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Inflammation and the microbiome: implications for


depressive disorders
Shawn Hayley, Marie-Claude Audet and Hymie Anisman

Inflammatory processes have been linked to depressive illness, [8]. In this regard, appreciable efforts are being made to
possibly being driven by stressful experiences. As well changes identify biomarkers related to inflammation and other
in the balance between microbial species compromising the processes that might signal disorders [9], as well as
microbiome could be important in precipitating cytokines and inflammatory biomarkers that might be predictive of
other inflammatory factors that, in turn, influence several therapeutic responses to antidepressant agents [10]. In-
pathways leading to depression. In particular, hormonal (e.g. deed, the frequent failures to attenuate depression using
glucocorticoids), trophic (e.g. reductions of growth factors) and standard antidepressant medications (e.g., SSRIs) might
oxidative stress signaling in the brain can be altered by the stem from persistent inflammatory activation [11].
inflammatory milieu, including excessive cytokine release,
which contribute to the symptoms that characterize a
depressed state (e.g. anhedonia, lethargy, disturbed feeding).
Evidence tying inflammatory processes to
Identifying the ‘signature’ of inflammatory changes evident in
depressive illnesses
The confluence of several independent lines of evidence
the microbiome of specific depressed patients could yield
has provided increasing support for the position that
important biomarkers to guide the development of
inflammatory factors are causally linked to depressive
personalized approaches to treatment.
illnesses. Genome-wide association and differential gene
Address expression in transcriptomic studies using tissue from
Carleton University and the Royal Ottawa Hospital, Canada depressed humans or stressed rodents revealed over-
representation of genes related to immune system func-
Corresponding author: Hayley, Shawn (Shawn_Hayley@Carleton.ca)
tioning and the inflammatory response [12]. Moreover,
depression was accompanied by elevated circulating cyto-
Current Opinion in Pharmacology 2016, 29:42–46 kines, such as interleukin-6 (IL-6) and tumor necrosis
This review comes from a themed issue on Immunomodulation factor-a (TNF-a), as well as acute phase proteins (e.g.,
Edited by Fulvio D’Acquisto
C-reactive protein) and were especially notable when
depressed symptoms included suicidal ideation [13].
For a complete overview see the Issue and the Editorial
Likewise, the anhedonia (reflected by reduced sucrose
Available online 18th June 2016 consumption) elicited by a chronic mild stressor regimen
http://dx.doi.org/10.1016/j.coph.2016.06.001 in rodents, was accompanied by increased up-regulated
1471-4892/Published by Elsevier Ltd. 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
Inflammatory process are believed to contribute to a could offer viable biomarkers to facilitate diagnosis, treat-
variety of illnesses, including metabolic syndrome, dia- ments, and perhaps recurrence of depressive disorders
betes and heart disease [1,2]. Aside from these conditions, [15]. Yet, it was also recognized that numerous factors,
which are among the most pernicious world-wide, inflam- such as sleep problems, associated with depression, might
matory process have also been linked to poor recovery be responsible for the cytokine changes [16].
from stroke [3] and neurodegenerative disorders [4]. As
well, there has been ever increasing evidence pointing Various treatments (e.g., endotoxin administration) that
to a role for inflammatory processes in psychological promoted inflammation elicited a constellation of symp-
disorders, such as depressive illnesses [5], and might toms, including anhedonia, in animal models of the
contribute to the comorbidity that is frequently apparent disorder [17] and induced signs of depression in humans
between depression and other conditions [6,7]. Excessive [11]. There were also several reports indicating that
pro-inflammatory cytokine levels, or a failure of inflam- anti-inflammatory agents (e.g., aspirin or the NSAID
mation resolving appropriately, are thought to be key in celecoxib), may bolster the impact of SSRI treatments
the evolution of such disturbances, and thus appreciable in humans and in animal models of the illness [18].
efforts are being made to define the processes associated Although such effects were not always apparent, a
with persistent inflammation, with the goal of facilitating meta-analysis indicated that celecoxib acted as a
approaches to delay the onset and progression of illnesses 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 Germ-free mice (born and raised in a sterile environment)
patients who displayed persistently elevated TNF-a displayed immune disturbances, including defective
[20]. Intriguingly, ‘traditional’ antidepressants themselves microglia that could be restored by later colonization with
might have anti-inflammatory properties, as the SSRI, commensal bacteria [29]. In line with the view that the
