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FEMS Microbiology Reviews
doi: 10.1093/femsre/fuu010
Review Article
REVIEW ARTICLE
Microbial endocrinology: the interplay between
the microbiota and the endocrine system
Hadar Neuman1, Justine W. Debelius2, Rob Knight2,$ andOmryKoren
1,∗
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;
E-mail: Omry.Koren@biu.ac.il
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 inuencing 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
ABSTRACT
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 inuence metabolism, immunity and even
behavior. Essential questions, which are just starting to be answered, are what are the mechanisms by which these bacteria
affect specic host characteristics. One important but understudied mechanism appears to involve hormones. Although
the precise pathways of microbiota-hormonal signaling have not yet been deciphered, specic 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
INTRODUCTION
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
C
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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 dene the eld of micro-
bial endocrinology research, after observing that stress-induced
neuroendocrine hormones can inuence 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 inuence 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 (specic microbes thought to be
benecial 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.
BEHAVIOR
The gut microbiota inuences 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 inuence
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 inammation 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 inuence 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
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, biolm 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 inuence
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.
Functional
class Hormone Model Finding
Microbial
species Ref
Bacterial
growth and
expres-
sions
Epinephrine,
dopamine, dopa
Bacterial growth Catecholamines induce bacterial growth E. coli, Yersinia.
enterocolitica
and
Pseudomonas
aeruginosa
Lyte and Ernst
(1992)
Epinephrine,
norepinephrine
QS QS and host hormone crosstalk E. coli Sperandio et al.
(2003)
Epinephrine Bacterial gene
expression
Hormones affect bacterial virulence
gene expression
E. coli Sperandio et al.
(2003)
Norepinephrine,
epinephrine,
dopamine
Bacterial growth Catecholamines induce bacterial growth E. coli,
Salmonella
enterica and Y.
enterocolitica
Freestone and
Lyt e (2008)
Norepinephrine Bacterial growth
and
characteristics
Enhanced bacterial growth and
virulence
P. aeruginosa Hegde et al.
(2009)
Norepinephrine Biolm growth Catecholamines induce biolm growth Staphylococcus
epidermidis
Lyt e et al. (2003)
Estriol, estradiol QS Hormones decrease bacteria virulence Agrobacterium
tumefaciens, P.
aeruginosa
Roshchina
(2010)
Norepinephrine Bacterial
production
Gut microbiota produce and respond to
norepinephrine
N/A Roshchina
(2010)
Epinephrine Bacterial
resistance
Epinephrine decreases bacterial
resistance to host antimicrobial peptides
Salmonella Sperandio et al.
(2003)
Estrogen,
progesterone
Bacterial growth Estradiol and progesterone enhance
bacterial growth
Platysaurus
intermedius
Kornman and
Loesche (1982)
Host
behavior
Tryptophan, 5-HT
and 5-
hydroxyindoleacetic
acid
GF mice Elevated hipocampal levels in male GF
mice
N/A Clarke et al.
(2013)
Serotonin Bacterial
production of
neurotransmitter
Gut microbiota produce serotonin Streptococcus,
Escherichia and
Enterococcus
spp.
Roshchina
(2010)
Dopamine Bacterial
production
Gut microbiota produce and respond to
dopamine
Bacillus and
Serratia
Roshchina
(2010)
Serotonin GF mice Low plasma serotonin levels in GF mice N/A Wikoff et al.
(2009)
Tryptophan, 5-HT Infected rats Higher plasma levels in infected rats B. infantis Desbonnet et al.
(2008)
Norepinephrine,
dopamine
GF mice Low free lumen catecholamines in GF
mice
N/A Asano et al.
(2012)
GABA Bacterial
production
Microbiota produce GABA Lactobacillus Asano et al.
(2012)
GABA Probiotics in
mice
Bacteria alter host GABA receptors L. rhamnous Bravo et al.
(2011)
Corticosterone Probiotics in
mice
Low levels of corticosterone in treated
mice
L. rhamnous Bravo et al.
(2011)
Corticosterone,
adrenocorticos-
terone
GF mice Elevated levels in GF mice N/A Grenham et al.
(2011)
Corticosterone,
adrenocorticos-
terone
Probiotics in rats
and humans
Bacteria reduce levels of stress
hormones
L. helveticus and
B. longum
Messaoudi et al.
