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



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.
Eur J Neurosci. 2019;00:1–14.
© 2019 Federation of European Neuroscience Societies
and John Wiley & Sons Ltd
Received: 14 August 2019
Revised: 18 November 2019
Accepted: 20 November 2019
DOI: 10.1111/ejn.14631
Gut microbiota–brain axis in depression: The role of
Anelise S.Carlessi1
Laura A.Borba1
Alexandra I.Zugno1
Gislaine Z.Réus1
Edited by Dr. Michel Barrot.
The peer review history for this article is available at https ://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,
Gislaine Z. Réus, Translational Psychiatry
Laboratory, University of Southern Santa
Catarina, Criciuma, SC, 88806-000, Brazil.
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
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.
gut microbiota–brain axis, inflammasome, kynurenine pathway, major depressive disorder,
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
(21days) 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).
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
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.,
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
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
(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.,
Association among microbiota,
periphery inflammation, and brain–blood
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,
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
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).
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 24hr 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.
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
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
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
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).
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.
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.
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.
ASC, LAB, AIZ, JQ, and GZR contributed with writing
manuscript. ASC prepared the figure. GZR contributed with
study design and manuscript revision.
The data associated with this review paper are available on
Gislaine Z. Réus
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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.
... The GBM axis functions bidirectionally through a number of mechanisms, including via the vagus nerve, generation of metabolites such as SCFAs and enteroendocrine hormones, dysregulation of the HPA axis to alter intestinal motility, integrity, and mucus production, cross-reaction of the bacterial proteins with human antigens, and immune signaling [22]. The stimulation of immune/inflammatory pathways further reveals a potentially important link between gut "dysbiosis" and the current inflammatory theory of depression in humans [23]. Additionally, it plays a role in the development of other neurological and psychiatric diseases such as Parkinson's disease (PD), Alzheimer's disease, multiple sclerosis, and autism spectrum disorder [20]. ...
... Multiple studies have found associations between diet and mood/anxiety symptoms [32,43,44]. For example, a randomized control trial (RCT) of young adults (aged [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] with elevated levels of depression and poor diet undergoing a brief three-week diet intervention compared to habitual diet found that the diet group reported lower depression symptoms than controls [45]. ...
... E-cigarettes have been the most commonly used tobacco product among youth since 2014 [75]. One in nine high school students reported using E-cigarettes in 2021 in the United States [76], and one in four of European youth (aged [15][16][17][18][19][20][21][22][23][24] reported trying E-cigarettes in a 2020 report [77]. ...
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Emerging adulthood (ages 18–25) is a critical period for neurobiological development and the maturation of the hypothalamic–pituitary–adrenal axis. Recent findings also suggest that a natural perturbation of the gut microbiota (GM), combined with other factors, may create a unique vulnerability during this period of life. The GM of emerging adults is thought to be simpler, less diverse, and more unstable than either younger or older people. We postulate that this plasticity in the GM suggests a role in the rising mental health issues seen in westernized societies today via the gut–brain–microbiota axis. Studies have paid particular attention to the diversity of the microbiota, the specific function and abundance of bacteria, and the production of metabolites. In this narrative review, we focus specifically on diet, physical activity/exercise, substance use, and sleep in the context of the emerging adult. We propose that this is a crucial period for establishing a stable and more resilient microbiome for optimal health into adulthood. Recommendations will be made about future research into possible behavioral adjustments that may be beneficial to endorse during this critical period to reduce the probability of a “dysbiotic” GM and the emergence and severity of mental health concerns.
... In fact, while dysbiosis may promote the onset of pathological conditions such as metabolic syndrome, type 2 diabetes and inflammatory bowel disease (IBD), on the other hand, changes in microbiota composition may result from these same pathological states (see [32] and references therein). A similar bidirectional effect may apply also to neurodevelopmental and psychiatric disorders characterized by neuroinflammation through the microbiota-gut-brain axis [30,[68][69][70] Changes in microbiota composition have been suggested to contribute to the endocrine, neurochemical and inflammatory alterations underlying obesity and the often-associated psychiatric disorders, a role that might be already at play during fetal life [33,34,65,72]. ...
