Inflammation and The Microbiome: Implications For Depressive Disorders
Inflammation and The Microbiome: Implications For Depressive Disorders
Inflammation and The Microbiome: Implications For Depressive Disorders
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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 ([email protected])
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
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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