(2011)
L-DOPA Antibiotics in
Parkinson’s
patients
Eliminating H. Pylori elevates L-DOPA
levels
H. pylori Pierantozzi
et al. (2006)
Host
mating
cVA and CHs D. melanogaster Pheromone levels affected by antibiotics
and bacteria addition
L. plantarum Sharon et al.
(2010)
Guaiacol S. gregaria Pheromone produced by commensal
bacteria, abolished in GF locust
P. agglomerans;
K. pneumonia; E.
cloacae
Dillon, Vennard
and Charnley
(2002)
Volatile fatty acids Hyena Species-specic volatiles correlated to
bacterial populations in scent glands
N/A Theis et al.
(2013)
4FEMS Microbiology Reviews
Tab l e 1 . (continued.)
Functional
class Hormone Model Finding
Microbial
species Ref
Host
appetite
and
metabolisms
Leptin Antibiotics in
rats
Vancomycin leads to decrease in
circulating leptin levels
N/A Lam et al. (2012)
Probiotics in
smokers
Reduced serum leptin L. plantarum Naruszewicz
et al. (2002)
Male rats Specic bacteria positively correlated
with circulating leptin
Bidobacterium,
Lactobacillus,
Queipo-Ortuno
et al. (2013)
Male rats Specic bacteria negatively correlated
with circulating leptin
Clostridium,
Bacteroides and
Prevotella
Queipo-Ortuno
et al. (2013)
Mice (including
leptin decient)
Specic bacteria positively correlated
with circulating leptin
Mucispirillium,
Lactococcus and
an uncultured
member of the
Lach-
nospiraceae
Ravussin et al.
(2012)
Mice (including
leptin decient)
Specic bacteria negatively correlated
with circulating leptin
Allobaculum Ravussin et al.
(2012)
Ghrelin Male rats Specic bacteria positively correlated
with ghrelin
Bacteroides and
Prevotella spp.
Queipo-Ortuno
et al. (2013)
Male rats Specic bacteria negatively correlated
with ghrelin
Bidobacterium,
Lactobacillus
and B.
coccoides–E.
rectale group
Queipo-Ortuno
et al. (2013)
Prebiotics
(oligofructose) in
obese humans
Prebiotics decrease secretion of ghrelin Promoted
growth of
Bidobacterium
and
Lactobacillus
Parnell and
Reimer (2009)
Insulin Metagenomics of
diabetic women
Negative correlations between insulin
levels and bacterial populations
Clostridium spp.
B. intestinalis
Karlsson et al.
(2013)
Insulin Bacterial transfer
from lean donors
to metabolic
syndrome
patients
Lean human subjects have increased
insulin sensitivity due to their
microbiome, compared to metabolic
syndrome patients
Correlated with
butyrate-
producing
intestinal
microbiota
Vrieze et al.
(2012)
GLP-1 GF and antibiotic
treated mice
Intestinal microbiota lower GLP-1 levels N/A Wichmann
et al. (2013)
GLP-1 Probiotics in
mice
Intestinal microbiota increase GLP-1
levels
B. breve, B.
longum, B.
infantis, L.
acidophilus, L.
plantarum, L.
paracasei, L.
bulgaricus,
Streptococcus
thermophilus
Yad av et al.
(2013)
GLP-1 Bariatric surgery
in rats
Intestinal microbiota changes correlate
with elevated GLP-1 levels
N/A Osto et al. (2013)
Angptl4 Probiotics in
mice
Elevated Angptl4 levels in treated mice L. paracasei Aronsson et al.
(2010)
Somatostatin Bacterial
production
Bacteria produce somatostatin Bacillus subtilis LeRoith et al.
(1985)
Alpha-melanocyte-
stimulating
hormone,
neuropeptide Y,
agouti-related
protein, ghrelin and
leptin
GF rats Altered levels of autoantibodies against
appetite hormones
N/A Fetissov et al.
(2008)
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
microbiota
Suppression of Angptl4 expression
following colonization
N/A Backhed (2009)
Neuman et al. 5
Tab l e 1 . (continued.)
Functional
class Hormone Model Finding
Microbial
species Ref
Sex
hormones
and repro-
duction
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-
Clostridiales
and three
genera in the
Ruminococ-
caceae
family
Adlercreutz
et al. (1984)
Androgens Enzymatic and
kinetic
experiments
Bacteria convert glucocorticoids to
androgens
C. scindens Winter et al.
(1984)
Testosterone NOD mice Microbes raise testosterone levels in
male NOD mice
N/A Markle et al.
