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The new field of microbiome research studies the microbes within multicellular hosts and the many effects of these microbes on the host's health and well-being. We now know that microbes influence metabolism, immunity and even behavior. Essential questions, which are just starting to be answered, are what are the mechanisms by which these bacteria affect specific host characteristics. One important but understudied mechanism appears to involve hormones. Although the precise pathways of microbiota-hormonal signaling have not yet been deciphered, specific changes in hormone levels correlate with the presence of the gut microbiota. The microbiota produces and secretes hormones, responds to host hormones and regulates expression levels of host hormones. Here, we summarize the links between the endocrine system and the gut microbiota. We categorize these interactions by the different functions of the hormones, including those affecting behavior, sexual attraction, appetite and metabolism, gender and immunity. Future research in this area will reveal additional connections, and elucidate the pathways and consequences of bacterial interactions with the host endocrine system. © FEMS 2015. All rights reserved. For permissions, please e-mail:
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FEMS Microbiology Reviews
doi: 10.1093/femsre/fuu010
Review Article
Microbial endocrinology: the interplay between
the microbiota and the endocrine system
Hadar Neuman1, Justine W. Debelius2, Rob Knight2,$ andOmryKoren
1Faculty of medicine, Bar-Ilan University, 1311502 Safed, Israel and 2Department of Chemistry and
Biochemistry and BioFrontiers Institute, University of Colorado at Boulder, Boulder, CO 80309, USA
Corresponding author: Omry Koren, Faculty of medicine, Bar-Ilan University, 8 Henrietta Szold St., 1311502 Safed, Israel. Tel: +972-72-2644954;
One sentence summary: This review summarizes the links between the host endocrine system and microbiota functions, reporting both effects of the
host hormones on bacteria and effects of the microbiota on host hormones inuencing behavior, appetite and metabolism, gender and immunity.
$Current address: Departments of Pediatrics and Computer Science & Engineering, University of California at San Diego, La Jolla, CA 92093, USA
Editor: Ehud Banin
The new eld of microbiome research studies the microbes within multicellular hosts and the many effects of these
microbes on the host’s health and well-being. We now know that microbes inuence metabolism, immunity and even
behavior. Essential questions, which are just starting to be answered, are what are the mechanisms by which these bacteria
affect specic host characteristics. One important but understudied mechanism appears to involve hormones. Although
the precise pathways of microbiota-hormonal signaling have not yet been deciphered, specic changes in hormone levels
correlate with the presence of the gut microbiota. The microbiota produces and secretes hormones, responds to host
hormones and regulates expression levels of host hormones. Here, we summarize the links between the endocrine system
and the gut microbiota. We categorize these interactions by the different functions of the hormones, including those
affecting behavior, sexual attraction, appetite and metabolism, gender and immunity. Future research in this area will
reveal additional connections, and elucidate the pathways and consequences of bacterial interactions with the host
endocrine system.
Key words: microbiota; microbiome; hormones; germfree; endocrine system; immunity
We are only beginning to understand the pervasive importance
of gut microbial communities (microbiota) in health and disease.
In the past, bacteria were mostly regarded as either pathogens or
irrelevant to host function. However, the growing eld of micro-
biome research—human microbial ecology, studying the com-
munities of bacteria residing within our bodies and the genes
they contain—has yielded new perspectives. We now realize
that the number of microbial cells we carry can be as much as 10
times greater than the total cell number in the human body, and
their genetic information is at least 150-fold greater than that
of our human genome. Thus, it is not surprising that microbiota
and their hosts interact in numerous complex ways. The gut mi-
crobiota in particular plays important roles in host metabolism,
immunity and even behavior. Mechanisms by which the micro-
biota are known to mediate these functions include breaking
down dietary components, educating the immune system and
degrading toxins (Flint et al., 2012;Elahiet al., 2013; Maurice,
Haiser and Turnbaugh 2013).
However, only recently has a critical mechanism of bacterial
interaction been revealed: modulation of hormonal secretion.
From birth, bacterial colonization of the intestine has a role in
the maturation of the immune system (Elahi et al., 2013)andthe
endocrine system (Clarke et al., 2013). Surprisingly, commensal
Received: 4 August 2014; Accepted: 21 December 2014
FEMS 2015. All rights reserved. For permissions, please e-mail:
FEMS Microbiology Reviews Advance Access published February 19, 2015
2FEMS Microbiology Reviews
bacteria can produce and secrete hormones. The crosstalk be-
tween microbes and hormones can affect host metabolism, im-
munity and behavior. This interplay is bidirectional, because the
microbiota has shown to be both affected by and to affect host
hormones, as summarized in Table 1.
Lyte and Ernst were the rst to dene the eld of micro-
bial endocrinology research, after observing that stress-induced
neuroendocrine hormones can inuence bacterial growth (Lyte
and Ernst 1992). Further research of microbial endocrinology
discovered hormone receptors in microorganisms and hypoth-
esized that they represent a form of intercellular communica-
tion (Lyte 1993). Pathogenic neurotoxins such as neurotoxin 6-
hydroxydopamine were shown to alter norepinephrine levels in
mice presenting the bidirectional nature of the host–microbe in-
teraction (Lyte and Bailey 1997). A more evolutionary-oriented
study showed that many enzymes involved in host hormone
metabolism (including epinephrine, norepinephrine, dopamine,
serotonin, melatonin, etc.) might have evolved from horizontal
gene transfer from bacteria (Iyer et al., 2004).
More clues to the existence of crosstalk between bacteria
and the endocrine system came from the discovery of inter-
kingdom signaling, including the hormonal communication be-
tween microorganisms and their hosts (Hughes and Sperandio
2008). This eld evolved from the initial observation that bac-
teria perform quorum sensing (QS), communication based on
producing and sensing autoinducer (AI) molecules. These AI
molecules are hormone-like elements that regulate functions
including coordinated bacterial growth, motility and virulence
(Fuqua, Winans and Greenberg 1996). In addition to affecting
bacteria, these signals can modulate host cell signal transduc-
tion. Some AI molecules have crosstalk with host hormones for
activating signaling pathways (Karavolos et al., 2013).
Host hormones also affect bacterial gene expression
(Sperandio et al., 2003), which in turn can have consequences
on their hosts. For example, catecholamines enhance bacterial
attachment to host tissues, and affect growth and virulence of
bacteria (Freestone and Lyte 2008; Hegde, Wood and Jayaraman
2009). In contrast, the human sex hormones estriol and estra-
diol decrease bacterial virulence by inhibiting QS (Beury-Cirou
et al., 2013).
The effects of host hormones on the microbiota are summa-
rized in Fig. 1.
In this review, we summarize interactions between hor-
mones and the gut microbiota, and propose an important role
for the microbiota in hormone regulation. These endocrine ef-
fects of bacteria inuence a variety of host responses includ-
ing behavior, metabolism and appetite, and immune responses
(Fig. 2). Much of the advances in this eld have been made
through experiments using germfree (GF) animals (Fig. 3)aswell
as experiments using probiotics (specic microbes thought to be
benecial to the host) and prebiotics (non-digestible carbohy-
drates that act as food for probiotics), together with advances in
sequencing and bioinformatics platforms.
While this eld is in its infancy, future research will likely
identify additional strong interconnections between hormones
and our microbiome. Microbial endocrinology may also explain
how the microbiota affect the host’s gastrointestinal (GI) and
psychological health (Lyte 2011). We suggest that hormones are
an important mechanism for host–microbial interaction.
The gut microbiota inuences animal and human behavior in
several ways. GF mice have altered cognitive function, memory,
stress-response, anxiety and social behavior (Diaz et al., 2011;
Neufeld et al., 2011). The gut microbiota may even inuence
human emotional states and disease states, such as stress-
related irritable bowel syndrome (IBS; reviewed elsewhere in
Cryan and O’Mahony 2011), and autism (Sandler et al., 2000;Fine-
gold et al., 2010; Hsiao et al., 2013). These surprising ndings
show that the microbiota can modulate host behavior, raising
the question of how these effects work functionally. The com-
munication between the gut microbiota and the brain has been
termed the ‘gut-brain axis’, and is mediated mainly by the long
branching vagus nerve. Although the precise pathways of the
gut-brain axis have not yet been deciphered, it is thought that
the effects are achieved by several different mechanisms medi-
ated by hormones. The effects of the microbiota on host hor-
mone levels may be direct, where the microbiota produce the
hormones, or indirect, where microbes may modulate the func-
tion of the adrenal cortex (which controls the anxiety and stress
responses), or modulate inammation and immune responses.
