Available online at www.sciencedirect.
com
ScienceDirect
Inflammation and the microbiome: implications for
depressive disorders
Shawn Hayley, Marie-Claude Audet and Hymie Anisman
Inflammatory processes have been linked to depressive illness,
possibly being driven by stressful experiences. As well changes
in the balance between microbial species compromising the
microbiome could be important in precipitating cytokines and
other inflammatory factors that, in turn, influence several
pathways leading to depression. In particular, hormonal (e.g.
glucocorticoids), trophic (e.g. reductions of growth factors) and
oxidative stress signaling in the brain can be altered by the
inflammatory milieu, including excessive cytokine release,
which contribute to the symptoms that characterize a
depressed state (e.g. anhedonia, lethargy, disturbed feeding).
Identifying the ‘signature’ of inflammatory changes evident in
the microbiome of specific depressed patients could yield
important biomarkers to guide the development of
personalized approaches to treatment.
Address
Carleton University and the Royal Ottawa Hospital, Canada
Corresponding author: Hayley, Shawn (Shawn_Hayley@Carleton.ca)
Current Opinion in Pharmacology 2016, 29:42–46
This review comes from a themed issue on Immunomodulation
Edited by Fulvio D’Acquisto
For a complete overview see the Issue and the Editorial
Available online 18th June 2016
http://dx.doi.org/10.1016/j.coph.2016.06.001
1471-4892/Published by Elsevier Ltd.
Inflammatory process are believed to contribute to a
variety of illnesses, including metabolic syndrome, dia-
betes and heart disease [1,2]. Aside from these conditions,
which are among the most pernicious world-wide, inflam-
matory process have also been linked to poor recovery
from stroke [3] and neurodegenerative disorders [4]. As
well, there has been ever increasing evidence pointing
to a role for inflammatory processes in psychological
disorders, such as depressive illnesses [5], and might
contribute to the comorbidity that is frequently apparent
between depression and other conditions [6,7]. Excessive
pro-inflammatory cytokine levels, or a failure of inflam-
mation resolving appropriately, are thought to be key in
the evolution of such disturbances, and thus appreciable
efforts are being made to define the processes associated
with persistent inflammation, with the goal of facilitating
approaches to delay the onset and progression of illnesses
Current Opinion in Pharmacology 2016, 29:42–46
[8]. In this regard, appreciable efforts are being made to
identify biomarkers related to inflammation and other
processes that might signal disorders [9], as well as
inflammatory biomarkers that might be predictive of
therapeutic responses to antidepressant agents [10]. In-
deed, the frequent failures to attenuate depression using
standard antidepressant medications (e.g., SSRIs) might
stem from persistent inflammatory activation [11].
Evidence tying inflammatory processes to
depressive illnesses
The confluence of several independent lines of evidence
has provided increasing support for the position that
inflammatory factors are causally linked to depressive
illnesses. Genome-wide association and differential gene
expression in transcriptomic studies using tissue from
depressed humans or stressed rodents revealed over-
representation of genes related to immune system func-
tioning and the inflammatory response [12]. Moreover,
depression was accompanied by elevated circulating cyto-
kines, such as interleukin-6 (IL-6) and tumor necrosis
factor-a (TNF-a), as well as acute phase proteins (e.g.,
C-reactive protein) and were especially notable when
depressed symptoms included suicidal ideation [13].
Likewise, the anhedonia (reflected by reduced sucrose
consumption) elicited by a chronic mild stressor regimen
in rodents, was accompanied by increased up-regulated
IL-1b and IL-6 expression in the hippocampus and
prefrontal cortex, together with markers of microglia
activation, and each of these effects was attenuated by
antidepressant treatments [14]. Collectively, these stud-
ies raise the possibility that genetic (as well as proteomic)
indices of cytokines or circulating cytokines themselves
could offer viable biomarkers to facilitate diagnosis, treat-
ments, and perhaps recurrence of depressive disorders
[15]. Yet, it was also recognized that numerous factors,
such as sleep problems, associated with depression, might
be responsible for the cytokine changes [16].
Various treatments (e.g., endotoxin administration) that
promoted inflammation elicited a constellation of symp-
toms, including anhedonia, in animal models of the
disorder [17] and induced signs of depression in humans
[11]. There were also several reports indicating that
anti-inflammatory agents (e.g., aspirin or the NSAID
celecoxib), may bolster the impact of SSRI treatments
in humans and in animal models of the illness [18].
Although such effects were not always apparent, a
meta-analysis indicated that celecoxib acted as a
positive adjunctive treatment [19] and another found that
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 The microbiome, inflammation and depression Hayley, Audet and Anisman 43
treatment resistance was most likely to occur among
patients who displayed persistently elevated TNF-a
[20]. Intriguingly, ‘traditional’ antidepressants themselves
might have anti-inflammatory properties, as the SSRI,
fluoxetine, and the tricyclic agent, imipramine, produced
a reduction IL-6 and IFN-a mRNA expression, while
increasing that of the anti-inflammatory IL-4 within the
hypothalamus [21].