(2013)
Host
growth
Bovine growth
hormone
Cows SCFAs inhibit bovine growth hormone N/A Wang et al.
(2013)
Growth hormones Probiotics in D.
melanogaster
Probiotics promote growth hormone
signaling
L. plantarum Storelli et al.
(2011)
Insulin-like
peptides
Probiotics in D.
melanogaster
Bacterial genes are required for growth
factors
A. pomorum Shin et al. (2011)
Other Oxytocin Probiotics in
mice
Upregulation of oxytocin in treated mice L. reuteri Poutahidis et al.
(2013)
TSH GF rats ∼25% higher TSH levels in GF rats N/A Wostmann
(1996)
Prolactin GF rats ∼25% higher prolactin levels in GF rats N/A Wostmann
(1996)
Prolactin Cow cells SCFAs inhibit prolactin gene
transcription
N/A Wang et al.
(2013)
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-specic or tissue-specic. Serotonin
can also be produced by Streptococcus,Escherichia and Enterococcus
species (Roshchina 2010), and Bidobacterium 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 signicantly 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 insufcient 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-
tions.
Gamma-aminobutyric acid (GABA), the main inhibitory
neurotransmitter in the mammalian CNS, is also produced by
the microbiota and may inuence 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 specic 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).
MATING AND PHEROMONES
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
specic 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
behavior.
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 specic 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 proles of scent
secretions. The authors speculate that the symbiotic bacte-
ria make metabolites that provide species-specic 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 prole that affects host behavior (Singh et al., 1990). Bac-
terial communities producing specic scents may be linked to
host genetic background, as scent-mark communities differed
signicantly 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.
SEX HORMONES AND REPRODUCTION
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 modication (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 signicant 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-specic differences in fatty acid proles (Mittelstrass
et al., 2011). There are also gender-specic 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, specically in
the third trimester, and these changes lead to differences in
metabolism (Koren et al., 2012). These microbial changes include
a signicant increase in Proteobacteria and Actinobacteria as
pregnancy progresses. The third trimester is also characterized
by elevated low-grade inammation 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 inammatory
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.
APPETITE AND METABOLISM
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 proles 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 signicant 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, Bidobacterium 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 inammation and/or regulation
of mucus production (Ravussin et al., 2012; Queipo-Ortuno
et al., 2013). Recently, Rajala et al. demonstrated that leptin
might also inuence the gut microbiota independently of diet
(Rajala et al., 2014). Another model proposes that L. plantarum
specically 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
effects.
Ghrelin, another important appetite-regulating hormone, is
negatively correlated with the abundance of Bidobacterium, Lac-
tobacillus and B. coccoides–Eubacterium 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 Bidobacterium 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. Signicant
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 zebrash
model found a tissue-specic 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, specic 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).
IMMUNE RESPONSE
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 inuence 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 inammation 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 specic bacteria including
SFB, E. coli and Shigella-like bacteria. Together, they are proposed to activate the immune system and lead to gender-specic 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-inammatory 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 specic 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).
GROWTH AND DEVELOPMENT
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 signicantly 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).
CONCLUSIONS
Although the eld of microbiome research is new and develop-
ing, a signicant number of studies already link hormones and
the gut microbiota. Hormones regulated by the microbiota span
all functional classes and exert broad inuences 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. Specic 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-
phered.
ACKNOWLEDGEMENTS
We are grateful for the Marie Curie Career Integration Grant and
the Ihel Foundation for their support.
Conict of interest statement.None declared.
REFERENCES
Adlercreutz H, Pulkkinen MO, Hamalainen EK, et al. Studies on
the role of intestinal bacteria in metabolism of synthetic and
natural steroid hormones. J Steroid Biochem 1984;20:217–29.
Alex S, Lange K, Amolo T, et al. Short-chain fatty acids stimu-
late angiopoietin-like 4 synthesis in human colon adenocar-
cinoma cells by activating peroxisome proliferator-activated
receptor gamma. Mol Cell Biol 2013;33:1303–16.