Two major groups of hormones likely involved in bacterial ef-
fects on host behavior are neurohormones, including serotonin
and the catecholamines dopamine, epinephrine (adrenaline)
and norepinephrine (noradrenaline), and stress hormones, in-
cluding cortisol, corticosterone, adrenocorticosterone and corti-
cotropin. Hormones in both groups can inuence physiological
changes preparing the body for physical activity (ght-or-ight
response), such as increased heart rate and blood pressure, and
decreased metabolism (Romero and Butler 2007).
Neurohormones are secreted from neuroendocrine cells in re-
sponse to a neuronal input. Although they are secreted into the
blood for a systemic effect, they can also act as neurotransmit-
ters. Modulation of behavior by the microbiota (such as anxi-
ety in mice) is believed to occur through neurohormone precur-
sors (e.g. serotonin, dopamine) (Lyte 2013). Recently, gut bacte-
ria were shown both to produce and respond to neurohormones
such as serotonin, dopamine and norepinephrine (Roshchina
2010). Catecholamines can alter growth, motility, biolm for-
mation and/or virulence of bacteria (Lyte et al., 2003;Sperandio
et al., 2003; Freestone and Lyte 2008; Karavolos et al., 2008; Hegde,
Wood and Jayaraman 2009). These mechanisms are intriguing
for researchers studying pathogens because they may inuence
pathogen susceptibility to host defense responses. For exam-
ple, in response to host adrenaline, Salmonella downregulates its
resistance to host antimicrobial peptides and induces key metal
transport systems, which affect the oxidative stress balance in
the cells (Karavolos et al., 2008). These mechanisms also involve
QS: the bacterial QS AI molecule AI-3 and host adrenaline and
noradrenaline display crosstalk for activation of the same sig-
naling pathways. These responses most likely depend on bacte-
rial receptor-based sensing and signaling cascades, as they are
inhibited by αand β-adrenergic receptor antagonists (Karavolos
et al., 2013).
Serotonin, also termed 5-hydroxytryptamine (5-HT), is one
of the main neurotransmitters in the brain. However, over 90%
of the mammalian host’s serotonin is found in the intestine.
Intestinal serotonin secretion is affected by diet, and regulates
intestinal movement, mood, appetite, sleep and cognitive func-
tions. This dual role suggests that serotonin may link the in-
testine (including its microbiota) to host behavior. Brain 5-HT
can cross the blood–brain barrier to the blood through the 5-
HT transporter, suggesting another link in the gut-brain axis
(Nakatani et al., 2008). Serotonin has been implicated in GI
Neuman et al. 3
Tab l e 1 . A list of known correlations between hormones and the microbiota.
class Hormone Model Finding
species Ref
growth and
dopamine, dopa
Bacterial growth Catecholamines induce bacterial growth E. coli, Yersinia.
Lyte and Ernst
QS QS and host hormone crosstalk E. coli Sperandio et al.
Epinephrine Bacterial gene
Hormones affect bacterial virulence
gene expression
E. coli Sperandio et al.
Bacterial growth Catecholamines induce bacterial growth E. coli,
enterica and Y.
Freestone and
Lyt e (2008)
Norepinephrine Bacterial growth
Enhanced bacterial growth and
P. aeruginosa Hegde et al.
Norepinephrine Biolm growth Catecholamines induce biolm growth Staphylococcus
Lyt e et al. (2003)
Estriol, estradiol QS Hormones decrease bacteria virulence Agrobacterium
tumefaciens, P.
Norepinephrine Bacterial
Gut microbiota produce and respond to
N/A Roshchina
Epinephrine Bacterial
Epinephrine decreases bacterial
resistance to host antimicrobial peptides
Salmonella Sperandio et al.
Bacterial growth Estradiol and progesterone enhance
bacterial growth
Kornman and
Loesche (1982)
Tryptophan, 5-HT
and 5-
GF mice Elevated hipocampal levels in male GF
N/A Clarke et al.
Serotonin Bacterial
production of
Gut microbiota produce serotonin Streptococcus,
Escherichia and
Dopamine Bacterial
Gut microbiota produce and respond to
Bacillus and
Serotonin GF mice Low plasma serotonin levels in GF mice N/A Wikoff et al.
Tryptophan, 5-HT Infected rats Higher plasma levels in infected rats B. infantis Desbonnet et al.
GF mice Low free lumen catecholamines in GF
N/A Asano et al.
GABA Bacterial
Microbiota produce GABA Lactobacillus Asano et al.
GABA Probiotics in
Bacteria alter host GABA receptors L. rhamnous Bravo et al.
Corticosterone Probiotics in
Low levels of corticosterone in treated
L. rhamnous Bravo et al.
GF mice Elevated levels in GF mice N/A Grenham et al.
Probiotics in rats
and humans
Bacteria reduce levels of stress
L. helveticus and
B. longum
Messaoudi et al.
L-DOPA Antibiotics in
Eliminating H. Pylori elevates L-DOPA
H. pylori Pierantozzi
et al. (2006)
cVA and CHs D. melanogaster Pheromone levels affected by antibiotics
and bacteria addition
L. plantarum Sharon et al.
Guaiacol S. gregaria Pheromone produced by commensal
bacteria, abolished in GF locust
P. agglomerans;
K. pneumonia; E.
Dillon, Vennard
and Charnley
Volatile fatty acids Hyena Species-specic volatiles correlated to
bacterial populations in scent glands
N/A Theis et al.
4FEMS Microbiology Reviews
Tab l e 1 . (continued.)
class Hormone Model Finding
species Ref
Leptin Antibiotics in
Vancomycin leads to decrease in
circulating leptin levels
N/A Lam et al. (2012)
Probiotics in
Reduced serum leptin L. plantarum Naruszewicz
et al. (2002)
Male rats Specic bacteria positively correlated
with circulating leptin
et al. (2013)
Male rats Specic bacteria negatively correlated
with circulating leptin
Bacteroides and
et al. (2013)
Mice (including
leptin decient)
Specic bacteria positively correlated
with circulating leptin
Lactococcus and
an uncultured
member of the
Ravussin et al.
Mice (including
leptin decient)
Specic bacteria negatively correlated
with circulating leptin
Allobaculum Ravussin et al.
Ghrelin Male rats Specic bacteria positively correlated
with ghrelin
Bacteroides and
Prevotella spp.
et al. (2013)
Male rats Specic bacteria negatively correlated
with ghrelin
and B.
rectale group
et al. (2013)
(oligofructose) in
obese humans
Prebiotics decrease secretion of ghrelin Promoted
growth of
Parnell and
Reimer (2009)
Insulin Metagenomics of
diabetic women
Negative correlations between insulin
levels and bacterial populations
Clostridium spp.
B. intestinalis
Karlsson et al.
Insulin Bacterial transfer
from lean donors
to metabolic
Lean human subjects have increased
insulin sensitivity due to their
microbiome, compared to metabolic
syndrome patients
Correlated with
Vrieze et al.
GLP-1 GF and antibiotic
treated mice
Intestinal microbiota lower GLP-1 levels N/A Wichmann
et al. (2013)
GLP-1 Probiotics in
Intestinal microbiota increase GLP-1
B. breve, B.
longum, B.
infantis, L.
acidophilus, L.
plantarum, L.
paracasei, L.
Yad av et al.
GLP-1 Bariatric surgery
in rats
Intestinal microbiota changes correlate
with elevated GLP-1 levels
N/A Osto et al. (2013)
Angptl4 Probiotics in
Elevated Angptl4 levels in treated mice L. paracasei Aronsson et al.
Somatostatin Bacterial
Bacteria produce somatostatin Bacillus subtilis LeRoith et al.
neuropeptide Y,
protein, ghrelin and
GF rats Altered levels of autoantibodies against
appetite hormones
N/A Fetissov et al.
