriosis patients may have higher densities
of β-glucuronidase producing bacteria than the controls [86]. In fact, a study reported that
Biology 2022, 11, 1683 9 of 17

gut microbiota alterations were observed in the rhesus monkey model of endometriosis,
namely, fewer Lactobacilli shedding in feces [88]. Interestingly, cyclic alterations in the gut
microbiome may be linked with premenstrual syndrome, but this hypothesis is still under
study and future work needs to be accomplished [89]. Thus, while research is required
to confirm this speculation, we hypothesize that alterations in the gut microbiome may
potentially bring about menstruation-related diseases.
There is a scarcity of studies investigating the relationship between the hormonal fluc-
tuations accompanying the menstrual cycle and the gut microbiota [32]. However, studies
investigating the relationship between menstruation and other human microbiomes have
been performed. A study reports a lack of significant menstruation-driven changes in the
saliva and fecal microbiomes, yet discloses an increased diversity in the vaginal microbiome
during menses, which is ensured by an expansion of Lactobacillus during the follicular
and luteal phases [90]. Similarly, another recent study reports increased vaginal microbial
diversity and a correlation between Lactobacillus abundances and predicted estradiol levels
across the menstrual cycle [91]. Analyses of the oral microbiome were also carried out. Inter-
estingly, anaerobic bacterial counts in saliva are reported to increase during ovulation [85].
An analysis of the salivary profile of 309 women in their reproductive age during the
menstrual, follicular, and luteal phases of the cycle reports a lack of significant differences
in α-diversity or phase-specific clustering of the overall microbiome but discloses variance
in the abundances of Prevotella, Campylobacter, Haemophilus, and Oribacterium throughout
the cycle, where a higher species-richness was noted in the luteal phase [85].

7. Gut Microbiota Composition Alterations Accompanying Menopause

Female sex hormones such as estrogen impact microbiota in various body sites, espe-
cially the gut [16]. When women possess sufficient estrogen, their gut microbiota displays
species diversity where beneficial bacteria are dominant and harmful bacteria growth is
inhibited [38]. The gut microbiome has been correlated with menopause: the cessation of
menstruation accompanied by estrogen down-regulation, ovary function loss, and hormone
receptors dysfunction [16,38]. Menopause is associated with a lower gut microbial species
diversity [92]. Thus, there are marked differences in the gut microbiomes and their metabo-
lites in premenopausal and postmenopausal women, as shown in Table 1 and Figure 1 [93].
Changes in the gut microbiome have been reported in the perimenopausal period, the
period before menopause occurs. Namely, during the perimenopausal period, the relative
abundance of beneficial bacteria such as Lactobacillus and Bifidobacteria is markedly reduced
while that of harmful bacteria such as Enterobacter is increased in women [38]. In a study, bi-
lateral ovariectomizing was employed to investigate gut microbiota changes accompanying
perimenopause and it revealed that ovariectomized mice displayed the lowest abundances,
which was regulated by estrogen supplementation, implying a bidirectional relationship
between the microbiota and estrogen [38]. Moreover, the study discloses that obesity in
peri- and post-menopausal women is associated with possessing a gut microbiota unable
to metabolize the soy isoflavone daidzein to O-desmethylangolensin [94].
Of note, the gut microbiota of post-menopausal women was observed to be closer in
resemblance to men than that of pre-menopausal women [39]. Namely, postmenopausal
women, similar to age-matched men, have a lower abundance of SCFA-producing bacte-
ria [39]. Furthermore, the number of species from genera that differentiate men from women
decreased after menopause implying a masculinization of the gut microbiota composition
postmenopause [39]. Studies report that premenopausal women have higher abundances
of several Alistipes, Bifidobacterium, and Ruminococcus species and lower abundances of
Bacteroides, Prevotella, and Haemophilus species, while postmenopausal women have fewer
Firmicutes and Roseburia spp., and more Bacteroidetes and Tolumonasare in their fecal sam-
ples [39,93]. Furthermore, the ratio of Firmzicutes/Bacteroides, and the relative abundances
of Lachnospira and Roseburia, are elevated in the gut microbiota of postmenopausal women,
while the relative abundances of Prevotella, Parabacteroides, and Bilophila are reduced [38].
Another study reported a higher Firmicutes/Bacteroidetes ratio and relative abundance of
Biology 2022, 11, 1683 10 of 17