Armougom F, Henry M, Vialettes B, et al. Monitoring bacterial
community of human gut microbiota reveals an increase in
Lactobacillus in obese patients and Methanogens in anorexic
patients. PloS One 2009;4:e7125.
Aroniadis OC, Brandt LJ. Fecal microbiota transplantation: past,
present and future. Curr Opin Gastroen 2013;29:79–84.
Aronsson L, Huang Y, Parini P, et al. Decreased fat storage
by Lactobacillus paracasei is associated with increased levels
of angiopoietin-like 4 protein (ANGPTL4). PloS One 2010;5:
e13087.
Asano Y, Hiramoto T, Nishino R, et al. Critical role of gut mi-
crobiota in the production of biologically active, free cate-
cholamines in the gut lumen of mice. Am J Physiol-Gastr L
2012;303:G1288–95.
Backhed F. Changes in intestinal microora in obesity: cause or
consequence? J Pediatr Gastr Nutr 2009;48 (Suppl 2):S56–57.
Beury-Cirou A, Tannieres M, Minard C, et al. At a supra-
physiological concentration, human sexual hormones act as
quorum-sensing inhibitors. PloS One 2013;8:e83564.
Bhalla AK, Williams MM, Lal S, et al. 1,25-Dihydroxyvitamin D3,
but not retinoic acid, induces the differentiation of U937
cells. Clin Exp Immunol 1989;76:274–7.
Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus
strain regulates emotional behavior and central GABA recep-
tor expression in a mouse via the vagus nerve. P Natl Acad Sci
USA 2011;108:16050–5.
Brown CT, Davis-Richardson AG, Giongo A, et al. Gut microbiome
metagenomics analysis suggests a functional model for the
development of autoimmunity for type 1 diabetes. PloS One
2011;6:e25792.
Camp JG, Jazwa AL, Trent CM, et al. Intronic cis-regulatory
modules mediate tissue-specic and microbial control of
angptl4/af transcription. PLoS Genet 2012;8:e1002585.
Cherbut C, Ferrier L, Roze C, et al. Short-chain fatty acids modify
colonic motility through nerves and polypeptide YY release
in the rat. Am J Physiol 1998;275:G1415–22.
Cho I, Yamanishi S, Cox L, et al. Antibiotics in early life al-
ter the murine colonic microbiome and adiposity. Nature
2012;488:621–6.
Clarke G, Grenham S, Scully P, et al. The microbiome-gut-
brain axis during early life regulates the hippocampal sero-
tonergic system in a sex-dependent manner. Mol Psychiatr
2013;18:666–73.
Crabbe PA, Nash DR, Bazin H, et al. Antibodies of the IgA type
in intestinal plasma cells of germfree mice after oral or par-
enteral immunization with ferritin. J Exp Med 1969;130:723–
44.
Cryan JF, O’Mahony SM. The microbiome-gut-brain axis: from
bowel to behavior. Neurogastroent Motil 2011;23:187–92.
Davie JR. Inhibition of histone deacetylase activity by butyrate. J
Nutr 2003;133:2485S–93S.
Desbonnet L, Garrett L, Clarke G, et al. The probiotic Bidobacte-
ria infantis: an assessment of potential antidepressant prop-
erties in the rat. J Psychiatr Res 2008;43:164–74.
Diaz Heijtz R, Wang S, Anuar F, et al. Normal gut microbiota mod-
ulates brain development and behavior. P Natl Acad Sci USA
2011;108:3047–52.
Dillon RJ, Vennard CT, Charnley AK. Exploitation of gut bacteria
in the locust. Nature 2000;403:851.
Dillon RJ, Vennard CT,Charnley AK. A note: gut bacteria produce
components of a locust cohesion pheromone. J Appl Microbiol
2002;92:759–63.
Dobbs RJ, Charlett A, Dobbs SM, et al. Towards dening a rigidity-
associated pathogenic pathway in idiopathic parkinsonism.
Neurodegener Dis 2012;10:183–6.
Elahi S, Ertelt JM, Kinder JM, et al. Immunosuppressive CD71
+erythroid cells compromise neonatal host defence against
infection. Nature 2013;504:158–62.
Fetissov SO, Hamze Sinno M, Coefer M, et al. Autoantibod-
ies against appetite-regulating peptide hormones and neu-
ropeptides: putative modulation by gut microora. Nutrition
2008;24:348–59.