GIP, GLP-1, insulin Gastric bypass
surgery in
diabetic patients
Intestinal microbiota changes correlate
with elevated hormone levels
N/A Laferrere (2011)
Angptl4 GF mice
colonized with
normal gut
Suppression of Angptl4 expression
following colonization
N/A Backhed (2009)
Neuman et al. 5
Tab l e 1 . (continued.)
class Hormone Model Finding
species Ref
and repro-
Estrogen Antibiotics Antibiotics lead to lower estrogen levels N/A Adlercreutz
et al. (1984)
Estrogen Humans Correlations between urinary estrogen
levels and fecal microbiome
composition and richness
Clostridia taxa,
including non-
and three
genera in the
et al. (1984)
Androgens Enzymatic and
Bacteria convert glucocorticoids to
C. scindens Winter et al.
Testosterone NOD mice Microbes raise testosterone levels in
male NOD mice
N/A Markle et al.
Bovine growth
Cows SCFAs inhibit bovine growth hormone N/A Wang et al.
Growth hormones Probiotics in D.
Probiotics promote growth hormone
L. plantarum Storelli et al.
Probiotics in D.
Bacterial genes are required for growth
A. pomorum Shin et al. (2011)
Other Oxytocin Probiotics in
Upregulation of oxytocin in treated mice L. reuteri Poutahidis et al.
TSH GF rats 25% higher TSH levels in GF rats N/A Wostmann
Prolactin GF rats 25% higher prolactin levels in GF rats N/A Wostmann
Prolactin Cow cells SCFAs inhibit prolactin gene
N/A Wang et al.
Figure 1. Host effects on the microbiota. A variety of host factors (such as diet, exercise, mood, general health state, stress and gender) lead to alterations in hormonal
levels, which in turn lead to a variety of effects on the microbiota (including growth, virulence and resistance).
6FEMS Microbiology Reviews
Figure 2. The effects of the gut microbiota on the host via hormones. Gray arrows and text refer to the effects of the gut microbiota on various hormone levels. Pink
arrows and text refer to the effects of these hormonal alterations on host outcomes (e.g. behavior).
pathologies such as IBS and Crohn’s disease (Manocha and Khan
2012), and these diseases are also associated with differences in
the microbiota (Morgan et al., 2012).
To our knowledge, the rst direct effect of the micro-
biome on serotonin was demonstrated in GF mice, which had
lower plasma serotonin levels than conventional mice (Wikoff
et al., 2009). However, in another study, levels of tryptophan (the
precursor of serotonin) and hippocampal concentration of 5-HT
and 5-hydroxyindoleacetic acid (its main metabolite) were ele-
vated in male GF mice (Clarke et al., 2013), suggesting that ei-
ther the effects are facility-specic or tissue-specic. Serotonin
can also be produced by Streptococcus,Escherichia and Enterococcus
species (Roshchina 2010), and Bidobacterium infantis modulates
5-HT levels by increasing plasma tryptophan levels (Desbonnet
et al., 2008).
Dopamine is also produced by bacteria including Bacillus and
Serratia, although little is known about its function in these mi-
croorganisms (Roshchina 2010). Levels of free lumen dopamine
were signicantly lower in GF than conventional mice, and
were elevated again upon inoculation with bacteria express-
ing β-glucuronidase (Asano et al., 2012). These results suggest
that there may be correlations between intestinal bacteria and
dopamine levels in conditions such as Parkinson’s disease, char-
acterized by insufcient dopamine formation. Because the eti-
ology of Parkinson’s disease is poorly understood, and one of
the early symptoms of disease is constipation, it has been hy-
pothesized that bacteria may be involved in its progression
or development (Dobbs et al., 2012). Moreover, several rodent
models of Parkinson’s disease-like syndrome are established by
injection of bacteria such as Nocardia asteroides (Kohbata and
Beaman 1991). So far, Helicobacter pylori has been shown to in-
crease the risk for Parkinson’s disease by affecting L-DOPA lev-
els (Pierantozzi et al., 2006), and fecal transplants may have al-
leviated some neurological symptoms in a Parkinson’s patient
Neuman et al. 7
Figure 3. Hormonal alterations reported in GF rodents (Based on Wostmann 1996; Fetissov et al., 2008; Backhed 2009; Wikoff et al., 2009; Grenham et al., 2011; Asano
et al., 2012; Clarke et al., 2013; Markle et al., 2013; Wichmann et al., 2013). The arrows refer to the hormone levels in GF compared to conventionally raised rodents.
treated for constipation (Aroniadis and Brandt 2013). These re-
sults require further investigation but point to interesting direc-
Gamma-aminobutyric acid (GABA), the main inhibitory
neurotransmitter in the mammalian CNS, is also produced by
the microbiota and may inuence host behavior. This is inter-
esting because alterations in central GABA receptor expression
are implicated in the pathogenesis of anxiety and depression.
GABA production by Lactobacillus has been studied in an attempt
to ferment safe GABA on a large scale (Li et al., 2008). Accordingly,
administration of Lactobacillus rhamnosus to mice alters the ex-
pression of GABA receptors in different CNS regions, decreasing
anxiety- and depression-related behavior (Bravo et al., 2011).
Stress hormones
The microbiota may help keep us calm and balanced by al-
tering stress hormone levels. GF mice have elevated plasma
levels of the stress hormones corticosterone and adrenocor-
ticotropic hormone (ACTH) in response to mild stress (Sudo
et al., 2004; Grenham et al., 2011), increasing behaviors asso-
ciated with anxiety and stress. ACTH plays an important role
in the hypothalamic–pituitary–adrenal axis by further produc-
ing corticosteroids. Accordingly, two specic species, L. helveti-
cus and B. longum, reduce levels of the stress hormone corti-
sol and anxiety-like behavior in both rats and healthy humans
(Messaoudi et al., 2011). Furthermore, mice chronically treated
with the probiotic L. rhamnosus had lower levelsof corticosterone
and less depressive behavior in a forced swim test than controls
(Bravo et al., 2011).
Pheromones are hormones that play important roles in sexual
recognition, attraction and mating behavior as well as aggres-
sion behavior and dominance. Pheromones are also termed ec-
tohormones, chemicals secreted outside of the body of one in-
dividual and affect the behavior of others.
In Drosophila melanogaster (D. melanogaster), the most abun-
dant pheromones are cuticular hydrocarbons (CHs), and the
most studied pheromone is cis-vaccenyl acetate (cVA). Levels
of CHs and cVA are affected by antibiotics, suggesting a role for
the microbiota in pheromone regulation (Sharon et al., 2010). In
a study characterizing mating preferences between two groups
of D. melanogaster fed different diets, assortative mating pref-
erences were eliminated with antibiotics, and depended on a
specic gut microbe, L. plantarum (Sharon et al., 2010). Together,
these ndings suggest a mechanism whereby the microbiota
affect host pheromone levels, which in turn affect mating
8FEMS Microbiology Reviews
Guaiacol (2-methyoxyphenol) and related phenolic com-
pounds, which are produced by commensal bacteria involved
in vanillate decarboxylation, are another indication of the in-
volvement of the microbiota in pheromone secretion. In re-
sponse to guaiacol, the desert locust Schistocerca gregaria swarms
(Dillon, Vennard and Charnley 2000). Accordingly, GF animals do
not release guaiacol or volatile phenols, but monocultures with
the commensal species, Pantoea agglomerans,Klebsiella pneumo-
niae or Enterobacter cloacae lead to pheromone production. Inter-
estingly, this phenomenon is specic to the commensal species,
because locusts colonized by a pathogenic bacterial species
did not produce guaiacol or other phenolic compounds (Dillon,
Vennard and Charnley 2002).
This linkage between commensal bacteria and volatile host
social signals may also occur in mammals. Two hyena species
harbored different bacterial communities in the scent glands,
which correlated with distinct volatile fatty acid proles of scent
secretions. The authors speculate that the symbiotic bacte-
ria make metabolites that provide species-specic odors (Theis
et al., 2013).
Additionally, Singh et al. demonstrated in a major histocom-
patibility complex congenic rat model that discriminative uri-
nary odors that exist in conventional rats do not exist in GF
rats. This further supports the idea that bacteria can produce an
odor prole that affects host behavior (Singh et al., 1990). Bac-
terial communities producing specic scents may be linked to
host genetic background, as scent-mark communities differed
signicantly between strains of mice, even when co-housed in a
shared environment (Lanyon et al., 2007). Bacteria can also play
a role in mate selection: female mice are not attracted to the
urine of Salmonella-infected males (Raveh et al., 2014). Because
chemosignals and olfactory stimulation also play a role in hu-
man behavior, future research will help us understand whether
bacterially produced odors affect our own interactions and per-
haps evolution.