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Obesity is a main risk factor for the onset and the precipitation of many non-communicable diseases. This condition, which is associated with low-grade chronic systemic inflammation, is of main concern during pregnancy leading to very serious consequences for the new generations. In addition to the prominent role played by the adipose tissue, dysbiosis of the maternal gut may also sustain the obesity-related inflammatory milieu contributing to create an overall suboptimal intrauterine environment. Such a condition here generically defined as “inflamed womb” may hold long-term detrimental effects on fetal brain development, increasing the vulnerability to mental disorders. In this review, we will examine the hypothesis that maternal obesity-related gut dysbiosis and the associated inflammation might specifically target fetal brain microglia, the resident brain immune macrophages, altering neurodevelopmental trajectories in a sex-dependent fashion. We will also review some of the most promising nutritional strategies capable to prevent or counteract the effects of maternal obesity through the modulation of inflammation and oxidative stress or by targeting the maternal microbiota.
... Furthermore, female hormones play an important protective role in immunity. Estradiol, for instance, has been convincingly shown to reduce the levels of inflammatory cytokines (77). This accords with preclinical animal research, which finds both greater levels of inflammatory signaling molecules and activated immune cells in healthy males than in healthy females (78). ...
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Sex differences are prevalent in multiple mental disorders. Internalizing disorders are more commonly diagnosed in women, whereas externalizing and neurodevelopmental disorders are more often diagnosed in men. Significant sex/gender differences are reported in prevalence, symptom profile, age of onset, comorbidities, functional impairment, prognosis, as well as in responses to various treatments. In this conceptual article, we discuss theories and empirical studies of sex- and gender-related influences in mental health, by focusing on three examples: autism spectrum disorder (ASD), acknowledged as a disorder whose roots are mainly biological; eating disorders, whose origins are considered to be mainly psychosocial, and posttraumatic stress disorder (PTSD), an environmentally caused disorder with both psychosocial and biological underpinnings. We examine the ways in which sex differences emerge, from conception through adulthood. We also examine how gender dichotomies in exposures, expectations, role assumptions, and cultural traditions impact the expression of our three selected mental illnesses. We are especially interested in how sex-based influences and gender-based influences interact with one another to affect mental illness. We suggest that sex and gender are multi-faceted and complex phenomena that result in variations, not only between men and women, but also within each sex and gender through alterations in genes, hormone levels, self-perceptions, trauma experiences, and interpersonal relationships. Finally, we propose a conceptual diatheses-stress model, depicting how sex and gender come together to result in multiple sex/gender differences across mental disorders. In our model, we categorize diatheses into several categories: biological, intrapersonal, interpersonal, and environmental. These diatheses interact with exposure to stressors, ranging from relatively minor to traumatic, which allows for the sometimes bidirectional influences of acute and long-term stress responses. Sex and gender are discussed at every level of the model, thereby providing a framework for understanding and predicting sex/gender differences in expression, prevalence and treatment response of mental disorders. We encourage more research into this important field of study.
... Among the main biological mechanisms implicated in the pathophysiology of these disorders, compelling evidence has pointed to neuroinflammation as a key factor in the onset and progression of these disorders [6]. Notably, other biological mechanisms that have been implicated in depression and anxiety, such as gut dysbiosis, impaired neurogenesis, and monoaminergic dysfunction, may be triggered by a neuroinflammatory process, opening new perspectives for studying molecular targets and neuroprotective agents against these mood disturbances [4,[7][8][9]. In this regard, in recent years, vitamin D has gained prominence due to its antioxidant, anti-inflammatory, pro-neurogenic, and neuromodulatory properties that appear to be fundamental to its antidepressant and anxiolytic effects [10][11][12][13]. ...
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Major depressive disorder and anxiety disorders are common and disabling conditions that affect millions of people worldwide. Despite being different disorders, symptoms of depression and anxiety frequently overlap in individuals, making them difficult to diagnose and treat adequately. Therefore, compounds capable of exerting beneficial effects against both disorders are of special interest. Noteworthily, vitamin D deficiency has been associated with an increased risk of developing depression and anxiety, and individuals with these psychiatric conditions have low serum levels of this vitamin. Indeed, in the last few years, vitamin D has gained attention for its many functions that go beyond its effects on calcium–phosphorus metabolism. Particularly, antioxidant, anti-inflammatory, pro-neurogenic, and neuromodulatory properties seem to contribute to its antidepressant and anxiolytic effects. Therefore, in this review, we highlight the main mechanisms that may underlie the potential antidepressant and anxiolytic effects of vitamin D. In addition, we discuss preclinical and clinical studies that support the therapeutic potential of this vitamin for the management of these disorders.