Finegold SM, Dowd SE, Gontcharova V, et al. Pyrosequencing
study of fecal microora of autistic and control children.
Anaerobe 2010;16:444–53.
Flak MB, Neves JF, Blumberg RS. Immunology. Welcome to the
microgenderome. Science 2013;339:1044–5.
Flint HJ, Scott KP, Louis P, et al. The role of the gut microbiota in
nutrition and health. Nat Rev Gastroentero 2012;9:577–89.
Fox HS. Androgen treatment prevents diabetes in nonobese dia-
betic mice. J Exp Med 1992;175:1409–12.
Franchimont D. Overviewof the actions of glucocorticoids on the
immune response: a good model to characterize new path-
ways of immunosuppression for new treatment strategies.
AnnNYAcadSci2004;1024:124–37.
Freestone PP, Lyte M. Microbial endocrinology: experimental de-
sign issues in the study of interkingdom signalling in infec-
tious disease. Adv Appl Microbiol 2008;64:75–105.
Fukumoto S, Tatewaki M, Yamada T, et al. Short-chain fatty acids
stimulate colonic transit via intraluminal 5-HT release in
rats. Am J Physiol-Reg I 2003;284:R1269–76.
Fuqua C, Winans SC, Greenberg EP. Census and consen-
sus in bacterial ecosystems: the LuxR-LuxI family of
quorum-sensing transcriptional regulators. Annu Rev Micro-
biol 1996;50:727–51.
Grenham S, Clarke G, Cryan JF, et al. Brain-gut-microbe commu-
nication in health and disease. Front Physiol 2011;2:94.
12 FEMS Microbiology Reviews
Hara N, Alkanani AK, Ir D, et al. The role of the intestinal micro-
biota in type 1 diabetes. Clin Immunol 2013;146:112–9.
Hegde M, Wood TK, Jayaraman A. The neuroendocrine hormone
norepinephrine increases Pseudomonas aeruginosa PA14 viru-
lence through the las quorum-sensing pathway. Appl Micro-
biol Biot 2009;84:763–76.
Hill DA, Artis D. Intestinal bacteria and the regulation of immune
cell homeostasis. Annu Rev Immunol 2010;28:623–67.
Honda K, Littman DR. The microbiome in infectious disease and
inammation. Ann Rev Immunol 2012;30:759–95.
Hooper LV, Littman DR, Macpherson AJ. Interactions be-
tween the microbiota and the immune system. Science
2012;336:1268–73.
Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary
and hypothalamus that functions in growth hormone re-
lease. Science 1996;273:974–7.
Hsiao EY, McBride SW, Hsien S, et al. Microbiota modu-
late behavioral and physiological abnormalities associ-
ated with neurodevelopmental disorders. Cell 2013;155:
1451–63.
Hughes DT, Sperandio V. Inter-kingdom signalling: communi-
cation between bacteria and their hosts. Nat Rev Microbiol
2008;6:111–20.
Iyer LM, Aravind L, Coon SL, et al. Evolution of cell-cell signaling
in animals: did late horizontal gene transfer from bacteria
have a role? Trends Genet 2004;20:292–9.
Kamada N, Seo SU, Chen GY, et al. Role of the gut microbiota
in immunity and inammatory disease. Nat Rev Immunol
2013;13:321–35.
Karavolos MH, Spencer H, Bulmer DM, et al. Adrenaline modu-
lates the global transcriptional prole of Salmonella reveal-
ing a role in the antimicrobial peptide and oxidative stress
resistance responses. BMC Genomics 2008;9:458.
Karavolos MH, Winzer K, Williams P, et al. Pathogen es-
pionage: multiple bacterial adrenergic sensors eavesdrop
on host communication systems. Mol Microbiol 2013;87:
455–65.
Karlsson FH, Tremaroli V, Nookaew I, et al. Gut metagenome in
European women with normal, impaired and diabetic glu-
cose control. Nature 2013;498:99–103.
Kohbata S, Beaman BL. L-dopa-responsive movement disorder
caused by Nocardia asteroides localized in the brains of mice.
Infect Immun 1991;59:181–91.
Korecka A, de Wouters T, Cultrone A, et al. ANGPTL4 expression
induced by butyrate and rosiglitazone in human intestinal
epithelial cells utilizes independent pathways. Am J Physiol-
Gastr L 2013;304:G1025–37.
