Gut-microbiota-brain axis in depression: The role of neuroinflammation

Abstract

Major depressive disorder (MDD) is a psychiatric condition that affects a large number of people in the world and the treatment existents do not work for all individuals affected. Thus, it is believed that other systems or pathways which regulate brain networks involved in mood regulation and cognition are associated with MDD pathogenesis. Studies in humans and animal models have been shown that in MDD there are increased levels of inflammatory mediators, including cytokines and chemokines in both periphery and central nervous system (CNS). In addition, microglial activation appears to be a key event that triggers changes in signaling cascades and gene expression that would be determinant for the onset of depressive symptoms. Recent researches also points out that changes in the gut microbiota would lead to a systemic inflammation that in different ways would reach the CNS modulating inflammatory pathways and especially the microglia, which could influence responses to treatments. Moreover, pre- and probiotics have shown antidepressant responses and anti-inflammatory effects. This review will focus on studies that show the relationship of inflammation with the gut-microbiota brain axis and its relation with MDD.

Full text

Eur J Neurosci. 2019;00:1–14. wileyonlinelibrary.com/journal/ejn
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1
© 2019 Federation of European Neuroscience Societies
and John Wiley & Sons Ltd
Received: 14 August 2019
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Revised: 18 November 2019
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Accepted: 20 November 2019
DOI: 10.1111/ejn.14631
SPECIAL ISSUE REVIEW
Gut microbiota–brain axis in depression: The role of
neuroinflammation
Anelise S.Carlessi1
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Laura A.Borba1
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Alexandra I.Zugno1
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JoãoQuevedo1,2,3,4
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Gislaine Z.Réus1
Edited by Dr. Michel Barrot.
The peer review history for this article is available at https ://publo ns.com/publo n/10.1111/ejn.14631
Abbreviations: ACTH, adrenocorticotropic hormone; ANS, autonomic nervous system; ATP, adenosine triphosphate; BBB, blood–brain barrier; CNS, central
nervous system; CSF, cerebrospinal fluid; DAMPs, damage-associated molecular patterns; ENS, enteric nervous system; GABA, gamma-aminobutyric acid; GF,
germ-free; GOS, galactooligosaccharide; HAA, 3-hydroxyanthranilic acid; HPA, hypothalamic–pituitary–adrenal; IBS, irritable bowel syndrome; IDO, indoleam-
ine-2, 3-dioxygenase; IFN-γ, interferon gamma; IgA, immunoglobulin A; IL-10, interleukin-10; IL-5, interleukin-5; IL-6, interleukin-6; IL-7, interleukin-7; INF-γ,
Interferon gamma; KATs, kynurenine aminotransferases; KMO, quinurenine-3-mono-oxygenase; KP, kynurenine pathway; KYNA, kynurenic acid; LAC,
glycoprotein lactoferrin; LH, learned helplessness; LPS, lipopolysaccharide; MAOIs, monoamine oxidase inhibitors; MDD, major depressive disorder; MFGM, milk
fat globule membrane; MR16-1, anti-mouse IL-6 receptor antibody; NAD, nicotinamide adenine dinucleotide; NF-Κb, nuclear factor kappa B; NLRP3, receptor
family pyrin domain-containing 3; NMDA, antagonist of N-methyl-D-aspartate; NSAD, nonsteroidal anti-inflammatory drugs; OHK, 3-hydroxyquinurenine;
PAMPs, pathogen-associated molecular patterns; PDX, polydextrose; QUIN, quinolinic acid; SCFAs, short-chain fatty acids; SSRIs, selective serotonin reuptake
inhibitors; TCAs, tricyclic agents; TH1, T helper 1 effector cells; TLRs, Toll-like Receptors; TNF-α, tumor necrosis factor- α; TODO, tryptophan-2,3-dioxygenase.
1Translational Psychiatry Laboratory,
Graduate Program in Health Sciences,
University of Southern Santa Catarina
(UNESC), Criciúma, Brazil
2Translational Psychiatry Program,
Department of Psychiatry and Behavioral
Sciences, McGovern Medical School,
University of Texas Health Science Center
at Houston (UTHealth), Houston, TX, USA
3Center of Excellence on Mood Disorders,
Department of Psychiatry and Behavioral
Sciences, McGovern Medical School, The
University of Texas Health Science Center
at Houston (UTHealth), Houston, TX, USA
4Neuroscience Graduate Program, The
University of Texas Graduate School of
Biomedical Sciences at Houston, Houston,
TX, USA
Correspondence
Gislaine Z. Réus, Translational Psychiatry
Laboratory, University of Southern Santa
Catarina, Criciuma, SC, 88806-000, Brazil.
Email: gislainereus@unesc.net
Funding information
Texas Health Science Center; Pat
Rutherford Jr. Chair in Psychiatry; John
S. Dunn Foundation; Anne and Don Fizer
Foundation Endowment for Depression
Research; CNPq; FAPESC; Instituto
Cérebro e Mente; UNESC
Abstract
Major depressive disorder (MDD) is a psychiatric condition that affects a large num-
ber of people in the world, and the treatment existents do not work for all individuals
affected. Thus, it is believed that other systems or pathways which regulate brain net-
works involved in mood regulation and cognition are associated with MDD patho-
genesis. Studies in humans and animal models have been shown that in MDD there
are increased levels of inflammatory mediators, including cytokines and chemokines
in both periphery and central nervous system (CNS). In addition, microglial activa-
tion appears to be a key event that triggers changes in signaling cascades and gene
expression that would be determinant for the onset of depressive symptoms. Recent
researches also point out that changes in the gut microbiota would lead to a systemic
inflammation that in different ways would reach the CNS modulating inflammatory
pathways and especially the microglia, which could influence responses to treat-
ments. Moreover, pre- and probiotics have shown antidepressant responses and anti-
inflammatory effects. This review will focus on studies that show the relationship of
inflammation with the gut microbiota–brain axis and its relation with MDD.