Lachnospira and Roseburia, but a lower relative abundance of the Prevotella, Parabacteroides,
and Bilophila genera in pre-menopausal women than in post-menopausal women [40].
However, aside from β diversity, no differences of significance were reported in alpha
diversity indices among pre- and post-menopausal women [39]. With its secretion of
β-glucuronidase, the enzyme responsible for estrogen’s deconjugation into its active forms,
the gut microbiome can affect the circulating levels of estrogens [86]. Moreover, dysbio-
sis of the gut microbiome, leading to lower microbial diversity, may decrease circulating
estrogen as its deconjugation would be reduced [86]. Interestingly, the administration of
a novel strain (YT2) of Lactobacillus intestinalis was found to be significantly reduced in
ovariectomized rats, which led to a marked amelioration of menopausal symptoms such as
increased fat mass, decreased bone mineral density, and remarkably, it also restored the in-
testinal microbial composition and increased Firmicutes/Bacteroides ratio [95]. Nonetheless,
studies to determine the efficacy of these therapies in clinical trials are needed.

8. The Role of the Gut Microbiome in Postmenopausal Female Health

The gut microbiome has been correlated with various diseases accompanying menopause.
Obesity affects 65% of postmenopausal women and interestingly, the relationship between
the gut microbiota and estrogen is speculated to mediate this weight gain [16]. More-
over, the gut microbiome has been related to obesity, and menopause is associated with
a heightened risk of obesity [92,93]. Notably, other than the differences in Akkermansia
muciniphila, Bifidobacterium animalis, Dorea, and Desulfovibrio, the gut microbial characteris-
tics of diet-induced and bilaterally ovariectomized obese mice are reportedly similar [38].
However, a study reports that while menopausal obesity and dietary obesity led to similar
gut microbiome structures, menopausal obesity engenders a different intestinal microbiota,
namely, Bifidobacterium animalis, which was solely observed in the ovariectomized mice [96].
Notably, the gut microbiome was reported to impact skeletal muscle mass through
its synthesis of SCFA butyrate in healthy menopausal women [97]. Moreover, increased
capacity for gut microbial synthesis was markedly associated with serum butyrate levels
and skeletal muscle index, and two main butyrate-producing bacterial species, Faecalibac-
terium prausnitzii, and Butyricimonas virosa, were positively associated with this increased
capacity for gut microbial synthesis of butyrate and the skeletal muscle index [97]. Gut
ecology was also reported to contribute to the mediation of the protective effects increased
aerobic capacity may have against menopause-associated cardiometabolic risk, especially
the production of signaling molecules such as short-chain fatty acids produced by the
gut [98]. Moreover, another study reports that the response to physical exercise, which is
reported to modify the intestinal microbiota composition, is actually contingent upon the
initial microbiota profile [92].
Postmenopausal women with breast cancer have been reported to possess an altered
composition and estrogen-independent low diversity of their microbiota [16,54]. An anal-
ysis reports that postmenopausal women recently diagnosed with breast cancer had a
less diverse fecal microbiota with a composition that differs from that of postmenopausal
women without breast cancer and higher urinary estrogens [99]. This was confirmed by
another study reporting the potentially decreased postmenopausal breast cancer risk for
women who possess high intestinal microbial diversity [100]. Additionally, the abundance
of SCFA-producing bacteria was reduced in healthy premenopausal women while Pe-
diococcus and Desulfovibrio were relatively characteristic of premenopausal breast cancer
patients [101]. Thirty-eight species were increased in postmenopausal breast cancer pa-
tients, namely, Shewanella putrefaciens, Enterococcus gallinarum, Escherichia coli, Klebsiella
sp_1_1_55, Prevotella amnii, Actinomyces sp. HPA0247, and Erwinia amylovora, while seven
species were underrepresented such as Eubacterium eligens and Lactobacillus vaginalis [54].
The risk of Alzheimer’s disease is also reported to increase during the menopausal
transition [96]. Interestingly, postmenopausal women make up over 60% of all Alzheimer’s
patients [102]. The pathophysiology of AD commences 10–20 years before symptoms
can be detected clinically, corresponding with the hormonal transitions accompanying
Biology 2022, 11, 1683 11 of 17