... The potential of the diagnostic technology described here to detect CNS inflammation non-invasively resulting from active infection or as a byproduct of inoculation with adjuvant would have high value. Indeed, childhood infections have been positively correlated with later onset of mood and other neuropsychiatric disorders [18], which are associated with neuroinflammation [36][37][38]. ...
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Purpose Macrophages represent an essential means of sequestration and immune evasion for Mycobacterium tuberculosis. Pulmonary tuberculosis (TB) is characterized by dense collections of tissue-specific and recruited macrophages, both of which abundantly express CSF1R on their outer surface. 4-Cyano-N-(5-(1-(dimethylglycyl)piperidin-4-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)-1H-imidazole-2-carboxamide (JNJ-28312141) is a reported high affinity, CSF1R-selective antagonist. We report the radiosynthesis of 4-cyano-N-(5-(1-(N-methyl-N-([¹¹C]methyl)glycyl)piperidin-4-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)-1H-imidazole-2-carboxamide ([¹¹C]JNJ-28312141) and non-invasive detection of granulomatous and diffuse lesions in a mouse model of TB using positron emission tomography (PET). Methods Nor-methyl-JNJ-28312141 precursor was radiolabeled with [¹¹C]iodomethane to produce [¹¹C]JNJ-28312141. PET/CT imaging was performed in the C3HeB/FeJ murine model of chronic pulmonary TB to co-localize radiotracer uptake with granulomatous lesions observed on CT. Additionally, CSF1R, Iba1 fluorescence immunohistochemistry was performed to co-localize CSF1R target with reactive macrophages in infected and healthy mice. Results Radiosynthesis of [¹¹C]JNJ-28312141 averaged a non-decay-corrected yield of 18.7 ± 2.1%, radiochemical purity of 99%, and specific activity averaging 658 ± 141 GBq/µmol at the end-of-synthesis. PET/CT imaging in healthy mice showed hepatobiliary [13.39–25.34% ID/g, percentage of injected dose per gram of tissue (ID/g)] and kidney uptake (12.35% ID/g) at 40–50 min post-injection. Infected mice showed focal pulmonary lesion uptake (5.58–12.49% ID/g), hepatobiliary uptake (15.30–40.50% ID/g), cervical node uptake, and renal uptake (11.66–29.33% ID/g). The ratio of infected lesioned lung/healthy lung uptake is 5.91:1, while the ratio of lesion uptake to adjacent infected radiolucent lung is 2.8:1. Pre-administration of 1 mg/kg of unlabeled JNJ-28312141 with [¹¹C]JNJ-28312141 in infected animals resulted in substantial blockade. Fluorescence microscopy of infected and uninfected whole lung sections exclusively co-localized CSF1R staining with abundant Iba1 + macrophages. Healthy lung exhibited no CSF1R staining and very few Iba1 + macrophages. Conclusion [¹¹C]JNJ-28312141 binds specifically to CSF1R + macrophages and delineates granulomatous foci of disease in a murine model of pulmonary TB.
... Along with influencing other metabolites, gut-bacteria influence tryptophan metabolism (Carlessi, Borba, Zugno, Quevedo, & Réus, 2021). Tryptophan is an essential amino acid, which is metabolized by two main pathways, namely, the serotonin (5-HT) pathway and the kynurenine pathway. ...
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Major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia-spectrum disorders (SSD) are heterogeneous psychiatric disorders, which place significant burden on patient's well-being and global health. Disruptions in the gut-microbiome may play a role in these psychiatric disorders. This review presents current data on composition of the human gastrointestinal microbiota, and its interaction mechanisms in the gut–brain axis in MDD, BD and SSD. Diversity metrics and microbial relative abundance differed across studies. More studies reported inconsistent findings ( n = 7) or no differences ( n = 8) than studies who reported lower α -diversity in these psychiatric disorders ( n = 5). The most consistent findings across studies were higher relative abundances of the genera Streptococcus , Lactobacillus , and Eggerthella and lower relative abundance of the butyrate producing Faecalibacterium in patients with psychiatric disorders. All three increased genera were associated with higher symptom severity. Confounders, such as medication use and life style have not been accounted for. So far, the results of probiotics trials have been inconsistent. Most traditional and widely used probiotics (consisting of Bifidobacterium spp. and Lactobacillus spp.) are safe, however, they do not correct potential microbiota disbalances in these disorders. Findings on prebiotics and faecal microbiota transplantation (FMT) are too limited to draw definitive conclusions. Disease-specific pro/prebiotic treatment or even FMT could be auspicious interventions for prevention and therapy for psychiatric disorders and should be investigated in future trials.