Koren O, Goodrich JK, Cullender TC, et al. Host remodeling of the
gut microbiome and metabolic changes during pregnancy.
Cell 2012;150:470–80.
Kornman KS, Loesche WJ. Effects of estradiol and progesterone
on Bacteroides melaninogenicus and Bacteroides gingivalis.Infect
Immun 1982;35:256–63.
Laferrere B. Do we really know why diabetes remits after gastric
bypass surgery? Endocrine 2011;40:162–7.
Lam V, Su J, Koprowski S, et al. Intestinal microbiota de-
termine severity of myocardial infarction in rats. FASEB J
2012;26:1727–35.
Lanyon CV, Rushton SP, O’Donnell A G, et al. Murine scent mark
microbial communities are genetically determined. FEMS Mi-
crobiol Ecol 2007;59:576–83.
Lasarte S, Elsner D, Guia-Gonzalez M, et al. Female sex hormones
regulate the Th17 immune response to sperm and Candida
albicans.Hum Reprod 2013;28:3283–91.
Leroith D, Liotta AS, Roth J, et al. Corticotropin and beta-
endorphin-like materials are native to unicellular organisms.
P Natl Acad Sci USA 1982;79:2086–90.
LeRoith D, Pickens W, Vinik AI, et al. Bacillus subtilis contains mul-
tiple forms of somatostatin-like material. Biochem Bioph Res
Co 1985;127:713–9.
Levkovich T, Poutahidis T, Smillie C, et al. Probiotic bacteria in-
duce a ‘glow of health’. PloS one 2013;8:e53867.
Li H, Gao D, Cao Y, et al. Ahighγ-aminobutyric acid-producing
Lactobacillus brevis isolated from Chinese traditional paocai.
Ann Microbiol 2008;58:649–53.
Liou AP, Paziuk M, Luevano JM, et al. Conserved shifts in the gut
microbiota due to gastric bypass reduce host weight and adi-
posity. Sci Transl Med 2013;5:178ra141.
Littman DR, Pamer EG. Role of the commensal microbiota in nor-
mal and pathogenic host immune responses. Cell Host Mi-
crobe 2011;10:311–23.
Lyte M. The role of microbialendocrinology in infectious disease.
J Endocrinol 1993;137:343–5.
Lyte M. Probiotics function mechanistically as delivery vehi-
cles for neuroactive compounds: microbial endocrinology
in the design and use of probiotics. BioEssays 2011;33:574–
81.
Lyte M. Microbial endocrinology in the microbiome-gut-brain
axis: how bacterial production and utilization of neurochem-
icals inuence behavior. PLoS Pathog 2013;9:e1003726.
Lyte M, Bailey MT. Neuroendocrine-bacterial interactions in a
neurotoxin-induced model of trauma. JSurgRes1997;70:
195–201.
Lyte M, Ernst S. Catecholamine induced growth of gram negative
bacteria. Life Sci 1992;50:203–12.
Lyte M, Freestone PP, Neal CP, et al. Stimulation of Staphylococcus
epidermidis growth and biolm formation by catecholamine
inotropes. Lancet 2003;361:130–5.
Madsbad S, Dirksen C, Holst JJ. Mechanisms of changes in glu-
cose metabolism and bodyweight after bariatric surgery.
Lancet Diabetes Endocrinol 2014;2:152–64.
Manocha M, Khan WI. Serotonin and GI disorders: an update
on clinical and experimental studies. Clin Transl Gastroenterol
2012;3:e13.
Markle JG, Frank DN, Mortin-Toth S, et al. Sex differences in the
gut microbiome drive hormone-dependent regulation of au-
toimmunity. Science 2013;339:1084–118.
Maurice CF, Haiser HJ, Turnbaugh PJ. Xenobiotics shape the
physiology and gene expression of the active human gut mi-
crobiome. Cell 2013;152:39–50.
Menon R, Watson SE, Thomas LN, et al. Diet complexity
and estrogen receptor beta status affect the composition
of the murine intestinal microbiota. Appl Environ Microb
2013;79:5763–73.
Messaoudi M, Lalonde R, Violle N, et al. Assessment of
psychotropic-like properties of a probiotic formulation (Lac-
tobacillus helveticus R0052 and Bidobacterium longum R0175)
in rats and human subjects. Brit J Nutr 2011;105:755–
64.