the menopausal transition, in which many of the symptoms are risk factors themselves
for AD [102]. In fact, a nonnegligible body of data reported the neuroprotective effects
of estrogen and its modulatory role in female cognitive aging [102]. Thus, the prevalent
complaints of cognitive decline by menopausal women are plausible given that many
regions vulnerable to AD display significant overlap with the brain estrogen network [102].
As explained previously, the gut microbiota, through its deconjugation of estrogens in the
bile, plays a role in determining systemic estrogen levels [17,19]. Hence, since the cognitive
decline accompanying AD is largely correlated with that of estrogen, we can speculate
that the gut microbiome may mediate or contribute to the deflation in estrogen systemic
levels in menopausal women. Notably, studies utilizing a murine model disclose that gut
dysbiosis may be a risk factor for AD [103,104]. Moreover, using an AD-like pathology with
amyloid and neurofibrillary tangles (ADLPAPT ) transgenic mouse model of AD, a study
reports differences in the gut microbiota composition of healthy wild-type mice and that of
ADLPAPT [103]. Additionally, ADLPAPT mice displayed a loss of epithelial barrier integrity
and chronic intestinal and systemic inflammation [103]. Notably, transplantation of the
fecal microbiota from wild-type mice into ADLPAPT mice ameliorated the formation of
neurofibrillary tangles, amyloid β plaques, glial reactivity, and cognitive impairment [103].

9. The Role of the Gut Microbiome and Postmenopausal Bone Health

Among postmenopausal women, osteoporosis and its precursor osteopenia are preva-
lent metabolic bone diseases [41]. The gut microbiome has also been implicated in bone-
related diseases among postmenopausal women and their manifestations, as shown in
Table 1 and Figure 1. Moreover, an increase in gut permeability, which is associated with
lower bone mineral density, has been reported during perimenopause [105]. A study
reports decreased bacterial richness and diversity, and significant differences in abundance
levels among phyla and genera in the gut microbial community in postmenopausal os-
teoporosis [42]. However, the study negates any significant correlation between bacterial
diversity and estrogen [42]. An analysis of fecal samples from postmenopausal women
with osteoporosis and with normal bone mass reveals a marked discrepancy between the
gut microbiota of both groups [43]. Namely, the proportion of the genus Prevotella was
notably higher in postmenopausal women with normal bone mass, implying a poten-
tial bone-protective effect of Prevotella [43]. Moreover, fracture incidence was markedly
higher in postmenopausal women with low Bacteroides abundance than in controls [44].
Conversely, a recent study reports that Bacteroides were more prevalent in osteoporosis
and osteopenia groups [41]. That study also reveals significant taxonomic compositional
differences in osteoporotic and osteopenic, and healthy postmenopausal women, such as
a higher abundance of unclassified Clostridia and methanogenic archaea, than in healthy
postmenopausal women [41]. Another study recognized taxa-specific variations in the
intestinal microbiota associated with bone turnover markers, especially C-terminal cross-
linking telopeptide of type I collagen (CTX) [106]. This could be elucidated by the hormonal
changes characterizing menopause. Furthermore, the lack of female hormones brings about
bone loss and osteoporosis [96]. Interestingly, probiotic administration was reported to ame-
liorate osteopenia in postmenopausal women. Moreover, the administration of probiotic
treatment and bioavailable isoflavone attenuated bone mineral density loss brought about
by estrogen deficiency, promoted a favorable estrogen metabolite profile, and improved
bone turnover [107].

10. Therapeutic Strategies to Modulate the Gut Microbiome in Females

In light of reported gut microbial compositional changes accompanying various fe-
male diseases, investigating the therapeutic potential of probiotic administration or fecal
transplant is suggested. Moreover, the female diseases we discussed were reported to be
accompanied by gut dysbiosis. Hence, probiotic administration of certain bacterial species
to correct a deficiency or an overgrowth may be of therapeutic value. Firstly, PCOS patients
are reported to have a less diverse gut microbiome, specifically lower β diversity than con-
Biology 2022, 11, 1683 12 of 17