KEYWORDS
gut microbiota–brain axis, inflammasome, kynurenine pathway, major depressive disorder,
neuroinflammation

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CARLESSI ET AL.
1
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INTRODUCTION
1.1
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Depression
Mental disorders are one of the main causes of disability in
developed countries, overcoming illnesses such as coronary
diseases and cancer (Reeves et al., ; Whiteford et al., 2013).
Major depressive disorder (MDD) is the main psychiatric
disorder condition, and it is the leading cause of disability,
reaching the whole world (Ferrari et al., 2013). It is estimated
that MDD reaches 4.4% of the world population, correspond-
ing to 322 million people living with this disorder (World
Health Organization, 2017).
The symptoms of MDD include depressed mood, anhedo-
nia, irritability, difficulty concentrating, changes in appetite
and sleep, and others (Nestler et al., 2002). In addition, MDD
is associated with psychosocial and functional impairment,
cognitive deficits, increased risk of suicidal behavior, and in-
creased mortality (Amidfar, Réus, Quevedo, & Kim, 2018),
reaching close to 800,000 deaths per year due to suicides
(World Health Organization, 2017).
The pathophysiology of MDD has been not still completely
elucidated. The hypothesis of monoaminergic deficiency,
which a decrease in the levels of serotonin, noradrenaline,
and dopamine in the synaptic cleft is the most used theory
to explain depressive symptoms. Moreover, antidepressant
drugs used for MDD treatment act increase monoamine lev-
els (Berton & Nestler, 2006; Schildkraut, 1995).
The first generation of drugs used to treat MDD, known
as classical antidepressants, were monoamine oxidase in-
hibitors (MAOIs) and tricyclic agents (TCAs), following for
selective serotonin reuptake inhibitors (SSRIs; Réus et al.,
2016). Currently, MAOIs and TCAs are not the first options
in the treatment of MDD due to considerable side effects
(Elhwuegi, 2004), such as hypertensive crisis, tachycardia,
anxiety, orthostatic hypotension, myoclonus, and convul-
sion, among other effects (Aguiar et al., 2011). In fact, SSRIs
are the more prescribed antidepressant drugs due it milder
side effects, greater tolerance, and adherence to treatment
by individuals with MDD (Millan, 2006). However, classic
antidepressants have some limitations, such as the delay to
therapeutic response (around three-six weeks) and low remis-
sion rates (around 30%; Amidfar, Réus, Quevedo, Kim, &
Arbabi, 2017; Krishnan & Nestler, 2008; Machado-Vieira et
al., 2009). Thus, it is crucial to study new therapeutic strate-
gies, as well as new pathways to understand the pathophysiol-
ogy of MDD. In fact, other systems have been associated with
MDD, including genes involved in biological rhythm regula-
tion, and immune system (Delpech et al., 2016; Johnson &
Kaffman, 2018; Ketchesin, Becker-Krail, & McClung, 2018;
Réus et al., 2017).
There is evidence that inflammatory processes, including
proinflammatory cytokines levels and microglial activation,
could influence behavior and emotions (Delpech et al., 2016;
Johnson & Kaffman, 2018; Réus et al., 2017). Studies have
shown that proinflammatory cytokines from the periphery
can lead to a microglial activation which can induce neuroin-
flammation (Nakamura, Okada, Toyama, & Okano, 2005;
Zhang, Hu, Qian, O'Callaghan, & Hong, 2010). In fact, rats
exposed to maternal deprivation early in life exhibited de-
pressive-like behavior in adult life and also an increase in the
proinflammatory cytokines and microglial activation (Réus
et al., 2017, 2019) which supports the idea that neuroinflam-
mation is also one of the pathways related to the development
of MDD.
One of the new pathways that have been studied to un-
derstand the pathophysiology of MDD is the gut–brain axis,
which communicate in complex and bidirectional ways. Some
studies show that individuals with MDD have altered gut
microbiota compared to healthy subjects (Jiang et al., 2015;
Kelly et al., 2016; Zheng et al., 2016). Emerging evidence
has suggested that the gut microbiota has some involvement
with inflammation, brain development, and behavior (Bailey
& Coe, 1999; Buffington et al., 2016; Diaz Heijtz et al., 2011;
Evrensel & Ceylan, 2015; Hsiao et al., 2013; Scott, Pound,
Patrick, Eberhard, & Crookshank, 2017). There are several
factors that can cause a disturbance in the balance of the gut
microbiota, stress is one of them, and it stimulates inflam-
mation-to-brain mechanisms and leads to microglia activa-
tion (Maes, 2008). Mice exposed to chronic restraint stress
had depressive-like behavior and an increase in the neuroin-
flammatory markers; on the other hand, prolonged intake
(21days) of the probiotic Bifidobacterium adolescentis was
able to reverse these changes, suggesting that the antidepres-
sant effects of B.adolescentis are related to reducing inflam-
matory cytokines and rebalancing the gut microbiota (Guo et
al., 2019).
2
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NEUROINFLAMMATION IN
MDD
Advances in neuroscience have linked chemokines to neu-
robiological processes important to psychiatric disorders,
such as synaptic transmission, plasticity, neurogenesis, and
communication (Stuart & Baune, 2014). In this sense, clini-
cal (Enache, Pariante, & Mondelli, 2019) and experimental
studies (Giridharan et al., 2019) have been related stress
and MDD to an increase in the immune system activity.