Mittelstrass K, Ried JS, Yu Z, et al. Discovery of sexual dimor-
phisms in metabolic and genetic biomarkers. PLoS Genet
2011;7:e1002215.
Morgan XC, Tickle TL, Sokol H, et al. Dysfunction of the intestinal
microbiome in inammatory bowel disease and treatment.
Genome Biol 2012;13:R79.
Nakatani Y, Sato-Suzuki I, Tsujino N, et al. Augmented brain 5-
HT crosses the blood-brain barrier through the 5-HT trans-
porter in rat. Eur J Neurosci 2008;27:2466–72.
Neuman et al. 13
Naruszewicz M, Johansson ML, Zapolska-Downar D, et al. Effect
of Lactobacillus plantarum 299v on cardiovascular disease
risk factors in smokers. Am J Clin Nutr 2002;76:1249–55.
Neufeld KM, Kang N, Bienenstock J, et al. Reduced anxiety-like
behavior and central neurochemical change in germ-free
mice. Neurogastroent Motil 2011;23:255–64, e119.
Newbern D, Freemark M. Placental hormones and the control of
maternal metabolism and fetal growth. Curr Opin Endocrinol
Diabetes Obes 2011;18:409–16.
Ober C, Loisel DA, Gilad Y. Sex-specic genetic architecture of
human disease. Nat Rev Genet 2008;9:911–22.
Ostman S, Rask C, Wold AE, et al. Impaired regulatory T cell func-
tion in germ-free mice. Eur J Immunol 2006;36:2336–46.
Osto M, Abegg K, Bueter M, et al. Roux-en-Y gastric bypass
surgery in rats alters gut microbiota prole along the intes-
tine. Physiol Behav 2013;119:92–6.
Parnell JA, Reimer RA. Weight loss during oligofructose sup-
plementation is associated with decreased ghrelin and in-
creased peptide YY in overweight and obese adults. Am J Clin
Nutr 2009;89:1751–9.
Pierantozzi M, Pietroiusti A, Brusa L, et al. Helicobacter pylori erad-
ication and l-dopa absorption in patients with PD and motor
uctuations. Neurology 2006;66:1824–9.
Poutahidis T, Kearney SM, Levkovich T, et al. Microbial sym-
bionts accelerate wound healing via the neuropeptide hor-
mone oxytocin. PloS One 2013;8:e78898.
Priyanka HP, Krishnan HC, Singh RV, et al. Estrogen modulates
in vitro T cell responses in a concentration- and receptor-
dependent manner: effects on intracellular molecular tar-
gets and antioxidant enzymes. Mol Immunol 2013;56:328–39.
QinJ,LiY,CaiZ,et al. A metagenome-wide association study of
gut microbiota in type 2 diabetes. Nature 2012;490:55–60.
Queipo-Ortuno MI, Seoane LM, Murri M, et al. Gut microbiota
composition in male rat models under different nutritional
status and physical activity and its association with serum
leptin and ghrelin levels. PloS One 2013;8:e65465.
Rajala MW, Patterson CM, Opp JS, et al. Leptin acts indepen-
dently of food intake to modulate gut microbial composition
in male mice. Endocrinology 2014;155:748–57.
Raveh S, Sutalo S, Thonhauser KE, et al. Female partner prefer-
ences enhance offspring ability to survive an infection. BMC
Evol Biol 2014;14:14.
Ravussin Y, Koren O, Spor A, et al. Responses of gut microbiota
to diet composition and weight loss in lean and obese mice.
Obesity 2012;20:738–47.
Ridley EV, Wong AC, Westmiller S, et al. Impact of the resi-
dent microbiota on the nutritional phenotype of Drosophila
melanogaster.PloS One 2012;7:e36765.
Ridlon JM, Ikegawa S, Alves JM, et al. Clostridium scindens:ahu-
man gut microbe with a high potential to convert glucocor-
ticoids into androgens. J Lipid Res 2013;54:2437–49.
Romero LM, Butler LK. Endocrinology of stress. Int J Comp Psychol
2007;20:89–95.
Roshchina V. Evolutionary considerations of neurotransmitters
in microbial, plant, and animal cells. In: Lyte M, Fitzgerald
P (eds). Microbial Endocrinology: Interkingdom Signaling in Infec-
tious Disease and Health. New York: Springer, 2010, 17–52.