Examples of bacteria affected by sex hormones have been
reported since the 1980s. For instance, Prevotella intermedius
takes up estradiol and progesterone, which enhance its growth
(Kornman and Loesche 1982). Changes in expression of the
estrogen receptor, ER-β, also affect the intestinal microbiota
composition (Menon et al., 2013). This interaction goes both
ways, as several types of bacteria have also been implicated in
steroid secretion or modication (Ridlon et al., 2013). For exam-
ple, Clostridium scindens converts glucocorticoids to androgens,
a group of male steroid hormones (Ridlon et al., 2013). Intesti-
nal bacteria also play a signicant role in estrogen metabolism,
because use of antibiotics leads to lower estrogen levels (Adler-
creutz et al., 1984). Furthermore, strong correlations were found
between urinary estrogen levels and fecal microbiome richness,
as well as presence of Clostridia, including non-Clostridiales,
and three genera within the Ruminococcaceae.
Mittelstrass et al. suggested an interplay between the en-
docrine system, the gut bacteria and metabolism based on
gender-specic differences in fatty acid proles (Mittelstrass
et al., 2011). There are also gender-specic immune changes that
may be correlated with the microbiota. The new term ‘microgen-
derome’ refers to recent observations that the host microbiome
plays a role in the gender bias seen in numerous diseases (Flak,
Neves and Blumberg 2013). We discuss this topic further in the
immune response section below.
Pregnancy is an interesting period to study the micro-
biota changes that correlate with the drastic changes in host
hormone levels during this time. Normally, hormones such as
estrogen, progesterone and leptin increase dramatically with
gestational age, while adiponectin and pituitary GH decrease
(Newbern and Freemark 2011). The composition of the gut mi-
crobiota changes dramatically during pregnancy, specically in
the third trimester, and these changes lead to differences in
metabolism (Koren et al., 2012). These microbial changes include
a signicant increase in Proteobacteria and Actinobacteria as
pregnancy progresses. The third trimester is also characterized
by elevated low-grade inammation and insulin desensitization
compared to the rst trimester. This complex phenotype could
be transferred to GF mice, where mice receiving third trimester
microbiota gained more weight and had a greater inammatory
response than mice receiving rst trimester microbiota (Koren
et al., 2012). These changes might be correlated with hormonal
changes during gestation.
Dysbiosis of the gut microbiota may also play a role in the de-
velopment of diseases manifested by hormonal imbalance, such
as polycystic ovary syndrome, through their modulation of hor-
mone levels. According to this theory, poor diet leads to changes
in gut bacterial communities, creating an increase in gut mu-
cosal permeability, resulting in activation of the immune sys-
tem. This, in turn, raises serum insulin levels, increases andro-
gen production in the ovaries and interferes with normal follicle
development (Tremellen and Pearce 2012). A carbohydrate-poor
diet has been proven to alleviate symptoms of the syndrome.
A classic role of the gut microbiota is in digesting a variety
of carbohydrates and fermenting them into short-chain fatty
acids (SCFAs). GF mice have different metabolic proles than
conventionally raised mice, including low concentrations of SC-
FAs, hepatic triacylglycerol and glucose. Interestingly, subthera-
peutic doses of antibiotics, which do not eliminate the gut mi-
crobial community but rather cause signicant changes in its
composition, lead to increased levels of SCFAs and to weight
gain in mice (Cho et al., 2012). These metabolic effects of the
microbiome may further affect regulation of hormone produc-
tion from cholesterol, peptides or amino acids. For instance SC-
FAs have been shown to stimulate release of 5-HT and the pep-
tide YY, a hormone released after feeding involved in appetite
reduction and decreasing of gut motility (Cherbut et al., 1998;
Fukumoto et al., 2003). Additional hormones, mainly neuropep-
tides that have a role in controlling appetite and regulating
metabolism, are likely affected by the gut microbiota. These in-
clude alpha-melanocyte-stimulating hormone, neuropeptide Y,
agouti-related protein, ghrelin, leptin, insulin and others. An-
other effect of bacteria on metabolic hormones could be through
production of somatostatin, which suppresses the release of the
GI and pancreatic hormones (LeRoith et al., 1985).
Several pieces of evidence link the microbiota function
to leptin levels. First, use of antibiotics (vancomycin) in rats
leads to a dramatic decline (38%) in circulating leptin lev-
els (Lam et al., 2012). Second, the abundance of several bac-
terial genera (e.g. Mucispirillum,Lactococcus, Bidobacterium and
Lactobacillus) positively correlates with circulating leptin con-
centrations in mice, while other bacterial genera (e.g. Allobac-
ulum, Clostridium, Bacteroides and Prevotella) negatively corre-
late with leptin levels. These correlations may stem from bac-
teria affecting hormone levels, or vice versa. One proposed
Neuman et al. 9
mechanism is that diet composition may impact leptin con-
centrations, which, in turn, may change the microbial com-
munity composition through inammation and/or regulation
of mucus production (Ravussin et al., 2012; Queipo-Ortuno
et al., 2013). Recently, Rajala et al. demonstrated that leptin
might also inuence the gut microbiota independently of diet
(Rajala et al., 2014). Another model proposes that L. plantarum
specically suppresses leptin by reducing adipocyte cell size in
white fat tissue (Takemura, Okubo and Sonoyama 2010; Lam
et al., 2012). This ts the nding that use of the probiotic L.
plantarum in a group of human smokers reduced their serum
leptin levels (Naruszewicz et al., 2002). Because leptin is in-
volved in appetite inhibition, metabolism and behavior, deci-
phering its interconnections with bacteria is of great interest
and may help us understand and perhaps control its many
Ghrelin, another important appetite-regulating hormone, is
negatively correlated with the abundance of Bidobacterium, Lac-
tobacillus and B. coccoidesEubacterium rectale group, and pos-
itively correlated with a number of Bacteroides and Prevotella
species (Queipo-Ortuno et al., 2013). Intake of oligofructose (a
prebiotic that promotes growth of Bidobacterium and Lactobacil-
lus) decreases secretion of ghrelin in obese humans (Parnell and
Reimer 2009).
Insulin, the extremely important metabolic hormone in-
volved in diabetes and metabolic syndrome, may provide an-
other link between the microbiome and hormones. Signicant
variations in microbiome composition have been observed in di-
abetes patients compared to healthy controls. Certain bacterial
species have been positively or negatively correlated with in-
sulin levels (Qin et al., 2012; Karlsson et al., 2013). Transfer of the
intestinal microbiota (including butyrate-producing microbiota)
from lean donors to metabolic syndrome patients enhanced in-
sulin sensitivity (Vrieze et al., 2012). The effect is likely medi-
ated by altering immune components. However, additional hor-
mones may also be involved in this process.
One such example is glucagon-like peptide 1 (GLP1), asso-
ciated with appetite control and insulin secretion. The intesti-
nal microbiota have been recently implicated in lowering levels
of the GLP1, and thereby slowing intestinal transit (Wichmann
et al., 2013). However, alterations of the microbiome through pro-
biotics (Yadav et al., 2013) or bariatric surgery (Zhang et al., 2009;
Liou et al., 2013;Ostoet al., 2013) decrease adiposity and increase
GLP1 levels in mice. This is primarily attributed to butyrate pro-
duction by commensal bacteria, which can induce GLP1 produc-
tion by intestinal L cells (Yadav et al., 2013).
Another example is angiopoietin-like protein 4 (Angptl4,
also known as fasting-induced adipose factor), a hormone
implicated in many metabolic processes including regu-
lation of glucose and insulin sensitivity. Angptl4 is also
implicated in lipid metabolism, inhibiting lipoprotein li-
pase (LPL) and thereby reducing fat storage. Gut micro-
biota suppress expression of Angptl4, and in a GF mouse
study Angptl4 was shown to mediate protection against
diet-induced obesity (Adlercreutz et al., 1984). A zebrash
model found a tissue-specic cis-regulatory element that
reduced Angptl4 in the intestinal epithelial cells of colonized
animals (Camp et al., 2012). Despite the general trend toward
repression of Angptl4 by the microbiota, specic bacteria can
increase hormone expression. Mice treated with L. paracasei
were leaner than controls, had lower circulating lipids and
elevated levels of Angptl4 (Aronsson et al., 2010). This probiotic
may increase Angptl4 expression through butyrate-mediated
mechanisms. First, butyrate is proposed to induce Angptl4 by
signaling through peroxisome proliferator-activated receptor
γ(PPARγ)(Alexet al., 2013). Butyrate may also interact with
the Angptl4 promoter region independently of PPARγ(Korecka
et al., 2013) and has also been shown to inhibit proliferation,
induce differentiation and repress gene expression by inhibit-
ing histone deacetylase activity (Davie 2003). Hence, it is likely
that butyrate plays a role in the microbiota-induced weight
maintenance mechanisms that involve hormonal changes.