Neuroinflammation caused by the immune system activation
affects the central nervous system (CNS) through cytokines
releasing causing a dysregulation in brain activities and emo-
tions. Recent studies support the idea that cytokines affect
the brain signal patterns involved in the psychopathology of
MDD and in the mechanisms of antidepressant drugs. These
observations suggest that neuroinflammation and cytokines

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CARLESSI ET AL.
might cause and/or maintain depressive symptoms (Jeon &
Kim, 2016). Trials studies with classical anti-inflammatory
drugs such as celecoxib (Abbasi, Hosseini, Modabbernia,
Ashrafi, & Akhondzadeh, 2012) and nonsteroidal anti-in-
flammatory drugs (NSAD; Köhler, Krogh, Mors, & Benros,
2016) demonstrated an improvement of depressive symp-
toms with anti-inflammatory plus antidepressant treatment
compared to antidepressants plus placebo. In this sense, other
studies have been testing new anti-inflammatory therapies in
order to modulate the microglial activation. He et al. (2019)
tested paricalcitol, a vitamin D2 analogue that has been dem-
onstrated to have anti-inflammatory effects by modulating
nuclear factor kappa B (NF-κB) signaling. In this study, they
concluded that paricalcitol could alleviate the depressive-
like behavior induced by systemic lipopolysaccharide (LPS)
injection in mice, associating this to a potential anti-inflam-
matory effect. LPS is a component of the cell membrane of
gram-negative bacteria and has been used to induce depres-
sive behavior in animal models. Stress provoked by LPS
causes activation of the immune system and increase in the
expression of indoleamine-2, 3-dioxygenase (IDO) leading
to depressive-like behavior (Fu et al., 2010).
The imbalance produced by neuroinflammation can also
deregulate the hypothalamic–pituitary–adrenal (HPA) axis.
Some neurotransmitters, such as acetylcholine, dopamine,
noradrenaline, and serotonin, regulate peripheral cytokines
through cortisol levels, promoting or secreting corticotro-
pin-releasing hormone (CRH) in the hypothalamus, and adre-
nocorticotropic hormone (ACTH) in the pituitary (Calogero,
Gallucci, Chrousos, & Gold, 1988). In the normal state, pe-
ripheral cytokines are hydrophilic and have large molecular
weights; then, they are unable to cross through the blood–
brain barrier (BBB). However, they can cross through the
BBB in pathological states, including in the MDD situation.
In fact, increased BBB permeability is reported in depression
(Jeon & Kim, 2016).
Liu et al. (2019) describe in their review that important re-
gions involved in MDD are also correlated with higher levels
of proinflammatory cytokines. Experimental evidences have
been linked changes in the chemokine network to depressive
behavior. In addition, studies have been shown a relationship
between depression and microglial activation and an increase
in the proinflammatory cytokines, including interleukin-5
(IL-5), IL-6, IL-7, IL-10, tumor necrosis factor-α (TNF-α),
and interferon gamma (INF-γ), in the brain of rats subjected
to maternal deprivation (Giridharan et al., 2019). The au-
thors support the hypothesis that neuroinflammation and
microglial activation could be involved with changes in the
brain-resident cells, including excitotoxicity in neurons and
astrocytes atrophy following early life stress, which would be
associated with the development of depressive behavior.
Clinical studies have been also reported an association of
neuroinflammation and MDD. Enache et al. (2019) showed,
in a meta-analyses review, that an increase in the IL-6 and
TNF-α levels in cerebrospinal fluid (CSF) and brain paren-
chyma could be involved to microglial activation and reduc-
tion of astrocytes and oligodendrocytes. Müller et al. (2019)
examined an association of MDD with inflammation due to
a result of childhood maltreatment and threatening experi-
ences in the past year. They found significantly higher levels
of IL-6 and IL-10 in children with these adversities in life.
Moreover, it increased cytokine levels were related to the de-
velopment of MDD in the adulthood. In this context, IL-6
in higher concentration on serum of MDD patients who was
abused in their childhood was also detected (Munjiza et al.,
2018). Interestingly findings reported that female is dispro-
portionally affected by stress-primed inflammation. It could
be related to why women suffer more than men from mood
disorders (Bekhbat et al., 2019).
Considering these findings, the use of anti-inflammatory
agents in MDD has been investigated with growing interest.
In this sense, a recent meta-analysis concluded that anti-in-
flammatory agents improved antidepressant treatment effects.
However, the study calls the attention to future interventions
more personalized including measures of inflammation and
the somatic comorbidity profile in the overall assessment and
evaluation of the depressed patient (Köhler-Forsberg et al.,
2019).
3
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GUT MICROBIOTA
The gut microbiota has been shown to be one of the most im-
portant complex and bidirectional pathways between gut and
brain (Rhee, Pothoulakis, & Mayer, 2009). Other pathways
previously established include the autonomic nervous sys-
tem (ANS), the enteric nervous system (ENS), the neuroen-
docrine system, and the immune system (Foster & McVey
Neufeld, 2013). These pathways interact to form a complex
communication between the brain and gut. The brain influ-
ences the motor, sensory, and secretory modalities of the gas-
trointestinal tract; on the other hand, the gut influences brain
function, especially in areas of the brain involved to stress
regulation (Dinan & Cryan, 2012; Hannan, 2016). In fact, it
was demonstrated that germ-free (GF) mice, with microbiota
deficient from birth, had different parts of amygdala and hip-
pocampus with morphology impairment (Luczynski et al.,
2016). The function of insular brain area also appears to be
associated with microbiota diversity (Curtis et al., 2019).
