Microbial endocrinology: Why the intersection of microbiology and
neurobiology matters to poultry health
Daniel N. Villageliũ and Mark Lyte1
Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State
University, 1800 Christensen Drive, Ames, IA 50011–1134
ABSTRACT The union of microbiology and neurobi-
ology has led to a revolution in the way we view the mi-
crobiome. Now recognized as important symbionts, the
microorganisms which inhabit multiple niches in mam-
malian and avian (chicken) hosts, such as the intesti-
nal tract and skin, serve and influence many important
Key words: microbiome, neurobiology, enteric nervous system, stress, behavior
INTRODUCTION
Microbial endocrinology represents the union of the
fields of microbiology and neurobiology. It is defined
as the study of the ability of microorganisms to pro-
duce and recognize neurochemicals that originate ei-
ther within the microorganisms themselves or within
the host they inhabit. While term originated in 1993
(Lyte, 1993), evidence supporting some of the principle
tenants of this field can be traced to studies going back
as far as 1930. For a poultry producer two issues stand
out as especially important:
(1) Microorganisms do not live in isolation from each
other or their host. They communicate with, in-
fluence, and are influenced by their host and their
neighboring microbes.
(2) Systems of host-microbe communication appear
across a wide range of organisms from plants to
animals.
Microorganisms actively respond to signals produced
by the host in very significant ways. For example, the
same agent responsible for multibillion dollar losses
through necrotic enteritis in chickens, Clostridium per-
fringens, also turns out to be among the earliest docu-
mented cases of bacterial growth being influenced by a
stress related neurochemical.
In the early 1930 s, epinephrine was the first man-
ufactured hormone to be used in the clinical setting

C 2017 Poultry Science Association Inc.
Received April 3, 2017.
Accepted May 9, 2017.
1
Corresponding author: mlyte@iastate.edu
1
physiological functions. The realization that the gut mi-
crobiome serves as a kind of “microbial organ” has im-
portant implications for many areas of biology. In this
paper advances in the field of microbial endocrinology
which may hold relevance for the poultry industry are
examined.
2017 Poultry Science 96:1–8
http://dx.doi.org/10.3382/ps/pex148
and was used in the treatment of urticaria. (Commonly
referred to as hives, urticaria is a condition classically
described as raised and itchy areas of the skin which
may indicate exposure to an allergen). Reports of pa-
tients suffering from fulminating sepsis mere hours af-
ter treatment with epinephrine began to appear. The
cause was traced back to syringes used to drain bac-
terial abscesses. Though abscess drainage was a com-
mon surgical practice and practitioners of the day were
likely vigilant in the use of cleaning agents, methods
of the time were unable to completely sterilize spore
forming organisms like C. perfringens. Ordinarily, the
remaining spores were generally dormant and appar-
ently below the threshold necessary to cause infection.
However, with exposure to epinephrine, the organism’s
infective potential changes. Epinephrine increases the
growth rate of C. perfringens and decreases the in-
fective dose by up to a million-fold (Renaud, 1930;
Cooper, 1946). Cases related to this phenomenon were
reported throughout the 20th century. In 1968 Harvey
and Purnell commented on a fatal case of gas gangrene
in a 22-year-old who received intramuscular epinephrine
(Harvey and Purnell, 1968). Similarly, in 1983 a clinical
report described the development of gas gangrene in a
13-year-old girl (Teo and Balasubramaniam, 1983).
The potential for neurotransmitters to influence vir-
ulence is not solely limited to Clostridium. The growth
of the respiratory pathogen Bordetella bronchiseptica
is greatly increased by the presence of norepinephrine
in vitro (Anderson and Armstrong, 2008). The release
of catecholamines from injured enteric neurons is asso-
ciated with a rapid alteration of the microbiota com-
munity from one dominated by Gram-positive taxa
to one dominated by a single Gram-negative bacte-
rial species, Escherichia coli (Lyte and Bailey, 1997).
2 Villageliũ and Lyte
The overgrowth of E. coli has been proposed to be a
possible contributory factor in trauma-induced sepsis
(Freestone et al., 2002). Findings like this may hold
useful implications. For example, if the effects of stress
hormones could be suppressed, outbreaks of necrotic
enteritis in chickens might also be diminished. The con-
cept is not necessarily far off. Dopamine antagonists are
chemicals which block dopamine receptors through an-
tagonistic binding of the receptor. Often used in the
treatment of psychiatric illnesses such as schizophre-
nia, dopaminergic antagonists have been demonstrated
to block catecholamine-induced growth in Escherichia
coli O157: H7, Salmonella enterica, and Yersinia ente-
rocolitica (Freestone et al., 2007).