... Since approximately one-third of patients with depression do not respond to current antidepressants, new antidepressants must be developed for such treatment-resistant patients [27,39,40]. Moreover, numerous studies have suggested a strong association between inflammatory processes and the pathophysiology of depression [41][42][43][44][45][46][47]. ...
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It has been found that soluble epoxide hydrolase (sEH; encoded by the EPHX2 gene) in the metabolism of polyunsaturated fatty acids (PUFAs) plays a key role in inflammation, which, in turn, plays a part in the pathogenesis of neuropsychiatric disorders. Meanwhile, epoxy fatty acids such as epoxyeicosatrienoic acids (EETs), epoxyeicosatetraenoic acids (EEQs), and epoxyeicosapentaenoic acids (EDPs) have been found to exert neuroprotective effects in animal models of neuropsychiatric disorders through potent anti-inflammatory actions. Soluble expoxide hydrolase, an enzyme present in all living organisms, metabolizes epoxy fatty acids into the corresponding dihydroxy fatty acids, which are less active than the precursors. In this regard, preclinical findings using sEH inhibitors or Ephx2 knock-out (KO) mice have indicated that the inhibition or deficiency of sEH can have beneficial effects in several models of neuropsychiatric disorders. Thus, this review discusses the current findings of the role of sEH in neuropsychiatric disorders, including depression, autism spectrum disorder (ASD), schizophrenia, Parkinson’s disease (PD), and stroke, as well as the potential mechanisms underlying the therapeutic effects of sEH inhibitors.
A narrative review about the relationship between stress, inflammation, and depression is made as follows: Chronic stress leads to various stress-related diseases such as depression. Although most human diseases are related to stress exposure, the common pathways between stress and pathophysiological processes of different disorders are still debatable. Chronic inflammation is a crucial component of chronic diseases, including depression. Both experimental and clinical studies have demonstrated that an increase in the levels of pro-inflammatory cytokines and stress hormones, such as glucocorticoids, substantially contributes to the behavioral alterations associated with depression. Evidence suggests that inflammation plays a key role in the pathology of stress-related diseases; however, this link has not yet been completely explored. In this study, we aimed to determine the role of inflammation in stress-induced diseases and whether a common pathway for depression exists. Recent studies support pharmacological and non-pharmacological treatment approaches significantly associated with ameliorating depression-related inflammation. In addition, major depression can be associated with an activated immune system, whereas antidepressants can exert immunomodulatory effects. Moreover, non-pharmacological treatments for major depression (i.e., exercise) may be mediated by anti-inflammatory actions. This narrative review highlights the mechanisms underlying inflammation and provides new insights into the prevention and treatment of stress-related diseases, particularly depression.
Depression is a debilitating mental disorder that affects >322 million people worldwide. Despite the availability of several antidepressant agents, many patients remain treatment refractory. A growing literature study has indicated the role of gut microbiota in neuropsychiatric disorders. Herein, we examined the psychobiotic-like activity of multi-strain probiotic formulation in maternal separation (MS) and chronic unpredictable mild stress (CUMS) models of anxiety- and depression-like phenotypes in Sprague-Dawley rats. Early- and late-life stress was employed in both male and female rats by exposing them to MS and CUMS. The multi-strain probiotic formulation (Cognisol) containing Bacillus coagulans Unique IS-2, Lactobacillus plantarum UBLP-40, Lactobacillus rhamnosus UBLR-58, Bifidobacterium lactis UBBLa-70, Bifidobacterium breve UBBr-01, and Bifidobacterium infantis UBBI-01 at a total strength of 10 billion cfu along with l-glutamine was administered for 6 weeks via drinking water. Neurobehavioral assessment was done using the forced swim test (FST), sucrose preference test (SPT), elevated plus maze (EPM), and open field test (OFT). Animals were sacrificed after behavioral assessment, and blood, brain, and intestine samples were collected to analyze the levels of cytokines, metabolites, and neurotransmitters and histology. Animals exposed to stress showed increased passivity, consumed less sucrose solution, and minimally explored the open arms in the FST, SPT, and EPM, respectively. Administration of multi-strain probiotics along with l-glutamine for 6 weeks ameliorated the behavioral abnormalities. The locomotor activity of animals in the OFT and their body weight remained unchanged across the groups. Cognisol treatment reversed the decreased BDNF and serotonin levels and increased CRP, TNF-α, and dopamine levels in the hippocampus and/or frontal cortex. Administration of Cognisol also restored the plasma levels of l-tryptophan, l-kynurenine, kynurenic-acid, and 3-hydroxyanthranilic acid; the Firmicutes-to-Bacteroides ratio; the levels of acetate, propionate, and butyrate in fecal samples; the villi/crypt ratio; and the goblet cell count, which manifested in the restoration of intestinal functions. We suggest that the multi-strain probiotic and glutamine formulation (Cognisol) ameliorated the MS + UCMS-generated anxiety- and depression-like phenotypes by reshaping the gut microbiome-brain activity in both sexes.