The bidirectional communication between gut and brain
may be substantiated on the comorbidity between gastrointes-
tinal and neurodegenerative diseases, such as Parkinson, and
mood disorders, including MDD (Kennedy, Cryan, Dinan,
& Clarke, 2014; Smith & Parr-Brownlie, 2019; Whitehead,
Palsson, & Jones, 2002); for example, a significant number
of patients with irritable bowel syndrome (IBS) have MDD

4
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CARLESSI ET AL.
and/or anxiety (Spiller & Garsed, 2009). Furthermore, medi-
cations used to relieve the symptoms of patients with IBS and
eating disorders include are low-dose of antidepressants such
as tricyclic antidepressants (TCAs) or selective serotonin re-
uptake inhibitors (SSRIs; Ruepert et al., 2011).
Gut bacteria are essential in regulating important as-
pects of host health, such as brain development and function
(Diaz Heijtz et al., 2011; Hsiao et al., 2013). The microbi-
ota is influenced by different external stimuli, such as diet,
use of antibiotics, stress, and infections (Bercik, Park, et
al., 2011a). These factors can cause an imbalance between
pathogenic and beneficial bacteria (Forsythe, Sudo, Dinan,
Taylor, & Bienenstock, 2010), stimulating the process called
dysbiosis. Dysbiosis alters the permeability of the gut barrier,
and then, bacteria and its metabolic products could cross to
the periphery and activate immune response due release of
proinflammatory cytokines (Kiliaan et al., 1998). Dysbiosis
can increase inflammatory cytokines and bacterial metabo-
lites that can alter the gut and BBB permeability inducing
neuroinflammation (Roy & Banerjee, 2019). A study com-
pared oral and intraperitoneal administration of antibiotics in
adult mice and found that only animals treated by oral via had
transient changes in the composition of the gut microbiota
(Bercik, Denou, et al., 2011b).
Stress can dysregulate the gut microbiota, stimulating
immunological and brain mechanisms, including microglial
activation (Maes, 2008). Microglial cells are involved in the
release of proinflammatory cytokines in the brain in stress-
ful situations and seem to be altered in MDD (Réus, Fries,
et al., 2015a; Walker, Nilsson, & Jones, 2013). However, a
healthy microbiota can regulate these stress responses by
using the synthesis of hormones and neurotransmitters essen-
tial to minimize the effects of stress on the body (Asano et
al., 2012). Desbonnet et al. (2010) identified in their study
that the stress induced by early maternal deprivation in ro-
dents leads to depressive-like behavior and immune and
monoaminergic systems alterations (Desbonnet et al., 2010).
However, these changes were attenuated with the treatment
of Bifidobacterium infantis probiotic, which is a gram-posi-
tive anaerobic bacterium, existent in the gastrointestinal tract,
and it is one of the main genera of Actinobacteria that form
the colon microbiota in mammals (Duranti et al., 2016). This
study suggests that the microbiota by direct or indirect mech-
anisms may play an important role in CNS regulation and
psychiatric disorders.
In the context of early life stress, other studies also have
been shown that stress or changes in microbiota in early
life could lead to changes for all life. For example, dietary
interventions (milk fat globule membrane [MFGM] and
a polydextrose/galactooligosaccharide prebiotic blend) in
maternally separated rats improved HPA axis, changes, and
behavior impairment, and influenced abundance at family
and genus level as well as influencing beta-diversity levels
of microbiota (O'Mahony et al., 2019). Moreover, early life
supplementation of a blend of two prebiotics, galactooligo-
saccharide (GOS) and polydextrose (PDX), and the glyco-
protein lactoferrin (LAC) attenuated stress-induced learned
helplessness (Mika et al., 2017). Also, GOS, PDX, and LAC
diet was able to attenuate stress-evoked decreases in mRNA
for the 5-HT1A autoreceptor in the dorsal raphe nucleus and
increased basal BDNF mRNA in the prefrontal cortex (Mika
et al., 2017).
The gut microbiota plays important functions and modu-
lations that have been investigated and discussed as a potent
neuropharmacological target for MDD and other psychiatric
disorders conditions. Probiotics are described as living mi-
croorganisms that, when ingested in adequate amounts, bring
benefits to host health (Hill et al., 2014). The main mecha-
nisms by which probiotics exert their functions are through
modulation of the immune system, production of antimicro-
bial substances, competitive exclusion of pathogenic micro-
organisms, increase of the epithelial barrier, and gut mucosal
adhesion (Bermudez-Brito, Plaza-Díaz, Muñoz-Quezada,
Gómez-Llorente, & Gil, 2012). In addition, probiotics could
modulate opioid and cannabinoid receptors in gut epithelial
cells (Sanders, 2011). Opioids also have been associated with
neuroinflammatory processes induced by glial cells, such as
astrocytes and microglia (Hofford, Russo, and Kiraly (2018).
Probiotics also act on calcium-dependent potassium
channels in gut sensory neurons (Rousseaux et al., 2007).
Moreover, probiotics play a key role in the balance of the
gut flora, restoring the composition of the microbiota to a
more favorable state (Choi, Lee, & Paik, 2015). Some studies
also suggest that an improvement in the symptoms associated
to neurological and psychiatric disorders, as well as improve
the metabolic state, inflammatory biomarkers and oxidative
stress, through the probiotic effects on CNS circuits are me-
diated by the bowel-microbiota-brain axis (Messaoudi et al.,
2011; Réus, Fries, et al., 2015a).