One interesting mechanism by which the microbiota af-
fect peptide hormones is through autoantibodies. Fetissov et al.
found that autoantibodies against peptide hormones involved
in appetite control (including alpha-melanocyte-stimulating
hormone, neuropeptide Y, agouti-related protein, ghrelin and
leptin) exist in healthy humans and rats, and affect feeding and
anxiety. In GF rats, levels of these autoantibodies are altered,
suggesting a novel mechanism by which the microbiome can af-
fect appetite (Fetissov et al., 2008). These ndings have further
implications for the potential role of the microbiota in eating
disorders such as anorexia nervosa. In support of this notion,
differences in microbial composition have been found between
anorexic patients and healthy controls (Armougom et al., 2009).
Finally, new correlations among the microbiota composi-
tion, hormonal levels and metabolism come from studies of
gastric bypass surgery. Gastric bypass surgery has been shown
to alter the intestinal microbiota composition. Following Roux-
en-Y gastric bypass (RYGB), in both humans and rodents, the
relative abundance of Gammaproteobacteria (Escherichia)and
Verrucomicrobia (Akkermansia) increase. While microenviron-
mental changes such as reduced food intake and reduction of
bile acids likely affect this new microbiota composition (Mads-
bad, Dirksen and Holst 2014), some of the compositional changes
are likely due to alterations in the levels of intestinal hor-
mones including elevation of glucose-dependent insulinotropic
polypeptide (GIP), GLP1 and insulin following surgery (Laferrere
2011;Ostoet al., 2013). These alterations in the gut microbiome
further contribute to reduced host weight and adiposity. Accord-
ingly, transfer of the gut microbiota from RYGB-treated mice to
non-operated GF mice resulted in weight loss and decreased fat
mass in the recipient animals relative to recipients of the micro-
biota induced by sham surgery (Liou et al., 2013).
A growing amount of evidence has linked both hormones and
the microbiome to immune responses under healthy conditions
and autoimmune disease (AD). There are many interconnec-
tions between them, and the microbiome and hormones may
work through shared pathways to affect the immune response.
Hormones inuence the immune system in many ways. The
immune and neuroendocrine systems share a common set of
hormones and receptors. Glucocorticoids such as corticosterone
and cortisol regulate inammation levels and have effects both
on the innate and adaptive immune responses (Franchimont
2004). Additionally, vitamin D affects immune cell responses
by enhancing antigen presentation (Bhalla et al., 1989). More-
over, sex hormones affect the immune response in numerous
ways (Whitacre 2001; Lasarte et al., 2013; Priyanka et al., 2013;
Sankaran-Walters et al., 2013). Many AD are more common in
females, perhaps partly due to hormonal differences (Whitacre
2001; Ober, Loisel and Gilad 2008). Mouse models of AD in which
hormone levels were altered revealed changes in disease inci-
dence; for example, androgen treatment in a type 1 diabetes
(T1D) non-obese diabetic (NOD) mouse model prevents the de-
velopment of diabetes (Fox 1992).
10 FEMS Microbiology Reviews
Figure 4. A model describing the pathway leading to male protectionfrom T1D in NOD mice. Testosterone enriches the male microbiome with specic bacteria including
SFB, E. coli and Shigella-like bacteria. Together, they are proposed to activate the immune system and lead to gender-specic protection from T1D. Transplantation of
male microbiome into females elevates testosterone levels and leads to protection from T1D as well (Markle et al., 2013).
However, the gut microbiota also plays a role in modu-
lating the immune response, both locally and systemically
(Kamada et al., 2013), beyond repressing pathogenic microbes. In
the absence of commensal bacteria, GF mice have impaired de-
velopment of the innate and adaptive immune system (Hill and
Artis 2010; Littman and Pamer 2011; Honda and Littman 2012;
Hooper, Littman and Macpherson 2012), reduced numbers of
IgA-producing plasma cells (Crabbe et al., 1969) and a decreased
percentage of CD4+T cells (Ostman et al., 2006). Additionally,
T helper 17 (TH17) cells, which produce pro-inammatory cy-
tokines, are regulated by gut bacteria and are promoted specif-
ically by segmented lamentous bacteria (SFB) (Tanabe 2013).
Finally, AD have also been correlated with alterations of
the microbiome (dysbiosis). The most extensively studied ex-
ample is T1D as presented in Fig. 4(Brown et al., 2011;
Hara et al., 2013).
Thus, both hormones and the gut microbiota play essential
roles affecting immunity, and some of their roles may be linked
through shared pathways or additive effects. The rst to show
such a triangular link between the microbiota, hormones and
immunity were Markle et al. (2013), who demonstrated in the
NOD mouse model that microbes raise testosterone levels in
male hosts, causing protection from T1D. In this mouse model,
females are at higher risk of T1D. However, immature females
that received microbiome transplants from adult males showed
elevated levels of testosterone as well as protection from T1D.
In contrast, NOD mice under GF conditions had a similar dia-
betes risk for both sexes. Furthermore, the researchers found
metabolomic changes including levels of glycerophospholipid
and sphingolipid metabolites to be different in mice with typ-
ically male or typically female microbiota (Markle et al., 2013).
This study establishes a direct relationship between the micro-
biome and hormones and will open new research paths further
linking these components. Additional studies of these phenom-
ena, including high-throughput sequencing of the microbiota
and gene expression analysis, suggest that hormones and mi-
crobiota contribute in an additive manner to T1D protection in
NOD mice (Yurkovetskiy et al., 2013).
A different example linking the microbiota, hormones and
immunity comes from a study in mice, which showed that L.
reuteri enhances wound-healing properties in the host through
upregulation of the neuropeptide hormone oxytocin, by a vagus
nerve-mediated pathway (Poutahidis et al., 2013). The induced
hormonal levels lead to higher levels of specic regulatory T cells
required for wound healing. Lactobacillus reuteri also supports
thick healthy fur in mice, and greater grooming activity, due to
a bacteria-triggered interleukin-10-dependent mechanism and
higher oxytocin levels, respectively (Levkovich et al., 2013).
Although no direct connection has been shown to date between
the microbiota and growth hormones, the microbiome’s effects
on ghrelin and sex hormones may indirectly promote release
of growth hormones (Howard et al., 1996). Additionally, SCFAs
have been shown to inhibit growth hormones in cows, by affect-
ing gene transcription in a cAMP/PKA/CREB-mediated signaling
pathway (Wang et al., 2013). Furthermore, bacteria produce so-
matostatin, which is a known growth hormone inhibitor (Leroith
et al., 1982).
In D. melanogaster, both L. plantarum and Acetobacter pomo-
rum (A. pomorum) were found to be involved in growth promo-
tion. Lactobacillus plantarum promotes larval growth upon nutri-
ent scarcity, by acting genetically upstream of the host nutrient
sensing system controlling hormonal growth signaling (Storelli
et al., 2011). Accordingly, larval development is prolonged in GF
ies, and they exhibit signicantly reduced metabolic rates and
altered carbohydrate allocations, including elevated glucose lev-
els (Ridley et al., 2012). Moreover, late larval development in GF
ies and the metabolic alterations were reversed by adding A.
pomorum. Genes in the pyrroloquinoline quinone-dependent al-
cohol dehydrogenase (PQQ-ADH)pathway of A. pomorum are re-
quired for expression of Drosophila insulin-like peptides, which
act as growth factors and are necessary for normal larvae devel-
opment and metabolism (Shin et al., 2011).