fluoxetine, and the tricyclic agent, imipramine, produced microbiome might have immunoregulatory properties,
a reduction IL-6 and IFN-a mRNA expression, while supplementation with probiotic bacteria reduced intesti-
increasing that of the anti-inflammatory IL-4 within the nal markers of inflammation in animal models of colitis
hypothalamus [21]. [30] and attenuated sickness behaviors that were engen-
dered circulating cytokine levels and microglial activation
Strong evidence supporting a cytokine-depression link in a mouse model of liver inflammation [31]. Likewise,
have come from studies showing that interferon-a (IFN- cytokine elevations within the frontal cortex elicited by
a) administration in treating hepatitis C and malignant the bacterial endotoxin lipopolysaccharide (LPS) were
melanoma, frequently induced marked depressive symp- prevented in mice fed with a diet rich in prebiotics that
toms in many patients, especially those with preexisting comprise non-digestible fibers that promote gut microbial
symptoms, women with a history of depression or in growth [32].
individuals with high circulating IL-6 [22]. Importantly,
in some instances these effects could be attenuated by Implication of microbiota in inflammatory
treatment with antidepressant agents, such as escitalo- response to stressors
pram [23], and a meta-analysis suggested that antidepres- Gut bacterial communities are sensitive to a variety of
sants were moderately effective prophylactic treatments challenges, including stressors [33,34,35]. In addition to
[24]. As strong as these data were, it should be considered their role in pathogen-driven inflammation, gut bacteria
that patients in these studies were likely undergoing might thus also contribute to immune activation that
some distress, and there is reason to believe that stressors occurs in sterile conditions. In fact enhanced splenic
and cytokine treatments can have synergistic actions on macrophage reactivity elicited by a social stressor was
cytokine and neurochemical functioning, as well as on prevented in antibiotic-treated and germ-free mice [36],
signs of depression [25]. and prebiotics attenuated anxiety and colonicmicrobiota
alterations associated with stressors [35]. Moreover, inac-
Inflammatory changes in brain and depression tivation of gut-derived LPS (found in the outer mem-
While not denying the possible role of peripheral cyto- brane of gram-negative bacteria), attenuated plasma and
kines, brain cytokine variations (or downstream effects brain cytokine elevations ordinarily induced by an acute
of the cytokine alterations) are likely fundamental in stressor [37,38], suggesting that this microbial product
depression. In this regard, cytokines are produced by (and downstream cytokine signaling via Toll-like recep-
microglia (e.g., in the hypothalamus, hippocampus and tor 4) was required for the stressor-provoked cytokine
prefrontal cortex) in response to neuronal injury, im- changes.
mune challenge and in response to a variety of environ-
mental stressors. These cytokines could influence Microbiota–gut–brain axis and links with
depression through inhibition of growth factors (e.g., stress-related disorders
brain derived neurotrophic factors; BDNF) or the pro- Germ-free and antibiotic-treated mice exhibit several
duction of toxic metabolites related to aberrant neuro- anxiety-like and depressive-like phenotypes, as well as
transmission [26]. Indeed, these cytokines can give rise alterations of neurotransmitters and of their receptors
to the production of neurotoxic compounds, such as (e.g., 5-HT, GABA receptor subunits), neuroendocrine
quinolinic acid, and the consequent neuronal destruc- factors (e.g., CRH), and neurotrophins (e.g., BDNF)
tion could be responsible for the symptoms of depres- [39,40]. Further indications of microbiota influence on
sion. Likewise, activated microglia could stimulate brain processes and behaviors have come from reports
excitotoxic or pro-oxidative processes, including in- showing that probiotics attenuated anxiety-like and de-
creased glutamte activity, which favor cell loss and the pressive-like behaviors and limited plasma corticosterone
resultant depression [27,5]. elevations and IL-10 reductions as well as the hippocam-
pal monoamine (5-HT and NE) reductions elicited by a
Links between the microbiome, cytokines and chronic restraint stressor in rats [41]. Probiotics also pre-
depression vented impairments of neurogenesis and BDNF changes
Microorganisms that inhabit the gastrointestinal tract elicited by stressors [42].
share reciprocal connections with the host immune sys-
tem and can influence neurodevelopment and affect Increased permeability of the blood-brain barrier (BBB)
psychological processes [28]. Increasing evidence has and altered expression of tight junction proteins were
pointed to the involvement of gut bacteria (microbiome) reported in germ-free mice, and colonization with micro-
and in particular, its substantial inflammatory milieu, in biota from conventionally raised mice partially reversed
the induction of depressive illnesses [28]. this deficit [43]. These findings raise the possibility that