Strong evidence supporting a cytokine-depression link
have come from studies showing that interferon-a (IFN-
a) administration in treating hepatitis C and malignant
melanoma, frequently induced marked depressive symp-
toms in many patients, especially those with preexisting
symptoms, women with a history of depression or in
individuals with high circulating IL-6 [22]. Importantly,
in some instances these effects could be attenuated by
treatment with antidepressant agents, such as escitalo-
pram [23], and a meta-analysis suggested that antidepres-
sants were moderately effective prophylactic treatments
[24]. As strong as these data were, it should be considered
that patients in these studies were likely undergoing
some distress, and there is reason to believe that stressors
and cytokine treatments can have synergistic actions on
cytokine and neurochemical functioning, as well as on
signs of depression [25].
Inflammatory changes in brain and depression
While not denying the possible role of peripheral cyto-
kines, brain cytokine variations (or downstream effects
of the cytokine alterations) are likely fundamental in
depression. In this regard, cytokines are produced by
microglia (e.g., in the hypothalamus, hippocampus and
prefrontal cortex) in response to neuronal injury, im-
mune challenge and in response to a variety of environ-
mental stressors. These cytokines could influence
depression through inhibition of growth factors (e.g.,
brain derived neurotrophic factors; BDNF) or the pro-
duction of toxic metabolites related to aberrant neuro-
transmission [26]. Indeed, these cytokines can give rise
to the production of neurotoxic compounds, such as
quinolinic acid, and the consequent neuronal destruc-
tion could be responsible for the symptoms of depres-
sion. Likewise, activated microglia could stimulate
excitotoxic or pro-oxidative processes, including in-
creased glutamte activity, which favor cell loss and the
resultant depression [27,5].
Links between the microbiome, cytokines and
depression
Microorganisms that inhabit the gastrointestinal tract
share reciprocal connections with the host immune sys-
tem and can influence neurodevelopment and affect
psychological processes [28]. Increasing evidence has
pointed to the involvement of gut bacteria (microbiome)
and in particular, its substantial inflammatory milieu, in
the induction of depressive illnesses [28].
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Germ-free mice (born and raised in a sterile environment)
displayed immune disturbances, including defective
microglia that could be restored by later colonization with
commensal bacteria [29]. In line with the view that the
microbiome might have immunoregulatory properties,
supplementation with probiotic bacteria reduced intesti-
nal markers of inflammation in animal models of colitis
[30] and attenuated sickness behaviors that were engen-
dered circulating cytokine levels and microglial activation
in a mouse model of liver inflammation [31]. Likewise,
cytokine elevations within the frontal cortex elicited by
the bacterial endotoxin lipopolysaccharide (LPS) were
prevented in mice fed with a diet rich in prebiotics that
comprise non-digestible fibers that promote gut microbial
growth [32].
Implication of microbiota in inflammatory
response to stressors
Gut bacterial communities are sensitive to a variety of
challenges, including stressors [33,34,35]. In addition to
their role in pathogen-driven inflammation, gut bacteria
might thus also contribute to immune activation that
occurs in sterile conditions. In fact enhanced splenic
macrophage reactivity elicited by a social stressor was
prevented in antibiotic-treated and germ-free mice [36],
and prebiotics attenuated anxiety and colonicmicrobiota
alterations associated with stressors [35]. Moreover, inac-
tivation of gut-derived LPS (found in the outer mem-
brane of gram-negative bacteria), attenuated plasma and
brain cytokine elevations ordinarily induced by an acute
stressor [37,38], suggesting that this microbial product
(and downstream cytokine signaling via Toll-like recep-
tor 4) was required for the stressor-provoked cytokine
changes.
Microbiota–gut–brain axis and links with
stress-related disorders
Germ-free and antibiotic-treated mice exhibit several
anxiety-like and depressive-like phenotypes, as well as
alterations of neurotransmitters and of their receptors
(e.g., 5-HT, GABA receptor subunits), neuroendocrine
factors (e.g., CRH), and neurotrophins (e.g., BDNF)
[39,40]. Further indications of microbiota influence on
brain processes and behaviors have come from reports
showing that probiotics attenuated anxiety-like and de-
pressive-like behaviors and limited plasma corticosterone
elevations and IL-10 reductions as well as the hippocam-
pal monoamine (5-HT and NE) reductions elicited by a
chronic restraint stressor in rats [41]. Probiotics also pre-
vented impairments of neurogenesis and BDNF changes
elicited by stressors [42].