Although the eld of microbiome research is new and develop-
ing, a signicant number of studies already link hormones and
the gut microbiota. Hormones regulated by the microbiota span
all functional classes and exert broad inuences on host be-
havior, metabolism and appetite, growth, reproduction and im-
munity. As the understanding of the precise roles of the micro-
biome deepens, we expect that additional mechanisms will be
shown to involve hormones, including novel interactions. Re-
search in the near future will identify both direct and indirect
pathways (e.g. via immune system components) by which bacte-
ria affect hormones. Specic classes of bacteria (as well as other
Neuman et al. 11
microorganisms including archaea, bacteriophages, eukaryotes
and eukaryotic viruses) will likely have regulatory roles con-
trolling host hormone levels. These ndings may potentially
be used in the future for development of new treatments for
hormone-related diseases or disorders, autoimmune disorders
linked to gender or hormonal activity, and even emotional states
such as stress. In our vision, we see how behavior could be
controlled by the gut microbiota, we see the potential to al-
ter metabolic hormone levels, overcoming depression or stress
by swallowing a combination of ‘good bacteria’. While this still
sounds like science ction, these novel approaches may be-
come reality within a few years. However, in order to validate
such approaches, the mechanisms, precise bacterial strains and
endocrine-microbiome crosstalk must all be thoroughly deci-
We are grateful for the Marie Curie Career Integration Grant and
the Ihel Foundation for their support.
Conict of interest statement.None declared.
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... Sex steroid hormones, such as estradiol, progesterone, and testosterone play an important physiological role in reproduction, differentiation, cell proliferation, apoptosis, inflammation, metabolism, homeostasis, and brain function (Edwards, 2005;Qi et al., 2021). Bacteria can produce and secrete hormones, and the crosstalk between microbes and hormones can affect host metabolism, immunity, and behavior (Markle et al., 2013;Neuman et al., 2015). The microbiota also reported to participate the reproductive endocrine system by producing and interacting with estrogen, androgens, insulin, and other hormones (insulin like growth factor 1, leptin, serotonin, melatonin, etc.) in humans and animal models (Neuman et al., 2015;Yan and Charles, 2018;Jenson et al., 2020;Qi et al., 2021). ...
... Bacteria can produce and secrete hormones, and the crosstalk between microbes and hormones can affect host metabolism, immunity, and behavior (Markle et al., 2013;Neuman et al., 2015). The microbiota also reported to participate the reproductive endocrine system by producing and interacting with estrogen, androgens, insulin, and other hormones (insulin like growth factor 1, leptin, serotonin, melatonin, etc.) in humans and animal models (Neuman et al., 2015;Yan and Charles, 2018;Jenson et al., 2020;Qi et al., 2021). Imbalance of the gut microbiota composition can lead to several reproduction dysfunction, such as polycystic ovary syndrome (PCOS), endometriosis, and ovarian cancer in mammal (Baker et al., 2017;Insenser et al., 2018;Giudice et al., 2021;Qi et al., 2021). ...
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The underlying mechanism between the gut microbiota and reproductive function is not yet well-known. This study was conducted to investigate the effect of the administration of fecal microbiota transplantation (FMT) from highly laying rate donors on the cecal microbiota, intestinal health and ovarian function in broiler breeders. A total of 60 broiler breeders (53-wk-age) were selected by their laying rate [high (HP, 90.67% ± 0.69%; n = 10) and low (LP, 70.23% ±0.87%; n = 20)]. The LP breeders were then be transplanted with fecal microbiota from HP hens (FMTHP; n = 10) or the same dosage of PBS (FMTCON; n = 10) for 28 days. The results revealed that FMT from HP donors increased egg laying rate and serum hormone levels [17β-estradiol (E2), anti-Müller hormone], also decreased proinflammatory cytokine levels (interleukin-6, interleukin-8, tumor necrosis factor-α) of LP breeders (P < 0.05). The FMTHP group breeders had higher villus height, villus height/crypt depth ratio, and up-regulated mRNA expression of jejunum barrier related gene (ZO-2 and mucin-2) and estrogen, FSH and AMH receptor genes (ESR1, ESR2, FSHR, AMHR) (P < 0.05) than FMTCON group. FMT from HP donors led to higher mRNA expression of Bcl2 and sirtuin1 (SIRT1), while it down-regulated the proapoptotic genes (Bax, caspase-3, caspase-8 and caspase-9) mRNA expressions in ovary compared with the FMTCON breeders (P < 0.05), and this pattern was also observed in HP donors. Also, HP breeder had higher observed_species and alpha-diversity indexes (Chao1 and ACE) than FMTCON group, while FMTHP can increase observed_species and alpha-diversity indexes (Chao1 and ACE) than FMTCON group (P < 0.05). The bacteria enrichment of Firmicutes (phylum), Bacteroidetes (phylum), Lactobacillus (genus), Enterococcus (genus) and Bacteroides (genus) were increased by FMTHP treatment. The genera Butyricicoccus, Enterococcus, and Lactobacillus were positively correlated with egg-laying rate. Therefore, cecal microbiomes of breeders with high egg-laying performance have more diverse activities, which may be related to the metabolism and health of the host; and FMT from high-yield donors can increase the hormone secretion, intestinal health, and ovarian function to improve egg laying-performance and the SIRT1 related apoptosis and cytokine signaling pathway were involved in this process.
... EDs are a multifactorial health problem that depends on diet composition, genetic, and environmental factors, including the gut microbiota [151,152]. Such influence may be due to the modulatory effects of the gut microbiome (per transcriptome regulation) on hormones such as GLP-1, PYY, GIP and leptin [153,154]. ...
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The literature on the crosstalk between the brain and the gut has increased considerably in recent years. It is widely accepted now that the microbiome plays a significant role in several brain disorders, neurodevelopment, neurocognitive stages, and physiological functions. However, the mechanisms that influence such crosstalk are still not well elucidated. In this sense, one of the possible mechanisms by which the microbiome could influence brain function is through gut hormones released by enteroendocrine cells: ghrelin, cholecystokinin (CCK), peptide YY (PYY), vasoactive intestinal polypeptide (VIP), glucagon-like peptide (GLP1-2), corticotropin-releasing factor (CRF), glucose-dependent insulinotropic polypeptide (GIP), secretin, serotonin (5-HT), and oxytocin. Especially when one considers that the brain expresses receptors for these hormones in areas important to the neurobiology of brain disorders (e.g., depression), such as the hippocampus, amygdala, hypothalamus, and suprachiasmatic nucleus. To strengthen this hypothesis, gastrointestinal dysfunction (such as altered motility or pain) is relatively common in depressive patients, and changes in diet (low-carbohydrate diets, for example) positively affect mood. Additionally, alterations in the gut microbiome are relatively common in depressive patients and are related to the levels of Akkermansia, Lactobacillus, Bifidobacteria, Faecalibacterium, Roseburia and Clostridium. Finally, concerning the gut-released hormones, the literature reports that ghrelin can be a peripheral marker for the antidepressant treatment success rate and has elevated levels during depression. GLP-1 is tightly correlated with HPA axis activity being decreased by high cortisol levels. CCK seems to be altered in depression due to increased inflammation and activation of Toll-like receptor 4. Such finds allow the postulation that hormones, the microbiome and mood are intertwined and co-dependent. VIP is correlated with circadian rhythms. There is a bidirectional connection of the circadian rhythms between the host and the microbiota. Circadian rhythm disruption is associated with both poor outcomes in mental health and alterations in the microbiota composition. In sum, in the past year, more and more research has been published showing the tight connection between gut and brain health and trying to decipher the feedback in play. Here, we focus on depression.
... The bile acids and SCFAs that are arising from the maternal microbial metabolome can penetrate the placental barrier post absorption, thereby promoting the development and growth of the fetal organs (17). 5-Hydroxytryptamine (5-HT) is an important neurotransmitter found in the brain and intestines of mammals (18). Diet affects the secretion of 5-HT in the intestine, which regulates intestinal movement, mood, appetite, sleep, and cognitive functions (19). ...