Sandler RH, Finegold SM, Bolte ER, et al. Short-term benet
from oral vancomycin treatment of regressive-onset autism.
J Child Neurol 2000;15:429–35.
Sankaran-Walters S, Macal M, Grishina I, et al. Sex differences
matter in the gut: effect on mucosal immune activation and
inammation. Biol Sex Differ 2013;4:10.
Sharon G, Segal D, Ringo JM, et al. Commensal bacteria play a role
in mating preference of Drosophila melanogaster.P Natl Acad
Sci USA 2010;107:20051–6.
Shin SC, Kim SH, You H, et al. Drosophila microbiome modulates
host developmental and metabolic homeostasis via insulin
signaling. Science 2011;334:670–4.
Singh PB, Herbert J, Roser B, et al. Rearing rats in a germ-free
environment eliminates their odors of individuality. JChem
Ecol 1990;16:1667–82.
Sperandio V, Torres AG, Jarvis B, et al. Bacteria-host commu-
nication: the language of hormones. P Natl Acad Sci USA
2003;100:8951–6.
Storelli G, Defaye A, Erkosar B, et al. Lactobacillus plantarum pro-
motes Drosophila systemic growth by modulating hormonal
signals through TOR-dependent nutrient sensing. Cell Metab
2011;14:403–14.
Sudo N, Chida Y, Aiba Y, et al. Postnatal microbial coloniza-
tion programs the hypothalamic-pituitary-adrenal system
for stress response in mice. J Physiol 2004;558:263–75.
Takemura N, Okubo T, Sonoyama K. Lactobacillus plantarum
strain No. 14 reduces adipocyte size in mice fed high-fat diet.
Exp Biol Med 2010;235:849–56.
Tanabe S. The effect of probiotics and gut microbiota on Th17
cells. Int Rev Immunol 2013;32:511–25.
Theis KR, Venkataraman A, Dycus JA, et al. Symbiotic bacteria
appear to mediate hyena social odors. P Natl Acad Sci USA
2013;110:19832–7.
Tremellen K, Pearce K. Dysbiosis of Gut Microbiota (DOGMA)—a
novel theory for the development of Polycystic Ovarian Syn-
drome. Med Hypotheses 2012;79:104–12.
Vrieze A, Van Nood E, Holleman F, et al. Transfer of intesti-
nal microbiota from lean donors increases insulin sensitiv-
ity in individuals with metabolic syndrome. Gastroenterology
2012;143:913–6, e917.
Wang JF, Fu SP, Li SN, et al. Short-chain fatty acids in-
hibit growth hormone and prolactin gene transcription via
cAMP/PKA/CREB signaling pathway in dairy cow anterior pi-
tuitary cells. Int J Mol Sci 2013;14:21474–88.
Whitacre CC. Sex differences in autoimmune disease. Nat Im-
munol 2001;2:777–80.
Wichmann A, Allahyar A, Greiner TU, et al. Microbial modulation
of energy availability in the colon regulates intestinal transit.
Cell Host Microbe 2013;14:582–90.
Wikoff WR, Anfora AT, Liu J, et al. Metabolomics analysis reveals
large effects of gut microora on mammalian blood metabo-
lites. P Natl Acad Sci USA 2009;106:3698–703.
Winter J, Morris GN, O’Rourke-Locascio S, et al. Mode of ac-
tion of steroid desmolase and reductases synthesized by
Clostridium ‘scindens (formerly Clostridium strain 19). J Lipid Res
1984;25:1124–31.
Wostmann BS. Morphology and physiology, endocrinology and
biochemistry. In: Wostmann BS (ed). Germfree and Gnotobiotic
Animal Models. N.W. Boca Raton, Florida: CRC Press, 1996, 43–
71.
Yadav H, Lee JH, Lloyd J, et al. Benecial metabolic effects of a pro-
biotic via butyrate-induced GLP-1 hormone secretion. J Biol
Chem 2013;288:25088–97.
Yurkovetskiy L, Burrows M, Khan AA, et al. Gender bias
in autoimmunity is inuenced by microbiota. Immunity
2013;39:400–12.
Zhang H, DiBaise JK, Zuccolo A, et al. Human gut microbiota
in obesity and after gastric bypass. P Natl Acad Sci USA
2009;106:2365–70.