Evidence has been shown that the gut microbiota can
affect the brain (Smith, 2015). Some bacteria, such as
Lactobacillus and Bifidobacterium, secrete gamma-amino-
butyric acid (GABA), an inhibitory neurotransmitter in the
brain, which regulates physiological and psychological pro-
cesses, and it is involved in the pathophysiology of anxiety
and MDD (Schousboe & Waagepetersen, 2007). Studies
have been shown that B.infantis can increase the availabil-
ity of tryptophan and thus the concentration of serotonin in
the brain (Desbonnet, Garrett, Clarke, Bienenstock, & Dinan,
2008; Desbonnet et al., 2010). Streptococcus, Escherichia,
and Enterococcus also produce serotonin, whereas the bac-
teria Escherichia, Bacillus, and Saccharomyces produce nor-
epinephrine, and Bacillus and Serratia have the potential to
produce dopamine (Holzer & Farzi, 2014; Özogul, 2011).
The microbiota and probiotics also act through neuro-
active bacterial metabolites called short-chain fatty acids

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CARLESSI ET AL.
(SCFAs), such as acetate, butyrate, and propionate (Overduin,
Schoterman, Calame, Schonewille, & Bruggencate, 2013).
SCFAs are produced by the gut microbiota through the fer-
mentation of complex polysaccharides and have been shown to
have immunomodulatory effects (Macfarlane & Macfarlane,
2003). For example, Bifidobacterium can produce SCFAs by
lowering the pH of the intestine, forming biological barriers
and secreting antimicrobial compounds to attenuate patho-
genic bacteria (Liao et al., 2016). Another important aspect is
the strain specificity. In fact, a study demonstrated that mice
with anxiety and inflammation induced by parasite had an
improvement in anxious behavior after the treatment with
Bifidobacterium longum NC3001, but not with Lactobacillus
rhamnosus NCC4007 (Bercik et al., 2010).
Different probiotics have been investigated for neurolog-
ical and psychiatric disorders; however, Lactobacillus and
Bifidobacterium genera have been shown to be more effective
(Kim, Yun, On, & Choi, 2018). Yang et al. (2017) demonstrated
in their study that the resilience of mice subjected to chronic
social defeat stress may be associated with Bifidobacterium in
the host intestine. In fact, the oral ingestion of Bifidobacterium
significantly increased the number of resilient mice after stress.
The administration of probiotics may result in the improvement
of depressive symptoms by increasing plasma levels of tryp-
tophan, decreased concentrations of serotonin metabolites in
the frontal cortex, and dopamine metabolites in the amygdaloid
cortex (Desbonnet et al., 2008).
It is well known that resilience plays a role in stress-re-
lated psychiatric disorders such as MDD (Réus, de Moura,
Silva, Resende, & Quevedo, 2018). There are increasing
reports showing the role of gut–brain axis in resilience ver-
sus susceptibility in rodents exposed to stress (Cathomas,
Murrough, Nestler, Han, & Russo, 2019; Dantzer, Cohen,
Russo, & Dinan, 2018). In fact, it was demonstrated that sus-
ceptible male rats, which were exposed to inescapable elec-
tric stress under the learned helplessness (LH) paradigm, had
abnormal microbiota composition, including Lactobacillus,
Clostridium cluster III, and Anaerofustis, when compared to
resilient rats (Zhang, Fujita, et al., 2019; Zhang, Guo, et al.,
2019).
4
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MICROBIOTA AND
NEUROINFLAMMATION IN MDD
4.1
|
Association among microbiota,
periphery inflammation, and brain–blood
barrier
The gut microbiota plays a key role in the formation and func-
tion of the immune system. It is believed that the first con-
tact of the immune system with the microbiota occurs during
childbirth and that this interaction has a great influence on
the immune system throughout development (Palmer, Bik,
DiGiulio, Relman, & Brown, 2010). However, the compo-
nents of breast milk, such as live microorganisms, metabo-
lites, immunoglobulin A (IgA), immune cells, and cytokines,
are associated with host responses to this early colonization
and with the formation of the microbiota (Belkaid & Hand,
2014).
Studies indicate that the gut microbiota alters CNS func-
tions, leading to the development of mood and depressive
behavior (Neufeld, Kang, Bienenstock, & Jane, 2011). For
example, mice submitted to different stressors for five weeks
displayed depressive-like behavior and elevated levels of
IL-1 in the hippocampus (Goshen et al., 2008). In addition,
the human oral intake of probiotic B.infantis 35,624 is asso-
ciated with increased expression of IL-10 in peripheral blood
(Bilbo & Schwarz, 2012). Valkanova, Ebmeier, and Allan
(2013) reported increased levels of IL-1β, IL-6, and TNF-α
in the serum of depressed individuals. Therefore, the balance
between the brain and the gut can be modulated by the im-
mune system (Bengmark, 2013).
The immune system has a symbiotic relationship between
host and microbiota, and the disruption of this dynamic
interaction may lead to the development of CNS disor-
ders (Hooper, Littman, & Macpherson, 2012). Pathogen-
associated molecular patterns (PAMPs), such as LPS, are
recognized by pattern recognition receptors (Barton, 2008).
These receptors play an important role in the recognition of
microbial targets for inflammation, and one of the families
of these receptors is Toll-like receptors (TLRs), which are
expressed not only in innate immune cells but also in CNS-
resident cell populations, including neurons and glial cells
(Crack & Bray, 2007). TLRs recognize components of micro-
organisms, including bacteria, viruses, and fungi, and then
activate inflammatory and antimicrobial innate immune re-
sponses (Medzhitov, 2001).