Though neurochemical influences on the growth
rate of pathogens are of obvious importance to in-
fectious disease, it should be noted that the mech-
anisms through which neurochemicals achieve physi-
ological changes may be quite varied. Consider the
respiratory pathogen Actinobacillus pleuropneumoniae
which shows differential expression of 158 and 105 genes
respectively, for organisms exposed to epinephrine
or norepinephrine. Though both chemicals are cate-
cholamines, only 18 of the differentially expressed genes
were common to both epinephrine and norepinephrine
exposure. This suggests that organisms like A. pleu-
ropneumoniae may possess multiple responsive sys-
tems for individual catecholamines (Li et al., 2012).
This is not surprising; there are several distinct classes
of catecholamine receptors ranging from dopaminergic
to adrenergic, each with several subtypes and an un-
counted numbers of heteromers. The range of neuro-
chemicals and the variety of microorganisms in which
they have been identified is quite extensive (Lenard,
1992). Examples include acetylcholine (Stephenson and
Rowatt, 1947; Kawashima et al., 2007), histamine
(Devalia, 1988; Masson et al., 1996; Thomas et al.,
2012), serotonin (Hurley et al., 1971; Ozogul, 2011),
catecholamines (Tsavkelova et al., 2000; Shishov et al.,
2009; Asano et al., 2012), and agmatine (Raasch et al.,
1995; Arena and Manca de Nadra, 2001).
Given the observations above, it is also not surpris-
ing to learn that physiological changes caused by neu-
rotransmitters are similarly quite varied. For example,
it has been demonstrated that concentrations of nore-
pinephrine as low as 1.2 × 10−5 M could significantly
influence the aerotolerance of organisms like Clostrid-
ium jejuni and Spirillum volutsans (Bowdre et al.,
1976). At concentrations this low, norepinephrine is
not a useful metabolite but it can still serve as a sig-
naling molecule. Generally, C. jejuni and S. volutsans
can only be cultured in a microaerophilic environment.
In the presence of catecholamines however, these or-
ganisms become more aerotolerant. If norepinephrine
is present, Spirillum inoculations can successfully be
established in oxygen containing environments using
inoculums smaller than what was necessary without
catecholamines (Bowdre et al., 1976). Over the years
authors have suggested that neurotransmitters pro-
duced by the microbiome influence a range of physi-
ological and behavioral functions extending from main-
tenance of the gastrointestinal (GI) tract to iron uptake
by bacteria (Gross and Siegel, 1988; Freestone et al.,
2000; Grenham et al., 2011).
In addition to infectious considerations, it should also
be appreciated that microbial endocrinology has rel-
evance outside of the field of infectious disease. Neu-
rochemicals, isolated from microorganisms, which have
been shown to have biological activity in mammalian
cells include corticotropin from Tetrahymena pyri-
formis, somatostatin from Bacillus subtilis, and pro-
gesterone from Trichophyton mentagrophytes (LeRoith
et al., 1985; Schar et al., 1986). When viewed from
the standpoint of the microorganism, it becomes ap-
parent that the functions of many of these chemicals
are not pathological in nature. To successfully develop
the strong and reliable approaches needed to modify in
vivo systems, a more evolutionary-based approach must
be utilized to explore the mechanisms through which
microorganisms can influence their host. This includes
viewing these neurochemicals from the point of view of
the microorganism as well as the host.
THE MICROBIOTA-GUT-BRAIN AXIS AND
SUPPORT FOR ITS INCLUSION IN AN
AVIAN MODEL
In mammalian models, one physiological mechanism
by which microbes interact with their host has been
termed the microbiota-gut-brain axis (Figure 1). Food
ingested by the host can be metabolized by the mi-
crobiota in ways that generate or release neuroactive
components. These neuroactive molecules can be taken
up into the circulation or interact with the host locally
at the level of the enteric nervous system. Some signals
may be transduced to the brain where they can influ-
ence cognition and behavior whereas other signals may
result in changes in the enteric system which feedback
on the microbiota (Jarvis, 2005; Powley et al., 2011;
Furness et al., 2014).
Is there evidence for the modulation of
chicken behavior through a
microbiota-gut-brain axis?