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The maternal gut microbiome affects the duration of pregnancy, delivery, and lactation. It also coordinates the stability of maternal metabolism by regulating and modulating inflammatory cytokines and reproductive hormones. This has been shown in several species; however, the situation in ruminants remains a black box. Here, we aimed to elucidate the relationship between the hindgut microbiota, metabolism, and reproductive hormones in domestic goats (Capra hircus) during nonpregnancy, pregnancy, and lactation stages. The hindgut microbiota was altered during these three stages, with a drastic decrease in the abundance of Family_XIII_AD3011_group in the second and third trimesters of pregnancy. Additionally, a decline in the abundance of Christensenellaceae_R-7_group and Turicibacter was observed from the nonpregnancy stage to late gestation. Family_XIII_AD3011_group and Paeniclostridium were strongly correlated with decreased fecal estradiol and progesterone. Furthermore, we generated a metabolome atlas of the gut and serum from nonpregnancy to lactation to reveal the specific metabolic fingerprints of each physiological stage. Several specific gut metabolites, including carnitine C8:1, γ-aminobutyric acid, and indole-3-carboxylic acid, were negatively correlated with the fecal and serum estradiol concentrations. In contrast, 2'-deoxyinosine, deoxyadenosine, and 5'-deoxyadenosine were positively correlated with the fecal and serum estradiol concentrations. The levels of 2'-deoxyinosine, deoxyadenosine, and 5'-deoxyadenosine in fecal samples were positively correlated with Family_XIII_AD3011_group. Other serum metabolites, such as (±)12-HEPE (hydroxy eicosapentaenoic acid), (±)15-HEPE, (±)18-HEPE, cytidine, uracil, and 5-hydroxyindole-3-acetic acid, were negatively correlated with the serum concentrations of estradiol and progesterone. Finally, Corynebacterium and Clostridium_sensu_stricto_1 in the fecal samples were positively correlated with the abundance of 11,12-EET (epoxy-eicosatrienoic acid), (±)18-HEPE, (±)15-HEPE, and (±)12-HEPE in the serum. IMPORTANCE Our findings revealed that the activity of Family_XIII_AD3011_group and Corynebacterium is strongly correlated with the beneficial regulation of physiological hormones and metabolic changes during pregnancy and lactation. These findings are key for guiding targeted microbial therapeutic approaches to modulate microbiomes in gestating and lactating mammals.
... Nowadays, it is generally believed that the metabolic ability of the gut microbiota is far superior to that of the human host (12). Interactive diversity between the gut microbiota and the pathophysiology of the host makes it clear that the gut microbiota not only affects the intestinal milieu but also has ability to influence distant tissues and pathways (13). Th17 cells play pathogenetic functions in gut, adipose tissue, liver and bone. ...
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T Helper 17 (Th17) cells are adaptive immune cells that play myriad roles in the body. Immune–endocrine interactions are vital in endocrine organs during pathological states. Th17 cells are known to take part in multiple autoimmune diseases over the years. Current evidence has moved from minimal to substantial that Th17 cells are closely related to endocrine organs. Diverse tissue Th17 cells have been discovered within endocrine organs, including gut, adipose tissue, liver and bone, and these cells are modulated by various secretions from endocrine organs. Th17 cells in these endocrine organs are key players in the process of an array of metabolic disorders and inflammatory conditions, including obesity, insulin resistance, nonalcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), osteoporosis and inflammatory bowel disease (IBD). We reviewed the pathogenetic or protective functions played by Th17 cells in various endocrine tissues and identified potential regulators for plasticity of it. Furthermore, we discussed the roles of Th17 cells in crosstalk of gut-organs axis.
... Ninety percent of pathological problems are linked to intestinal chronic inflammation [61]. Disbalance of the gut microbiota has negative effects on the health and biology of metazoans because the gut integrity, biology, metabolism, nutrition, immunity, and neuroendocrine system are all dependent on a healthy microbiota [62][63][64][65][66][67], which is in constant interaction with the microbiota-brain-gut axis. In conclusion, it is justified to qualify oxidative stress and intestinal inflammation as the "secret killers" in animal farming, especially in poultry farming [56,62,68]. ...
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Chronic stress is recognized as a secret killer in poultry. It is associated with systemic inflammation due to cytokine release, dysbiosis, and the so-called leaky gut syndrome, which mainly results from oxidative stress reactions that damage the barrier function of the cells lining the gut wall. Poultry, especially the genetically selected broiler breeds, frequently suffer from these chronic stress symptoms when exposed to multiple stressors in their growing environments. Since oxidative stress reactions and inflammatory damages are multi-stage and long-term processes, overshooting immune reactions and their down-stream effects also negatively affect the animal’s microbiota, and finally impair its performance and commercial value. Means to counteract oxidative stress in poultry and other animals are, therefore, highly welcome. Many phytogenic substances, including flavonoids and phenolic compounds, are known to exert anti-inflammatory and antioxidant effects. In this review, firstly, the main stressors in poultry, such as heat stress, mycotoxins, dysbiosis and diets that contain oxidized lipids that trigger oxidative stress and inflammation, are discussed, along with the key transcription factors involved in the related signal transduction pathways. Secondly, the most promising phytogenic substances and their current applications to ameliorate oxidative stress and inflammation in poultry are highlighted.
... These body sites were selected because their microbial communities potentially influence function and health of the respiratory, digestive, and reproductive system in these animals [23]. Additionally, because of a putative cross talk that occurs between microbiota and their host, in ways that sometimes transcend body site [24,25], we not only explored core membership of each community but also ubiquitous features across these three environments. ...
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Background Exploring the microbiome in multiple body sites of a livestock species informs approaches to promote its health and performance through efficient and sustainable modulation of these microbial ecosystems. Here, we employed 16S rRNA gene sequencing to describe the microbiome in the oropharyngeal cavity, proximal colon, and vaginal tract of Jeju Black pigs (JBP), which are native to the Korean peninsula. Results We sampled nine 7-month-old JBP gilts raised under controlled conditions. The most abundant phyla that we found within the oropharyngeal microbiota were Proteobacteria , Bacteroidetes , Fusobacteria and Firmicutes, collectively providing core features from twenty-five of their genera. We also found a proximal colonic microbial core composed of features from twenty of the genera of the two predominant phyla, Firmicutes , and Bacteroidetes . Remarkably, within the JBP vaginal microbiota, Bacteroidetes dominated at phylum level, contrary to previous reports regarding other pig breeds. Features of the JBP core vaginal microbiota, came from seventeen genera of the major phyla Bacteroidetes , Firmicutes , Proteobacteria , and Fusobacteria. Although these communities were distinct, we found some commonalities amongst them. Features from the genera Streptococcus , Prevotella , Bacillus and an unclassified genus of the family Ruminococcaceae were ubiquitous across the three body sites. Comparing oropharyngeal and proximal colonic communities, we found additional shared features from the genus Anaerorhabdus . Between oropharyngeal and vaginal ecosystems, we found other shared features from the genus Campylobacter , as well as unclassified genera from the families Fusobacteriaceae and Flavobacteriaceae . Proximal colonic and vaginal microbiota also shared features from the genera Clostridium , Lactobacillus, and an unclassified genus of Clostridiales . Conclusions Our results delineate unique and ubiquitous features within and across the oropharyngeal, proximal colonic and vaginal microbial communities in this Korean native breed of pigs. These findings provide a reference for future microbiome-focused studies and suggest a potential for modulating these communities, utilizing ubiquitous features, to enhance health and performance of the JBP.
In recent decades, various roles of the gut microbiota in physiological and pathological conditions have been uncovered. Among the many interacting pathways between the host and gut flora, the gut-brain axis has drawn increasing attention and is generally considered a promising way to understand and treat brain tumors, one of the most lethal neoplasms. In this narrative review, we aimed to unveil and dissect the sophisticated mechanisms by which the gut-brain axis exerts its influence on brain tumors. Furthermore, we summarized the latest research regarding the gastrointestinal microbial landscape and the effect of gut-brain axis malfunction on different brain tumors. Finally, we outlined the ongoing developing approaches of microbial manipulation and their corresponding research related to neuro-malignancies. Collectively, we recapitulated the advances in gut microbial alterations along with their potential interactive mechanisms in brain tumors and encouraged increased efforts in this area.