Backgrounds The mechanism of drug-resistant epilepsy has been incompletely understood, and the transporter hypothesis is one of the most cited theories. The association between gut microbiome and epilepsy is increasingly recognized but the mechanism remains unclear. We hypothesize that gut microbiome plays a role of pharmacokinetics of antiseizure medicines (ASMs) through transporters at the host-microbe interface. This study aimed to screen the key subspecies of gut microbiota related to drug-resistant epilepsy and explore their effects on the ASMs resistance mechanism through the regulation of transporter ATP-binding cassette B1 (ABCB1). Methods Three groups of participants were designed, 10 drug-resistant epilepsy patients (DR group), 10 non-drug-resistant epilepsy patients (NDR group), and 19 healthy controls (Control group). Fresh stool samples were collected. Based on the 16 S rRNA sequencing results of their fecal samples, we selected the Bacillus subtilis (B. subtilis) to explore its effect on the ASMs efflux mediated by transporter ABCB1 whose expression were detected through quantitative PCR and Western blot analysis in Caco-2 cell model. Further, we conducted the Rhodamine 123 accumulation assay to evaluate the activity of the transporter ABCB1 in Caco-2 cell and the high-performance liquid chromatography (HPLC) to measure the concentrations of ASMs. Results We found that the Phylum Firmicutes were enriched in the patients with drug-resistant epilepsy (70.82%) and picked up B. subtilis as the key type of bacteria relevant to drug-resistant epilepsy. The B. subtilis not only downregulated the expression level and the efflux activity of ABCB1 in Caco-2 cells treated with ASMs (P<0.01), but also reduced the carbamazepine efflux in the Caco-2 cells (P<0.05). Conclusion Our study identified B. subtilis as the key bacterial type associated with patients affected by drug-resistant epilepsy and revealed that it also ameliorated resistance to ASMs by downregulating the transporter ABCB1.
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Increasing evidence indicates that abnormalities in the composition of gut microbiota might play a role in stress-related disorders. In the learned helplessness (LH) paradigm, ~60–70% rats are susceptible to LH in the face of inescapable electric stress. The role of gut microbiota in susceptibility in the LH paradigm is unknown. In this study, male rats were exposed to inescapable electric stress under the LH paradigm. The compositions of gut microbiota and short-chain fatty acids were assessed in fecal samples from control rats, non-LH (resilient) rats, and LH (susceptible) rats. Members of the order Lactobacillales were present at significantly higher levels in the susceptible rats than in control and resilient rats. At the family level, the number of Lactobacillaceae in the susceptible rats was significantly higher than in control and resilient rats. At the genus level, the numbers of Lactobacillus, Clostridium cluster III, and Anaerofustis in susceptible rats were significantly higher than in control and resilient rats. Levels of acetic acid and propionic acid in the feces of susceptible rats were lower than in those of control and resilient rats; however, the levels of lactic acid in the susceptible rats were higher than those of control and resilient rats. There was a positive correlation between lactic acid and Lactobacillus levels among these three groups. These findings suggest that abnormal composition of the gut microbiota, including organisms such as Lactobacillus, contributes to susceptibility versus resilience to LH in rats subjected to inescapable electric foot shock. Therefore, it appears likely that brain–gut axis plays a role in stress susceptibility in the LH paradigm.