Recent advances in neurobiology have shown a great
deal of similarity between avian neural structure and
that of their mammalian cousins. It has been demon-
strated that the avian brain has cortex-like struc-
tures which are not unlike the structures found in a
mammalian brain (Jarvis, 2005). The avian pallium
contains functional columns similar to those in the
mammalian cortex. The cortex is the outer layer of cere-
bral gray matter associated with what can be crudely
described as “higher brain function” which includes,
but is not limited to, activities such as coordination of
sensory information, voluntary movement, and learning
 Relevance of microbial endocrinology to poultry
Figure 1. A hypothetical gut-brain axis in chickens.
and memory. Structures analogous to the mammalian
septal neuroendocrine system can also be found in avian
species (Kuenzel, 2014). Septal nuclei are part of the
limbic system which is a region of the brain associated
with motivation and emotion. The limbic system can
exert influence through the endocrine system as well as
autonomic system.
Similarities between the chicken gut microbiome
and mammalian counterparts are also apparent. The
avian small intestine harbors large populations of
Lactobacillus and Enterococcus. Common phyla found
in the chicken GI tract are Firmicutes, Bacteroides,
Proteobacteria, and Actinobacteria (Oakley et al.,
2014). This is not unlike reports of the mammalian
microbiome being dominated by Firmicutes (65.7%
by sequencing), Bacteroidetes (16.3%), Proteobacteria
(8.8%), and Actinobacteria (4.7%) (Ley et al., 2008).
Given the abundance of similarities between birds
and mammals, it seems highly probable that an avian
gut-brain axis should exist. Until recently, evidence sup-
porting this contention was elusive. However, reports
in chickens is now available which shows a relation-
ship between intestinal inflammation, behavioral pat-
terns, corticosterone serum levels, and central nervous
system activity (Calefi et al., 2016). Chickens exposed
to intestinal stressors were found to have activation of
the hypothalamic-pituitary-adrenal axis as well as in-
creased corticosterone serum levels. Interestingly, ani-
mals infected with Clostridium perfringens and exposed
to other endocrine influencing conditions such as heat
demonstrated fewer symptomatic behaviors and less
intestinal lesions than animals solely challenged with
Clostridium perfringens. Albeit correlational, this work
provides useful insight and validates research efforts
which seek to improve livestock productivity through
influences on neuroendocrine pathways.
3
STRESS MANAGEMENT AND OTHER
POTENTIAL APPLICATIONS OF
MICROBIAL ENDOCRINOLOGY FOR THE
POULTRY INDUSTRY
In reviewing the state of the poultry industry, at least
six major issues become quickly apparent. Feed cost,
disease outbreaks, discontinuation of feed antibiotics,
poultry welfare, and issues related to the environment.
Although the solutions to these complex problems will
likely be multifactorial, approaches to all of these issues
can be conceived of with the aid of microbial endocrinol-
ogy.
Stress in chickens can lead to numerous issues rang-
ing from cannibalism to the premature termination of
egg production. Stressful factors for a chicken are some-
times surprising and difficult to predict. Even the move
to less restrictive environments can result in stresses
that can cause a profound impact. For example, a re-
cent study found that mortality was over twice as high
in less restricted aviary reared hens (5.52%) in compar-
ison to cage reared hens (2.48%) during their producing
phase (Tahamtani et al., 2014). A large proportion of
the birds that were found dead had bloody sores to the
head and neck region indicative of injurious pecking.
The development of injurious pecking behavior in ex-
tended range chickens highlights the potential for the
environment to exacerbate social stresses in unforeseen
ways.
How could microbial endocrinology play a role in the
management of stress? The link between social stress
and the neuroendocrine system is well established if not
completely understood. Social stress can act through
the central nervous system to trigger the release of neu-
rotransmitters and stress hormones from the sympa-
thoadrenal and hypothalamic-pituitary-adrenal axes. In
4 Villageliũ and Lyte

Figure 2. Social stress activates the central nervous system. (1) The stress signal may be transduced by neurons of the autonomic nervous
system as well as the hypothalamic-pituitary-adrenal (HPA) axis. (2) Chemicals released by these systems can act on the microbiome. (3) Changes
in host microbiome and the production of metabolites may then be detected by the host through the gut-brain axis (4) and transmitted by vagal
sensory neurons back to the central nervous system (CNS) or otherwise effect changes in the host (5).

chickens, physiological differences have been observed
between behaviorally distinct dominant and subordi-
nate animals. Such differences include differing levels
of dopamine and dopamine receptors in the dopaminer-
gic system as well as hypertrophy of the adrenal glands
and changes in corticosteroid levels in the adrenergic
system (Harvey et al., 1984; Blanchard et al., 1993;
Shively, 1998; Fano et al., 2001). Some have suggested
that changes such as these may result in abnormal and
detrimental behaviors or an inability for chickens to
cope with environmental stresses (Cheng et al., 2002).