Recent findings have supported an association between deviations in gut microbiome composition and schizophrenia. However, the extent to which the gut microbiota contributes to schizophrenia remains unclear. Moreover, studies have yet to explore variations in ecological associations among bacterial types in subjects with schizophrenia, which can reveal differences in community interactions and gut stability. We examined the dataset collected by Nguyen et al. (2021) to investigate the similarities and differences in gut microbial constituents between 48 subjects with schizophrenia and 48 matched non-psychiatric comparison cases. We re-analyzed alpha- and beta-diversity differences and completed modified differential abundance analyses and confirmed the findings of Nguyen et al. (2021) that there was little variation in alpha-diversity but significant differences in beta-diversity between individuals with schizophrenia and non-psychiatric subjects. We also conducted mediation analysis, developed a machine learning (ML) model to predict schizophrenia, and completed network analysis to examine community-level interactions among bacterial taxa. Our study offers new insights, suggesting that the gut microbiome mediates the effects between schizophrenia and smoking status, BMI, anxiety score, and depression score. Our differential abundance and network analysis findings suggest that the differential abundance of Lachnospiraceae and Ruminococcaceae taxa fosters a decrease in stabilizing competitive interactions in the gut microbiome of subjects with schizophrenia. Loss of this competition may promote ecological instability and dysbiosis, altering gut-brain axis interactions in these subjects.
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The psychosomatic approach to medically unexplained symptoms, myalgic encephalomyelitis and chronic fatigue syndrome (MUS/ME/CFS) is critically reviewed using scientific criteria. Based on the 'Biopsychosocial Model', the psychosomatic theory proposes that patients' dysfunctional beliefs, deconditioning and attentional biases cause or make illness worse, disrupt therapies, and lead to preventable deaths. The evidence reviewed suggests that none of these psychosomatic hypotheses is empirically supported. The lack of robust supportive evidence together with the use of fal-lacious causal assumptions, inappropriate and harmful therapies, broken scientific principles, repeated methodological flaws and an unwillingness to share data all give the appearance of cargo cult science. The psychosomatic approach needs to be replaced by a scientific, biologically grounded approach to MUS/ME/CFS that can be expected to provide patients with appropriate care and treatments. Patients with MUS/ME/CFS and their families have not been treated with the dignity, respect and care that is their human right. Patients with MUS/ME/CFS and their families could consider a class action legal case against the injuring parties.
Sex steroid hormones are not only synthesized from the gonads but also by other tissues, such as the brain (i.e., neurosteroids) and colon (i.e., gut steroids). Gut microbiota can be shaped from sex steroid hormones synthesized from the gonads and locally interacts with gut steroids as in turn modulates neurosteroids. Type 1 diabetes mellitus (T1DM) is characterized by dysbiosis and also by diabetic encephalopathy. However, the interactions of players of gut-brain axis, such as gut steroids, gut permeability markers and microbiota, have been poorly explored in this pathology and, particularly in females. On this basis, we have explored, in streptozotocin (STZ)-induced adult female rats, whether one month of T1DM may alter (I) gut microbiome composition and diversity by 16S next-generation sequencing, (II) gut steroid levels by liquid chromatography-tandem mass spectrometry, (III) gut permeability markers by gene expression analysis, (IV) cognitive behavior by the novel object recognition (NOR) test and whether correlations among these aspects may occur. Results obtained reveal that T1DM alters gut β-, but not α-diversity. The pathology is also associated with a decrease and an increase in colonic pregnenolone and allopregnanolone levels, respectively. Additionally, diabetes alters gut permeability and worsens cognitive behavior. Finally, we reported a significant correlation of pregnenolone with Blautia, claudin-1 and the NOR index and of allopregnanolone with Parasutterella, Gammaproteobacteria and claudin-1. Altogether, these results suggest new putative roles of these two gut steroids related to cognitive deficit and dysbiosis in T1DM female experimental model.
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When an animal detects a stressor, it initiates a stress response. The physiological aspects of this stress response are mediated through two endocrine systems. The catecholamine hormones epinephrine and norepinephrine are released from the adrenal medulla very rapidly and have numerous effects on behavior, metabolism, and the cardiovascular system. This is commonly termed the Fight-or-Flight response. On a longer time scale, the glucocorticoid hormones are released from the adrenal cortex. They interact with intracellular receptors and initiate gene transcription. This production of new proteins means that glucocorticoids have a delayed, but more sustained, effect than the catecholamines. The glucocorticoids orchestrate a wide array of responses to the stressor. They have direct effects on behavior, metabolism and energy trafficking, reproduction, growth, and the immune system. The sum total of these responses is designed to help the animal survive a short-term stressful stimulus. However, under conditions of long-term stress, the glucocorticoid-mediated effects become maladaptive and can lead to disease.
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Assessment and characterization of gut microbiota has become a major research area in human disease, including type 2 diabetes, the most prevalent endocrine disease worldwide. To carry out analysis on gut microbial content in patients with type 2 diabetes, we developed a protocol for a metagenome-wide association study (MGWAS) and undertook a two-stage MGWAS based on deep shotgun sequencing of the gut microbial DNA from 345 Chinese individuals. We identified and validated approximately 60,000 type-2-diabetes-associated markers and established the concept of a metagenomic linkage group, enabling taxonomic species-level analyses. MGWAS analysis showed that patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulphate reduction and oxidative stress resistance. An analysis of 23 additional individuals demonstrated that these gut microbial markers might be useful for classifying type 2 diabetes.
Assortative mating, considered to be an early event in speciation, has been studied for decades in the context of divergent adaptation. In Drosophila it is commonly attributed to genetic elements in the flies that exhibit assortative mating. However, some cases have been reported where the genetic basis for these differences was unclear. In light of the Hologenome Theory of Evolution (Zilber-Rosenberg and Rosenberg, 2008), we considered the microbiota of Drosophila as an additional element, acting together with its host to better adapt to a changing environment. The microbiota of any organism is closely linked to its host. Many of the impacts of the microbiota on its host are known. New evidence shows an interesting, previously unknown, role of the microbiota in influencing its host’s behavior. In one case, as a result of adaptation to a new substrate, the microbiota changed with behavioral implications on its host flies. By changing its host’s mating preference, the microbiota has the potential of driving the evolution of its host. In this chapter, the mating process in Drosophila will be reviewed within the framework of the hologenome theory of evolution. Some conclusions and speculations on how microbes and their Drosophila host interact will be presented.
Background: The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis result from alterations in intestinal microbes and the immune system. However, the precise dysfunctions of microbial metabolism in the gastrointestinal microbiome during IBD remain unclear. We analyzed the microbiota of intestinal biopsies and stool samples from 231 IBD and healthy subjects by 16S gene pyrosequencing and followed up a subset using shotgun metagenomics. Gene and pathway composition were assessed, based on 16S data from phylogenetically-related reference genomes, and associated using sparse multivariate linear modeling with medications, environmental factors, and IBD status. Results: Firmicutes and Enterobacteriaceae abundances were associated with disease status as expected, but also with treatment and subject characteristics. Microbial function, though, was more consistently perturbed than composition, with 12% of analyzed pathways changed compared with 2% of genera. We identified major shifts in oxidative stress pathways, as well as decreased carbohydrate metabolism and amino acid biosynthesis in favor of nutrient transport and uptake. The microbiome of ileal Crohn's disease was notable for increases in virulence and secretion pathways. Conclusions: This inferred functional metagenomic information provides the first insights into community-wide microbial processes and pathways that underpin IBD pathogenesis.
Bariatric surgery is the most effective treatment for obesity and also greatly improves glycaemic control, often within days after surgery, independently of weight loss. Laparoscopic adjustable gastric banding (LAGB) was designed as a purely restrictive procedure, whereas vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) induce changes in appetite through regulation of gut hormones, resulting in decreased hunger and increased satiation. Thus, VSG and RYBG more frequently result in remission of type 2 diabetes than does LAGB. With all three of these procedures, remission of diabetes is associated with early increases in insulin sensitivity in the liver and later in peripheral tissues; VSG and RYBG are also associated with improved insulin secretion and an exaggerated postprandial rise in glucagon-like peptide 1. The vagal pathway could have a role in the neurohumoral regulatory pathways that control appetite and glucose metabolism after bariatric surgery. Recent research suggests that changes in bile acid concentrations in the blood and altered intestinal microbiota might contribute to metabolic changes after surgery, but the mechanisms are unclear. In this Series paper, we explore the possible mechanisms underlying the effects on glucose metabolism and bodyweight of LAGB, VSG, and RYGB surgery. Elucidation of these mechanisms is providing knowledge about bodyweight regulation and the pathophysiology of type 2 diabetes, and could help to identify new drug targets and improved surgical techniques.