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Accumulating evidence suggests that gut microbiota plays a role in the pathogenesis of schizophrenia via the microbiota-gut-brain axis. This study sought to investigate whether transplantation of fecal microbiota from drug-free patients with schizophrenia into specific pathogen-free mice could cause schizophrenia-like behavioral abnormalities. The results revealed that transplantation of fecal microbiota from schizophrenic patients into antibiotic-treated mice caused behavioral abnormalities such as psychomotor hyperactivity, impaired learning and memory in the recipient animals. These mice also showed elevation of the kynurenine-kynurenic acid pathway of tryptophan degradation in both periphery and brain, as well as increased basal extracellular dopamine in prefrontal cortex and 5-hydroxytryptamine in hippocampus, compared with their counterparts receiving feces from healthy controls. Furthermore, colonic luminal filtrates from the mice transplanted with patients' fecal microbiota increased both kynurenic acid synthesis and kynurenine aminotransferase II activity in cultured hepatocytes and forebrain cortical slices. Sixty species of donor-derived bacteria showed significant difference between the mice colonized with the patients' and the controls' fecal microbiota, highlighting 78 differentially enriched functional modules including tryptophan biosynthesis function. In conclusion, our study suggests that the abnormalities in the composition of gut microbiota contribute to the pathogenesis of schizophrenia partially through the manipulation of tryptophan-kynurenine metabolism.
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Stress disturbs the balance of the gut microbiota and stimulates inflammation-to-brain mechanisms. Moreover, stress leads to anxiety and depressive disorders. Bifidobacterium adolescentis displays distinct anti-inflammatory effects. However, no report has focused on the anxiolytic and antidepressant effects of B. adolescentis related to the gut microbiome and the inflammation on chronic restraint stress (CRS) in mice. We found that pretreatment with B. adolescentis increased the time spent in the center of the open field apparatus, increased the percentage of entries into the open arms of the elevated plus-maze (EPM) and the percentage of time spent in the open arms of the EPM, and decreased the immobility duration in the tail suspension test as well as the forced swimming test (FST). Moreover, B. adolescentis increased the sequence proportion of Lactobacillus and reduced the sequence proportion of Bacteroides in feces. Furthermore, B. adolescentis markedly reduced the protein expression of interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), p-nuclear factor-kappa B (NF-κB) p65 and Iba1 and elevated brain derived neurotrophic factor (BDNF) expression in the hippocampus. We conclude that the anxiolytic and antidepressant effects of B. adolescentis are related to reducing inflammatory cytokines and rebalancing the gut microbiota.
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Male middle age is a transitional period where many physiological and psychological changes occur leading to cognitive and behavioural alterations, and a deterioration of brain function. However, the mechanisms underpinning such changes are unclear. The gut microbiome has been implicated as a key mediator in the communication between the gut and the brain, and in the regulation of brain homeostasis, including brain immune cell function. Thus, we tested whether targeting the gut microbiome by prebiotic supplementation may alter microglia activation and brain function in ageing. Male young adult (8 weeks) and middle-aged (10 months) C57BL/6 mice received diet enriched with a prebiotic (10% oligofructose-enriched inulin) or control chow for 14 weeks. Prebiotic supplementation differentially altered the gut microbiota profile in young and middle-aged mice with changes correlating with faecal metabolites. Functionally, this translated into a reversal of stress-induced immune priming in middle-aged mice. In addition, a reduction in ageing-induced infiltration of Ly-6Chi monocytes into the brain coupled with a reversal in ageing-related increases in a subset of activated microglia (Ly-6C+) was observed. Taken together, these data highlight a potential pathway by which targeting the gut microbiome with prebiotics can modulate the peripheral immune response and alter neuroinflammation in middle age. Our data highlight a novel strategy for the amelioration of age-related neuroinflammatory pathologies and brain function.
Nutritional interventions targeting the microbiota‐gut‐brain axis are proposed to modulate stress‐induced dysfunction of physiological processes and brain development. Maternal separation (MS) in rats induces long‐term alterations to behavior, pain responses, gut microbiome and brain neurochemistry. In this study, the effects of dietary interventions (milk fat globule membrane (MFGM) and a polydextrose/galactooligosaccharide prebiotic blend (PDX/GOS)) were evaluated. Diets were provided from postnatal day 21 to both non‐separated (NS) and MS offspring. Spatial memory, visceral sensitivity and stress reactivity were assessed in adulthood. Gene transcripts associated with cognition and stress and the caecal microbiota composition were analysed. MS‐induced visceral hypersensitivity was ameliorated by MFGM and to greater extent with the combination of MFGM and prebiotic blend. Furthermore, spatial learning and memory were improved by prebiotics and MFGM alone and with the combination. The prebiotic blend and the combination of the prebiotics and MFGM appeared to facilitate return to baseline with regard to HPA axis response to the restraint stress which can be beneficial in times where coping mechanisms to stressful events are required. Interestingly, the combination of MFGM and prebiotic reduced the long‐term impact of MS on a marker of myelination in the prefrontal cortex. MS affected the microbiota at family level only while MFGM, the prebiotic blend and the combination influenced abundance at family and genus level as well as influencing beta diversity levels. In conclusion, intervention with MFGM and prebiotic blend significantly impacted the composition of the microbiota as well as ameliorating some of the long‐term effects of early‐life stress. This article is protected by copyright. All rights reserved.