Such outcomes are far from benign. It has been reported
that chickens with a poor ability to adjust to their social
environment also display a greater susceptibility to dis-
ease (Gross and Siegel, 1988; Awadalla, 1998). Behav-
ioral consequences can include an increased tendency
towards cannibalism, aggression, and feather pecking
(Burger and Kaiser, 1996; Via, 1999; Bilčı́k and Keel-
ing, 2000; El-Lethey et al., 2000).
Using an understanding of microbial endocrinology,
we can re-evaluate these host-centric models of social
stress to expand on the ideas above. As shown in Fig-
ure 1, the concept of animal social stress should in-
corporate the dynamic role that the microbiome plays
in responding to stress (Figure 2). Briefly, social stress
acts through the central nervous system and effects
changes to the microbiome through the sympathoad-
renal and hypothalamic-pituitary-adrenal axes. These
neurochemical axes release chemicals which can act on
and change the microbiome. Changes in the host’s mi-
crobiome may then feedback onto the host through the
gut-brain axis to effect further changes. Simply stated,
the microbiome and host are intimately linked in a bi-
directional way (Figure 3).
Evidence supporting this model is abundant. Numer-
ous studies have demonstrated that stress can affect
the gut’s microbial composition, influence microbiota-
gut-brain communication, and result in behavioral
alteration (Cryan and Dinan, 2012; Collins et al.,
2013; David et al., 2014). Physical and psychosocial
stress, as well as alteration of the circadian rhythm,
can alter the microbial community structure within
the gut (Bailey et al., 2011; Bangsgaard Bendtsen
et al., 2012; Thaiss et al., 2014). The microbial com-
munity structure can rapidly change as a response
to the influx of host stress-related neurochemicals in
the lumen.
The implications of this model for chickens are as
of yet mostly unexplored. Stress related disruptions to
the chicken microbiome could conceivably affect multi-
ple systems in deleterious ways. However, we can in-
fer from recent research that susceptibility to infec-
tion would be one area of great interest. In rodents,
investigations have shown that social conflict stress
leaves the animal more susceptible to infection. In
1991 to 1992 a series of experiments by Lyte et al.
were conducted with animals stressed by social conflict
(Foster et al., 2016; Lyte, 2016). These stressed animals
were then challenged with the oral pathogen Yersinia
enterocolitica. After 14 days, the stressed population
showed over 100% greater mortality. Cumulative sur-
vival rates of 80% for non-stressed infected animals but
less than 40% survival of stressed animals. Crucially,
Lyte went on to show a mechanistic link between stress
 Relevance of microbial endocrinology to poultry 5

Figure 3. Bi-directional nature of microbial endocrinology in which neurochemicals produced by the host can influence the microbiota (A) and
the very same neurochemicals produced by the microbiota can influence the host (B). The evolutionary-based neurochemical signaling pathway
between microbiota and host means that a neurochemical(s) produced by the host can influence the microbiota (A) and at the same time a
neurochemical(s) produced by the microbiota can, in turn, influence the host (B).

Figure 4. Initial experiment in microbial endocrinology. Yersinia enterocolitica culture plates in 1991 showing that bacterial growth in serum-
based medium was enhanced in the presence of the neuroendocrine stress hormone norepinephrine, but not epinephrine or control diluent (Lyte,
1993; Lyte, 2010).

and the behavior of the microbes (Lyte, 1993). Cate-
cholamines, the key chemical modulators of stress re-
sponses also induce growth changes in Y. enterocolit-
ica. Those catecholamines which are found in the GI
tract and are released as a consequence of stress, such
as dopamine and norepinephrine, increased the growth
of Y. enterocolitica over a million-fold. Y. enterocolit-
ica, which is almost exclusively a gut pathogen, does
not respond to epinephrine (Figure 4). This is likely be-
cause the enzyme responsible for producing epinephrine
from norepinephrine is not present in the enteric ner-
vous system. Thus, Y. enterocolitica which has adapted
to a gastrointestinal environment in which epinephrine
is not present has no reason to detect or respond
to epinephrine.