trols [25–28]. Notably, the abundance of certain bacterial species was shown to be reduced
while that of others was enhanced. Furthermore, the abundance of Bacteroides vulgatus
(B. vulgatus), streptococcus, ratio of Escherichia/Shigella, and Firmicutes is higher, while that of
Tenericutes ML615J-28, Tenericutes 124-7, Ruminococcaceae, Akkermansia, and Bacteroidetes
S24-7 is lower in PCOS patients than the controls [25,27,28]. Hence, the administration of
the latter species may ameliorate the condition. In fact, the administration of vitamin-D
in conjugation with a probiotic supplement containing Lactobacillus acidophilus, Bifidobac-
terium bifidum, Lactobacillus reuteri, and Lactobacillus fermentum for 12 weeks was shown to
ameliorate some of PCOS symptoms [108]. Similarly, the administration of selenium with a
probiotic supplement consisting of Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus
fermentum, and Bifidobacterium bifidum led to the same results [109]. Secondly, various
cancers affecting the female population, such as breast, cervical, and ovarian cancer, were
associated with gut microbiota alterations [45–47]. Namely, breast cancer patients were
reported to display a heightened abundance of Clostridiales in breast cancer, cervical cancer
patients had higher levels of Prevotella, Porphyromonas, and Dialister and lower levels of
Bacteroides, Alistipes, and members of Lachnospiracea, and ovarian cancer patients, displayed
an increase in Prevotella [45–47]. Thus, a correction of these compositional deviations could
be of relevance. For instance, several studies display promising evidence that diet, pro-
biotics, and prebiotics could have an important therapeutic effect on breast cancer [110].
Thirdly, various diseases arising during the period and the transition to menopause are
associated with gut alterations. Interestingly, Bifidobacterium animalis was observed in
a murine model of menopausal obesity [96]. Hence, an investigation of the role of this
bacterial species could be carried out and if found contributing to obesity, the introduction
of a competing species could be a possibility. Markedly, an administration of a probiotic
mix consisting of Bifidobacterium lactis W51, Bifidobacterium bifidum W23, Lactobacillus brevis
W63, Bifidobacterium lactis W52, Lactobacillus salivarius W24, Lactobacillus acidophilus W37,
Lactococcus lactis W19, Lactobacillus casei W56, and Lactococcus lactis W58 was shown to
positively affect vascular function and reduce arterial stiffness in obese postmenopausal
Women [111]. Postmenopausal normal bone mass was associated with higher Prevotella
abundance [43]. As mentioned previously, probiotic administration treatment and bioavail-
able isoflavone-attenuated bone mineral density loss are brought about by a deficiency
in estrogen and improved bone turnover [107]. However, the administration of Prevotella
may specifically prove protective against postmenopausal bone mass loss. Finally, studies
utilizing murine models reveal that gut dysbiosis may be a risk factor for AD [103,104].
Interestingly, probiotic supplementation improved cognitive function and mood in adults
above 65 years and had favorable outcomes on AD specifically [112,113].

11. Conclusions
Trillions of microorganisms populate the human GI tract and are known to protect
the host from adversities. The gut microbiome has a profound role in the elimination of
pathogens and may contribute to many diseases affecting females such as breast, cervical,
and ovarian cancer, polycystic ovarian syndrome, and postmenopausal period illnesses
such as menopausal obesity, Alzheimer’s disease, and bone diseases (Table 1 and Figure 1).
Traditionally most research has focused on male subjects and there is a need to undertake
more research on female health. A recent study, the first of its kind examined the impact of
menopause on women’s metabolism, as well as diet and how this related to their overall
health [114]. The study indicated that diet and gut microbial species may have been
responsible for changes observed after menopause such as higher blood pressure and a
greater risk of developing cardiovascular diseases. The study indicated the important
contribution of the gut microbiome and diet to female health. Future work should focus
on developing therapy based on an individual’s metabolic and hormonal status as well
as exploring the critical role of the microbiome. The modulation of the gut microbiome
via diet and through supplementation with pre/pro/postbiotics in various female health
issues should be undertaken. The precise optimal composition of microbial species is not
Biology 2022, 11, 1683 13 of 17

known. Furthermore, modulation of the gut microbiome as a therapeutic/preventative

strategy needs to be accomplished, with a focus on female health. Further studies are
essential to ascertain the metabolites/molecules produced by the gut microbiota and their
effects on female-related health issues are warranted.

Author Contributions: N.A.K. and R.S. envisioned the concept for the review. Z.M. and R.S. reviewed
the literature and prepared the first draft of the manuscript together with A.M.A. and H.A. N.A.K.
and R.S. corrected the manuscript. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: The authors are grateful to the American University of Sharjah and University
of Sharjah to support this work. The work in this paper was supported, in part, by the Open Access
Program from the American University of Sharjah. This paper represents the opinions of the author(s)
and does not mean to represent the position or opinions of the American University of Sharjah.
Conflicts of Interest: The authors declare no competing financial interest. The authors declare: (1) no
financial support for the submitted work from anyone other than their employer; (2) no financial
relationships with commercial entities that might have an interest in the submitted work; (3) no
spouses, partners, or children with relationships with commercial entities that might have an interest
in the submitted work; and (4) no non-financial interests that may be relevant to the submitted work.

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