The TLRs are divided into subfamilies that bind to each
other and become activated by specific binders; for exam-
ple, TLR4 recognizes LPS, TLR2 along with TLR1 or TLR6
recognizes a variety of PAMPs (Kawai & Akira, 2010),
and TLR5 recognizes bacterial flagellin (Akira, Uematsu,
& Takeuchi, 2006). After activation of a TLR, a signaling
cascade is initiated which results in activation of major in-
tracellular transcription factors such as interferon I (Giles &
Stagg, 2017) and NF-κB (Sanz & Moya-Perez, 2014). Once
activated, these cells produce numerous proinflammatory
cytokines, such as IL-1α, IL-1β, TNF-α, and IL-6 (Dantzer,
Konsman, Bluthe, & Kelley, 2000). These cytokines stim-
ulate the development of CD4+T helper 1 effector cells
(TH1) and TH17 cells. TH17 in turn produces IL-17A, IL-
17F, and IL-22, resulting in chronic inflammation (Maynard,
Elson, Hatton, & Weaver, 2012).
The gut microbiota can promote different subsets of
CD4+T cells through antigenic stimulation and activation of

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CARLESSI ET AL.
immune signaling pathways. Animals treated with long-act-
ing antibiotics showed a significant reduction of Treg cells
and CD4+T cells (Cording, Fleissner, & Heimesaat, 2013).
Bacteroides fragilis promotes the development of TH1
cells via the polysaccharide A pathway (Mazmanian, Liu,
Tzianabos, & Kasper, 2005). Besides, a study demonstrated
that GF mice have a defect in Foxp3+ Tregs lymphocytes,
these cells are responsible for controlling the function and
proliferation of effector T cells, and the gut microbiota plays
an important role in the induction of Treg cells (Atarashi et
al., 2011). SFCAs also induce the proliferation of Foxp3+
Tregs by histone modification (Van Loosdregt et al., 2011).
The excessive production of inflammatory cytokines in the
periphery, such as IL-1α, IL-1β, TNF-α, and IL-6, could cross
the BBB and reach the brain-resident cells. In the brain, these
cytokines act on receptors expressed by neurons and glial
cells (Dantzer et al., 2000). One of the possible mechanisms
by which cytokines can cross the BBB is by transmembrane
diffusion, requiring low molecular weight and high liposol-
ubility to enter (Oldendorf, 1974). The intestine metabolic
products have this characteristic and therefore allow their
access through the BBB (Stilling, Dinan, & Cryan, 2014).
A study showed that GF mice had increased permeability of
BBB compared to pathogen-free mice with a normal gut flora,
and this permeability was associated with reduced expression
of junction proteins; on the other hand, the exposure of GF
adult mice to a gut microbiota free of pathogens leads to a
decrease in the BBB permeability and positively regulates the
expression of junction proteins (Braniste et al., 2014).
4.2
|
Gut microbiota, inflammasome, and
microglial activation
Studies have been hypothesized the inflammasome as a key
mediator of the neuroinflammatory responses due to stress,
and its dysregulation may be implicated in the pathophysiol-
ogy of MDD (Akosile et al., 2018; Wong et al., 2016; Zhang,
Fujita, et al., 2019; Zhang, Guo, et al., 2019). Inflammasome
activation, specially nucleotide binding and oligomeriza-
tion domain-like receptor family pyrin domain-containing
3 (NLRP3), can occur by damage-associated molecular pat-
terns (DAMPs) or PAMPs mediated by Toll-like receptor 4
(TLR4) in microglial cells or by stimulus such as oxidative
stress and recruitment and activation of caspase-1, besides
IL-1β and IL-18 (Kaufmann et al., 2017). Wong et al. (2016)
conducted a study using mice with genetic deficiency or
pharmacological inhibition of caspase-1 and demonstrated
that the caspase-1 inhibition was able to reduce depressive-
and anxiety-like behavior. Also, such effects were associated
with a protective effect on the stress response by a modula-
tion in the microbiota–gut–inflammasome–brain axis (Wong
et al., 2016). In the prefrontal cortex of rats chronically
stressed, it was found an increase in the NF-κB, NLRP3, and
IL-1β; microglial activation and astrocyte impairment were
also observed; and on other hand, the treatment with the
antidepressant fluoxetine was able to reverse these changes
(Pan, Chen, Zhang, & Kong, 2014). Westfall and Pasinetti
(2019) demonstrated that a combination of a dietary polyphe-
nolic with Lactobacillus plantarum and B.longum was able
to reduce anxiety- and depressive-like behavior induced by
chronic stress. In addition, L.plantarum and B.longum were
suggested to inhibit NLRP3-mediated generation of IL-1β in
microglia cells (Westfall & Pasinetti, 2019). By targeting the
gut microbiome using prebiotic intervention (FOS-Inulin),
it was demonstrated a reversion in age-induced changes,
mainly monocyte infiltration into the brain and microglial ac-
tivation (van de Boehme et al., 2019), suggesting that prebi-
otic-driven changes in gut microbiota composition could be
a novel strategy for the improvement of age-related neuroin-
flammatory diseases and brain function. Other study revealed
that immobilization stress-induced anxiety/depression and
colitis in mice were prevented by probiotics Lactobacillus re-
uteri NK33 and B.adolescentis NK98. NK33 and NK98 also
were able to reduce microglial activation in the hippocampus
and IL-6 and corticosterone in the blood (Jang, Lee, & Kim,
2019). A study conducted by Zhang et al. (2017) demon-
strated that anti-mouse IL-6 receptor antibody (MR16-1) ad-
ministration leads to antidepressant effects in a social defeat
stress model and improved Firmicutes/Bacteroidetes ratio in
susceptible mice, suggesting that IL-6 blockade induces an-
tidepressant effects by normalizing the altered composition
of gut microbiota. Needed, IL-6 plays an important role in
MDD. Recently, the antidepressant effects of ketamine, an
antagonist of N-methyl-D-aspartate (NMDA) receptor, were
associated with reduction in serum IL-6 levels in treatment-
resistant patients with MDD (Yang et al., 2015). In addition,
Getachew et al. (2018) revealed that after 24hr of ketamine
treatment Wistar rats had change in microbiota diversity.