The results of this study may be generalized to poul-
try science. While the poultry producer may have lit-
tle concern with Y. enterocolitica, the stress neuro-
chemical norepinephrine has also been shown to stim-
ulate the growth and pathogenicity of other organ-
isms including E. coli and Campylobacter jejuni (Aroori
et al., 2014). C. jejuni is the predominant species as-
sociated with human foodborne infection derived from
poultry. Though Campylobacter often asymptomati-
cally colonizes the chicken GI track, sometimes the
species is associated with hemorrhagic enteritis, focal
hepatic necrosis, and chick death. What determines
whether an organism behaves in a benign or invasive
often depends on how the organism perceives its en-
vironment. Perhaps direct neurochemical-bacterial in-
teractions as already observed (and discussed above)
for several Gram-negative bacteria can be further ex-
tended to explain the differential infective behavior of
Campylobacter in chickens? If pathogenic microorgan-
isms perceive a stressed environment, this can lead to
increased pathogen colonization which in turn can lead
to more highly contaminated food and a greater risk of
foodborne infection.
Alteration of the microbiome
As the role of the microbiome in health and disease
is increasingly recognized, it follows that efforts to op-
timize the health of the organism would be better in-
formed with a more complete understanding of the mi-
crobiome. It may be questioned, what should an ideal
6 Villageliũ and Lyte
microbiome look like and how could one go about in-
fluencing or optimizing it? This question is of active
interest with many publications still offering differing
perspectives. However, while research in this field is
still in its infancy with correlational, not mechanistic
studies pre-dominating the literature, some useful ob-
servations have been made. These observations include
(but are not limited to) the following:
(1) Rich microbial diversity appears to be associated
with better host health whereas decreased diversity
has been associated with health problems rang-
ing from recurrent Clostridium difficile infection
to metabolic disturbances (Chang et al., 2008;
Claesson et al., 2012).
(2) Diet is one of the most important modifiers of the
intestinal microbiome and can influence its compo-
sition and functional metabolism (Albenberg and
Wu, 2014; David et. al. 2014). This is not limited to
digestible material. Dietary components like fiber,
xenobiotics, neurotransmitters, and their precur-
sors can all have an influence. For example, Suez
et al. found that artificial sweeteners can enrich for
Bacteroides (Suez et al., 2014).
As was discussed earlier, the behavior of a mi-
croorganism often depends on how the organism per-
ceives its environment. Obviously, a great deal of a
gut microbe’s environment will depend on the diet
of the host organism. It has been established that
the diet can profoundly impact the levels of certain
neurochemicals in a host (Fernstrom and Fernstrom,
2007) demonstrated that the rates of synthesis for sero-
tonin and catecholamines in the brain are sensitive
to local substrate concentrations. Physiologic factors
(particularly diet) which influence the pool of neu-
rochemical precursors in the brain also influence the
synthetic rate of neurochemical products. This finding
has functional consequences. For example, dietary con-
sumption of tyrosine, the catecholamine precursor, in-
creases anger in subjects exposed to psychological stress
(Lieberman, 2015). It is of note that corn is the grain
most routinely used in commercial poultry diets in the
United States. Interestingly, a reduced level of brain
serotonin and an elevated level of catecholamines can be
found in animals fed only a tryptophan-poor tyrosine-
rich diet such as corn (Fernstrom, 1977).
Just as a host organism can synthesize more neuro-
transmitters with an abundance of precursors, so can
microbes. Microbes which produce neurotransmitters
often use the same conserved synthetic pathways as
their eukaryotic host (Lyte, 2014). Therefore, it would
not be surprising to learn that increased dietary con-
sumption of food substrates which are neurochemical
precursors, could also lead to an abundance of neu-
rochemicals in the gut. Once produced, these neuro-
transmitters could influence the microbiome and the
host which would in turn influence each other bi-
directionally (Figure 3).
CONCLUDING REMARKS
The influence of the microbiome on host physiol-
ogy is an area of increasing poultry research especially
due to the introduction of new generation molecular
techniques that are revolutionizing the field of microbi-
ology itself. It is proposed that observations and re-
search undertaken from the perspective of microbial
endocrinology could lead to useful applications. For ex-
ample, could the design of new dietary approaches to
colonize the chicken GI tract with microorganisms ca-
pable of inactivation of stress-induced catecholamine re-
lease in the gut lead to increased resilience to pathogen
colonization in stressed poultry? Are there other as yet
unrealized benefits to poultry health that may be re-
alized by selecting for specific microbiomes based on
microbial endocrinology-based approaches? Ultimately,
the benefits that can be realistically obtained can only
be determined with more research. Through a rigorous
study of the microbial endocrinology-based mechanisms
by which microbiomes influence their host, we may de-
velop tools that will help address the problems facing
the chicken industry today.
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