Increased permeability of the blood-brain barrier (BBB)
and altered expression of tight junction proteins were
reported in germ-free mice, and colonization with micro-
biota from conventionally raised mice partially reversed
this deficit [43]. These findings raise the possibility that
Current Opinion in Pharmacology 2016, 29:42–46
44 Immunomodulation
microbiota alterations may facilitate the passage of circu-
lating molecules that could not have infiltrated (e.g.,
cytokines, bacterial metabolites) the brain and promote
their interactions with neurochemical factors.
Microbiota in clinical depression
Although reports are scant, it was shown that depressed
individuals had more bacteria from the Proteobacteria and
Actinobacteria phyla and in the Alistipes genus, as well as
decreased levels of several genera of the Firmicutes phy-
lum. Moreover, changes in the Faecalibacterium genus
were negatively correlated to depression severity, where-
as Faecalibacterium over-representation in healthy control
relative to depressed subjects [44] possibly reflecting a
protective effect against depression through anti-inflam-
matory processes. Despite the limited clinical data avail-
able in this regard, probiotics were reported to diminish
psychological distress, and prebiotics similarly modified
the cortisol awakening response (which is increased in
individuals at risk for depression) and reduced attentional
vigilance for negative versus positive stimuli (reflective of
an anxiolytic profile) [45]. The observation that probiotics
reduced plasma cytokine levels among individuals
suffering from inflammatory conditions and attenuated
mitogen-stimulated cytokine elevations in healthy parti-
cipants [46] and that among elderly participants prebiotics
decreased circulating immune markers such as IL-11,
while increasing IL-10 and natural killer cell activity [47],
suggests that the positive effects of these microbiota-
targeting compounds on mood states could be linked to
their actions on immune processes.
Microbial changes in relation to early life or
prenatal stressors
Environmental challenges faced early or late in life could
have dramatic consequences, especially in the face of a
compromised BBB stemming from developmental effects
of an imbalanced microflora. In fact, maternal prenatal
stressor experiences were linked to a greater abundance
of Proteobacterial groups that contain pathogens (e.g.,
those related to Escherichia, Serratia, and Enterobacter)
[48]. As well, consistent with the view that associations
between microbiota and temperament could be initiated
early in life, it was reported that among children of about
2 years of age, bacterial diversity was linked to tempera-
ment and certain bacteria were positively correlated with
sociability and activity levels [49]. Preclinical studies
likewise demonstrated that microbiota alterations that
occurred early in life modulated subsequent brain devel-
opment [50] and proactively influenced physical and
mental health in adulthood [34,51].
Summary
There is ample evidence indicating that qualitative, and
most likely quantitative, changes in the nature of the
species comprising the microbiome can have dramatic
long term consequences on the brain–immune axis. As
Current Opinion in Pharmacology 2016, 29:42–46
Figure 1
CNS
Trophic
Neurotransmitter
Oxidative/
Inflammatory
BBB
Hormonal
Cytokine/Inflammatory
Psychological
Vagal/Neural
Toxicant Stress
Infection Microbiome
Proteobacteria M
Firmicutes T
Current Opinion in Pharmacology
Environmental stressors ranging from infectious agents to chemical
toxicants to psychological challenges are posited to disrupt the
microbial species colonizing the gut. Shifts in the microbiome that
favor certain bacterial species that promote an inflammatory milieu
may influence central nervous system (CNS) processes that contribute
to depressive symptoms. At least three main communication routes
exist between the microbiome and the CNS: 1. Through soluble
hormonal messengers, such as glucocorticoids or peptides; 2. Neural
projections, including vagal afferents that mediate bi-directional
communication between the gut and CNS; and 3. Through the
mobilization of immune cells (including adaptive and innate cells, such
as T lymphocytes and macrophages, respectively), together with the
production of inflammatory cytokines. Each of these routes can
ultimately affect brain functioning and predispose towards depression
by modulating trophic factors (most notably BDNF), neurotransmitters
(particularly the monoamines) and fostering a general inflammatory
environment that can produce destructive oxidative stress factors.
depicted in Figure 1, Psychological, immunological
and chemical stressors serve to shape the inflammatory
milieu within the gut, and depending upon the severity
and timing of such insults, could adversely influence
brain–immune communication, including hormonal,
neurotransmitter, cytokine and other growth factor pro-
cesses, and hence favor the evolution of depressive
symptomatology (especially vegetative elements of the
illness). The recent promotion of individualized treat-
ments of depression, like that of other disease conditions,
might contribute to better treatments of first episode
depression and may provide targets that diminish illness
recurrence, which is notoriously high. Cytokine biomark-
ers have been proposed as being important in this
regard, and it may be useful to include research that
focuses on microbiome alterations in developing treat-
ment strategies.
Conflict of interest statement
Nothing declared.
www.sciencedirect.com
 The microbiome, inflammation and depression Hayley, Audet and Anisman 45
Acknowledgement
Supported by the Canadian Institutes of Health Research Grant
#MOP84283 and #MOP142234.
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