More studies investigating ketamine effects in microbiota in
human with MDD and in animal models of depression could
be promising.
4.3
|
Gut microbiota and
kynurenine pathway
The kynurenine pathway (KP) plays an important role in
the development of psychiatric disorders, including schizo-
phrenia (Réus, Becker, et al., 2018; Zhu et al., 2019) and
MDD (Réus, Jansen, et al., 2015b). Moreover, the gut
microbiota seems to be related to the regulation of tryp-
tophan, which is a precursor of KP (Clarke et al., 2014).
Colonization of the gut microbiota in early life as well
as changes in its composition and diversity throughout
life influences the availability of tryptophan and plays an

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CARLESSI ET AL.
important role in serotonergic signaling at the CNS level.
Modulation of host behavior by the gut microbiota can
occur through recruitment of tryptophan metabolism and
serotonergic signaling of the brain–gut axis (O'Mahony,
Clarke, Borre, Dinan, & Cryan, 2015). Microbial gut me-
tabolites, such as short-chain fatty acids, can promote the
production of serotonin through tryptophan, thus regulat-
ing this pathway and preventing the tryptophan conversion
to KP (Reigstad et al., 2015).
Tryptophan is an essential amino acid precursor of
the neurotransmitter serotonin and metabolites of the KP.
Through indoleamine-2,3-dioxygenase (IDO) enzymes,
found in all tissues, and tryptophan-2,3-dioxygenase
(TDO), located in the liver, a small part of tryptophan is
metabolized to serotonin and the remainder on the KP
(Salter & Pogson, 1985). The stimulation of inflammatory
cytokines during gut inflammation, especially interferon
gamma (IFN-γ) and IL-6, induces the production of IDO
and results in changes in the metabolism of tryptophan,
causing the shift of serotonin synthesis to the production
of kynurenine and its metabolites (Jürgens, Hainz, Fuchs,
Felzmann, & Heitger, 2009; Yeung, Terentis, King, &
Thomas, 2015). Cytokines, such as IFN-γ, IL-2, and TNF-
α, have been associated with a higher risk for MDD de-
velopment (Howren, Lamkin, & Suls, 2009), and intestinal
inflammation may lead to altered brain function and MDD
(Waclawiková & Aidy, 2018). Rodents treated with B.in-
fantis display increased tryptophan plasma concentrations
and reduced IDO activity (Desbonnet et al., 2008). In ad-
dition, the treatment with B.infantis promoted antidepres-
sant-like behavior (Desbonnet et al., 2008). GF rodents
have a decrease in the KP activity; on the other hand, a
healthy microbiota reposition in the same animal is able to
normalize the KP (Clarke et al., 2013).
The metabolites of kynurenine are divided into two path-
ways: (a) production of kynurenic acid (KYNA), which
is neuroprotector and NMDA receptor antagonist and (b)
production of quinolinic acid (QUIN), which is neurotoxic
FIGURE 1 Association between gut microbiota–brain axis and MDD. Stress situations can dysregulate the gut microbiota leading to
dysbiosis, decrease in SCFAs, and increase in the proinflammatory cytokines, mainly IL-6 and IFN-γ. This inflammatory status can induce gut
permeability and bacteria migration (leaky gut). Inflammatory cytokines induce increase in IDO, which can induce a impairment QUIN/KYNA
production. Kynurenine pathway toxic metabolites and inflammatory cytokines could lead to damage in BBB, inducing an increase in the IL-6,
IL-1β, and inflammasome NLRP3 in brain-resident cells. In the brain, the inflammatory process provokes microglial activation and astrocyte
atrophy and consequently more inflammation that can culminate in mood disorders, such as anxiety and MDD. Stress situation also can directly
affect brain-resident cells increasing inflammatory mediators and indirectly changing gut microbiota. On the other hand, prebiotics and probiotics
are able to change gut microbiota and intestinal barrier, thus indirectly decreasing inflammatory cytokines, toxic metabolic of kynurenine pathway,
and BBB permeability. BBB, brain–blood barrier; IDO, indoleamine-2, 3-dioxygenase; IFN-γ, interferon gamma; IL-6, interleukin-6; IL-1β,
interleukin-1β; KYNA, kynurenic acid; MDD; major depressive disorder, NLRP3, nucleotide binding and oligomerization domain-like receptor
family pyrin domain-containing 3; QUIN, quinolinic acid; SCFAs, short-chain fatty acids

8
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CARLESSI ET AL.
and NMDA receptor agonist (Le Floc'h, Otten, & Merlot,
2011; Schwarcz, Bruno, Muchowski, & Wu, 2012). In the
brain, QUIN causes excitotoxicity through the stimulation of
NMDA receptors, as KYNA acts by neutralizing these ef-
fects (Szalardy et al., 2012). MDD is associated with exces-
sive production of QUIN along with the reduction of KYNA
(Savitz et al., 2015). Reduced levels of KYNA were found in
patients with MDD (Wurfel et al., 2017), while elevated lev-
els of QUIN were found in the CSF of patients with suicide
attempts (Erhardt et al., 2013). Moreover, mice submitted to
chronic stress had altered gut microbiota composition, a de-
crease in Lactobacillus, and an increase in the kynurenine
levels. Though, restoration of gut Lactobacillus levels was
sufficient to improve metabolic changes and behavioral ab-
normalities (Marin et al., 2017).