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44 Immunomodulation

microbiota alterations may facilitate the passage of circu- Figure 1


lating molecules that could not have infiltrated (e.g.,
cytokines, bacterial metabolites) the brain and promote
CNS
their interactions with neurochemical factors.
Trophic
Neurotransmitter
Microbiota in clinical depression Oxidative/
Although reports are scant, it was shown that depressed Inflammatory
individuals had more bacteria from the Proteobacteria and BBB
Hormonal
Actinobacteria phyla and in the Alistipes genus, as well as
decreased levels of several genera of the Firmicutes phy- Cytokine/Inflammatory
Psychological
lum. Moreover, changes in the Faecalibacterium genus Vagal/Neural
Toxicant Stress
were negatively correlated to depression severity, where-
as Faecalibacterium over-representation in healthy control Infection Microbiome
relative to depressed subjects [44] possibly reflecting a Proteobacteria M
protective effect against depression through anti-inflam- Firmicutes T
matory processes. Despite the limited clinical data avail-
able in this regard, probiotics were reported to diminish
Current Opinion in Pharmacology
psychological distress, and prebiotics similarly modified
the cortisol awakening response (which is increased in
individuals at risk for depression) and reduced attentional Environmental stressors ranging from infectious agents to chemical
toxicants to psychological challenges are posited to disrupt the
vigilance for negative versus positive stimuli (reflective of microbial species colonizing the gut. Shifts in the microbiome that
an anxiolytic profile) [45]. The observation that probiotics favor certain bacterial species that promote an inflammatory milieu
reduced plasma cytokine levels among individuals may influence central nervous system (CNS) processes that contribute
suffering from inflammatory conditions and attenuated to depressive symptoms. At least three main communication routes
exist between the microbiome and the CNS: 1. Through soluble
mitogen-stimulated cytokine elevations in healthy parti-
hormonal messengers, such as glucocorticoids or peptides; 2. Neural
cipants [46] and that among elderly participants prebiotics projections, including vagal afferents that mediate bi-directional
decreased circulating immune markers such as IL-11, communication between the gut and CNS; and 3. Through the
while increasing IL-10 and natural killer cell activity [47], mobilization of immune cells (including adaptive and innate cells, such
suggests that the positive effects of these microbiota- as T lymphocytes and macrophages, respectively), together with the
production of inflammatory cytokines. Each of these routes can
targeting compounds on mood states could be linked to ultimately affect brain functioning and predispose towards depression
their actions on immune processes. by modulating trophic factors (most notably BDNF), neurotransmitters
(particularly the monoamines) and fostering a general inflammatory
Microbial changes in relation to early life or environment that can produce destructive oxidative stress factors.
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 depicted in Figure 1, Psychological, immunological
of an imbalanced microflora. In fact, maternal prenatal and chemical stressors serve to shape the inflammatory
stressor experiences were linked to a greater abundance milieu within the gut, and depending upon the severity
of Proteobacterial groups that contain pathogens (e.g., and timing of such insults, could adversely influence
those related to Escherichia, Serratia, and Enterobacter) brain–immune communication, including hormonal,
[48]. As well, consistent with the view that associations neurotransmitter, cytokine and other growth factor pro-
between microbiota and temperament could be initiated cesses, and hence favor the evolution of depressive
early in life, it was reported that among children of about symptomatology (especially vegetative elements of the
2 years of age, bacterial diversity was linked to tempera- illness). The recent promotion of individualized treat-
ment and certain bacteria were positively correlated with ments of depression, like that of other disease conditions,
sociability and activity levels [49]. Preclinical studies might contribute to better treatments of first episode
likewise demonstrated that microbiota alterations that depression and may provide targets that diminish illness
occurred early in life modulated subsequent brain devel- recurrence, which is notoriously high. Cytokine biomark-
opment [50] and proactively influenced physical and ers have been proposed as being important in this
mental health in adulthood [34,51]. regard, and it may be useful to include research that
focuses on microbiome alterations in developing treat-
Summary ment strategies.
There is ample evidence indicating that qualitative, and
most likely quantitative, changes in the nature of the
species comprising the microbiome can have dramatic Conflict of interest statement
long term consequences on the brain–immune axis. As Nothing declared.

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The microbiome, inflammation and depression Hayley, Audet and Anisman 45

16. Irwin MR: Why sleep is important for health: a


Acknowledgement psychoneuroimmunology perspective. Ann Rev Psychol 2015,
Supported by the Canadian Institutes of Health Research Grant 66:143-172.
#MOP84283 and #MOP142234.
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