Objectives: Synbiotics, the combination of probiotics and prebiotics, may optimize the production of polyphenolic metabolites, and act as therapeutic agents for inflammation-induced depression. Recent evidence suggests that dysregulated immune activity increases susceptibility to depression and that bioactive polyphenolic metabolites can effectively reduce that inflammation. The problem remains that bioactive metabolite production is dependent on the gut microbiota, leading to significant interpersonal variation in the metabolites' therapeutic efficacy. The hypothesis of the study is that the synbiotic will standardize production and bioavailability of bioactive metabolites capable of suppressing innate immune biological signatures of depression. Methods: To standardize the production of bioactive metabolites, the synbiotic will be designed in an innovative in vitro model of the human gastrointestinal tract using a multivariate regression algorithm to predict which probiotic formulation produces the most effective bioactive metabolites. Following in vivo bioavailability and toxicity testing, the synbiotic's therapeutic efficacy was tested in a chronic unpredictable stress (CUS) mouse model of depression by measuring specific behaviors and changes to the gut microbiota populations. These changes were correlated to biological markers of depression modulated by the synbiotic-derived metabolites including neurobiological markers of depression and variations in innate immune markers, including interleukin-1β (IL-1β). Results: In this study, we show that a synbiotic combining a dietary polyphenolic preparation with L. plantarum and B. longum can potentiate the reduction in anxiety and depression in male mice subjected to a 28 day CUS protocol, as compared to polyphenolic treatment alone. Interestingly, we found that the synbiotic may mediate microglia inflammasome activation.This finding was reflected by inhibition of NLRP3-mediated generation of IL-1β in microglia. Conclusions: Collectively, these results support the potential role of a synbiotic in the potentiation of attenuation of psychological impairment in a model of depression through mechanisms that involved innate immune NLRP3 inflammation mediation in microglia. Funding sources: This project was funding a P50 CARBON Center grant from the NCCIH/ODS (Pasinetti, PD/PI).
Background: Increased peripheral inflammation has been consistently reported in patients with major depressive disorder (MDD). However, only few studies have explored markers of central (brain) inflammation in patients with MDD. The aim of this study is to systematically review in vivo and post-mortem markers of central inflammation, including studies examining cerebrospinal fluid (CSF), positron emission tomography, and post-mortem brain tissues in subjects suffering with MDD compared with controls. Methods: PubMed and Medline databases were searched up to December 2018. We included studies measuring cerebrospinal fluid (CSF) cytokines and chemokines, positron emission tomography (PET) studies; and post-mortem studies measuring cytokines, chemokines and cell-specific markers of microglia and astrocytes, all in MDD. A meta-analysis was performed only for CSF and PET studies, as studies on post-mortem markers of inflammation had different cell-specific markers and analysed different brain regions. Results: A total of 69 studies met the inclusion criteria. CSF levels of IL-6 and TNF-α were higher in patients with MDD compared with controls (standardised mean difference SMD 0.37, 95%CI: 0.17-0.57 and SMD 0.58, 95%CI 0.26-0.90, respectively). CSF levels of IL-6 were increased in suicide attempters regardless of their psychiatric diagnosis. Translocator protein, a PET marker of central inflammation, was elevated in the anterior cingulate cortex and temporal cortex of patients with MDD compared with controls (SMD 0.78, 95%CI: 0.41-1.16 and SMD 0.52, 95%CI: 0.19-0.85 respectively). Abnormalities in CSF and PET inflammatory markers were not correlated with those in peripheral blood. In post-mortem studies, two studies found increased markers of microglia in MDD brains, while four studies found no MDD related changes. Of the studies investigating expression of cell-specific marker for astrocytes, thirteen studies reported a decreased expression of astrocytes specific markers, two studies reported increased expression of astrocytes specific markers, and eleven studies did not detect any difference. Four out of six studies reported decreased markers of oligodendrocytes in the prefrontal cortex. Post-mortem brain levels of tumor necrosis alpha (TNF-α) were also found increased in MDD. Conclusions: Our review suggests the presence of an increase in IL-6 and TNF-alpha levels in CSF and brain parenchyma, in the context of a possible increased microglia activity and reduction of astrocytes and oligodendrocytes markers in MDD. The reduced number of astrocytes may lead to compromised integrity of blood brain barrier with increased monocyte recruitment and infiltration, which is partly supported by post-mortem studies and by PET studies showing an increased TSPO expression in MDD.