At the end of the KP, the catabolism proceeds to com-
plete oxidation forming either adenosine triphosphate (ATP)
or nicotinamide adenine dinucleotide (NAD). This complete
oxidation begins with the degradation of tryptophan by TDO
or IDO in KYN. Kynurenine is subsequently degraded to
3-hydroxyquinurenine (OHK) by quinurenine-3-mono-ox-
ygenase (KMO) or kinurenic acid (KYNA) by kynurenine
aminotransferases (KATs). OHK continues to be degraded
by kynureninase to produce 3-hydroxyanthranilic acid
(HAA). Finally, HAA can be degraded in ATP or in small
amounts of picolinic acid or quinolinic acid (QUIN) and
subsequently in NAD (Réus, Jansen, et al., 2015b).
In the brain, IDO is expressed by various brain cells, includ-
ing astrocytes and microglia (Grant, Naif, Espinosa, & Kapoor,
2000). During inflammation and increased degradation of
tryptophan, induced by inflammatory cytokines (Pemberton,
Kerr, Smythe, & Brew, 1997), excessive production of ky-
nurenine can be transported through the BBB into the brain.
The metabolites of this pathway contribute to neuroprotec-
tive and/ or neurodegenerative changes in the brain (Myint,
Schwarz, & Muller, 2012). Microglia and macrophages appear
to be involved in the production of QUIN and KYNA in the
astrocytes. During infection, infiltration of activated macro-
phages and microglia activation in the brain may result in the
contribution of neurotoxicity astrocyte-mediated (Guillemin et
al., 2001). MDD is associated with an inflammatory state that
may stimulate the production of the neuropathic pathway of
KP, maintenance glial cells in constant imbalance which could
contribute to the recurrent and chronic nature of MDD (Myint
& Kim, 2003; Réus, Jansen, et al., 2015b).
5
|
CONCLUSION
The gut microbiota–brain axis dysregulation is evident in
MDD. This association has been reported by human and
animal studies. Stress situations could lead to an impair-
ment in the gut microbiota that in turn lead a production of
inflammatory mediators, mainly IFN-γ and IL-6, and a de-
crease in SCFAs. Changes in the gut microbiota could impact
the gut barrier and to produce higher levels of inflammatory
cytokines in the blood. In the periphery, the kynurenine path-
ways, metabolic, mainly toxic metabolic, are influenced by
changes in the gut microbiota and inflammatory mediators.
From periphery, toxic products from a microbiota impair-
ment or proinflammatory cytokines could disrupt BBB and
cross to the brain increasing cytokines, such as IL-6, IL-1β,
and the inflammasome NLPR3 in the brain-resident cells.
Microglial and astrocytes are influenced, suffering activation
and atrophy, respectively (Figure 1). Changes in these glial
cells influence brain networks involved in memory, learning,
emotions, and mood regulation, what could be behind the
onset of depressive symptoms or anxiety.
ACKNOWLEDGEMENTS
The Translational Psychiatry Program (USA) is funded
by the Department of Psychiatry and Behavioral Sciences,
McGovern Medical School, The University of Texas Health
Science Center at Houston (UTHealth). The Center of
Excellence on Mood Disorders (USA) is funded by the Pat
Rutherford Jr. Chair in Psychiatry, John S. Dunn Foundation,
and Anne and Don Fizer Foundation Endowment for
Depression Research. Translational Psychiatry Laboratory
(Brazil) is one of the centers of the National Institute for
Molecular Medicine (INCT-MM) and one of the members of
the Center of Excellence in Applied Neurosciences of Santa
Catarina (NENASC). Its research is supported by grants
from CNPq (JQ and GZR), FAPESC (JQ and GZR), Instituto
Cérebro e Mente (JQ, AIZ and GZR), and UNESC (JQ, GZR,
and AIZ). JQ is a 1A CNPq Research Fellow.
CONFLICT OF INTEREST
JQ has provided clinical research support to Janssen
Pharmaceutical and Allergan; has served on the speaker bu-
reau for Daiichi Sankyo, and on other advisory boards and
speaker bureaus as expert witness or consultant; is a stock-
holder for Instituto de Neurociencias; and is a copyright
holder for Artmed Editora and Artmed Panamericana. ASC,
LAB, AIZ, and GZR have no conflict of interest.
AUTHOR CONTRIBUTIONS
ASC, LAB, AIZ, JQ, and GZR contributed with writing
manuscript. ASC prepared the figure. GZR contributed with
study design and manuscript revision.
DATA AVAILABILITY STATEMENT
The data associated with this review paper are available on
pubmed.gov
ORCID
Gislaine Z. Réus https://orcid.org/0000-0001-6073-0855

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CARLESSI ET AL.
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How to cite this article: Carlessi AS, Borba LA,
Zugno AI, Quevedo J, Réus GZ. Gut microbiota–brain
axis in depression: The role of neuroinflammation.
Eur J Neurosci. 2019;00:1–14. https ://doi.
org/10.1111/ejn.14631