A relationship between neuroinflammation and the development of psychiatric disorder have been revealed by many studies in the past decade. Although studies have shown that stressors can induce long-term changes that may be related to behavioral responses, these alterations have been poorly studied soon after a stressor, such as maternal deprivation (MD). Thus, this study was designed to investigate the acute effect of experimental induction of MD on inflammatory and microglial activation markers in the brain of infant rats. Early MD was induced from postnatal day (PND) 1–10. On PND 10 the prefrontal cortex (PFC) and hippocampus from MD and control groups were removed to investigate microglial activation and neuroinflammatory markers. In the PFC the expressions of cluster of differentiation molecule 11B (CD11B), toll-like receptor (TLR)-2, and TLR-4 were increased in rats subjected to MD. The arginase expression was elevated in the PFC and hippocampus of maternally deprived rats. The cytokines interleukin-5 (IL-5), −6, −7, −10, tumor necrosis factor (TNF-α), and interferon gamma (INF-γ) were increased in the PFC of MD rats group. In the PFC the macrophage inflammatory proteins (MIP)-1α levels were reduced in MD rats group. In the hippocampus only the levels of TNF-α and INF-γ were elevated in infant rats subjected to MD. In conclusion, our results support the hypothesis that neuroinflammation and microglial activation, mainly in the PFC, could be involved with changes in the brain resident cells following MD, and these alterations could be associated to the development of psychiatric conditions late in life.
Background: Stress during early childhood, for example as a result of maltreatment, can predict inflammation in adulthood. The association of depression with inflammation and current and long-term stress resulting from childhood maltreatment and threatening experiences in the past year has not yet been studied. Therefore, we assessed these variables in a group of patients with major depressive disorder (MDD) and measured levels of the pro-inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10. High levels of IL-6 are associated with depression and of IL-10 with stress. Methods: We included 44 patients who fulfilled DSM-IV diagnostic criteria for MDD and 44 age- and gender-matched healthy controls. We used Cohen's Perceived Stress Scale (PSS), the list of life-threatening experiences questionnaire (LTE-Q) and the childhood trauma questionnaire (CTQ) to assess the level of stress and analyzed IL-6 and IL-10 cytokines in venous blood plasma. Results: The patient group showed significantly higher scores on the maltreatment scale LTE-Q (2.7 vs. 1.1; P = 0.001, and the stress scales CTQ (emotional abuse; P = 0.048 and physical neglect; P = 0.002) and PSS (35.2 vs 15.5; P < 0.001) as well as significantly higher levels of IL-6 (1.5pg/ml vs. 0.9pg/ml; P = 0.012). They also had significantly higher levels of IL-10 (1.1pg/ml vs. 0.7pg/ml; P < 0.001). Higher actual stress levels were associated with childhood maltreatment and higher IL-6 (tau = 0.004) and IL-10 (tau = 0.027) levels. Limitations: The results need to be replicated in a larger sample, and the study did not evaluate causal relationships. Although the assessment of childhood trauma was retrospective, the CTQ is a well-established assessment instrument. Conclusions: The patients with MDD in this study showed an immune activation in response to stress. This study highlights the association of childhood trauma and current and long-term stress with an increased immune activation in MDD.
Stress-related neuropsychiatric disorders, such as major depressive disorder and posttraumatic stress disorder, exact enormous socioeconomic and individual consequences. Resilience, the process of adaptation in the face of adversity, is an important concept that is enabling the field to understand individual differences in stress responses, with the hope of harnessing this information for the development of novel therapeutics that mimic the body's natural resilience mechanisms. This review provides an update on the current state of research of the neurobiological mechanisms of stress resilience. We focus on physiological and transcriptional adaptations of specific brain circuits, the role of cellular and humoral factors of the immune system, the gut microbiota, and changes at the interface between the brain and the periphery, the blood-brain barrier. We propose viewing resilience as a process that requires the integration of multiple central and peripheral systems and that elucidating the underlying neurobiological mechanisms will ultimately lead to novel therapeutic options.