10974547, 2019, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jnr.

24476 by Spanish Cochrane National Provision (Ministerio de Sanidad), Wiley Online Library on [20/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Received: 4 December 2018 | Revised: 26 April 2019 | Accepted: 15 May 2019

DOI: 10.1002/jnr.24476

REVIEW

The role of inflammation and the gut microbiome

in depression and anxiety

Jason M. Peirce1,2 | Karina Alviña1

1
Department of Biological Sciences, Texas
Tech University, Lubbock, Texas
2
Honors College, Texas Tech University,
Lubbock, Texas
Correspondence
Karina Alviña, Department of Biological
Sciences, Texas Tech University, 2901 Main
St. Room #05, Biology Building, Lubbock,
TX 79409.
Email: karina.alvina@ttu.edu
Abstract
The study of the gut microbiome has increasingly revealed an important role in mod‐
ulating brain function and mental health. In this review, we underscore specific path‐
ways and mechanisms by which the gut microbiome can promote the development of
mental disorders such as depression and anxiety. First, we review the involvement of
the stress response and immune system activation in the development of depression
and anxiety. Then, we examine germ‐free murine models used to uncover the role
of the gut microbiome in developing and modulating pertinent activity in the brain
and the immune system. We also document multiple pathways by which stress‐in‐
duced inflammation harms brain function and ultimately affects mental health, and
review how probiotic and prebiotic treatments have shown to be beneficial. Lastly,
we provide an overview of gut microbiome‐derived compounds (short‐chain fatty
acids, tryptophan catabolites, microbial pattern recognition) and related mechanisms
(vagal nerve activity and fecal microbiota transplants) involved in mediating the influ‐
ence of the gut microbiome to mental health. Overall, a picture of the gut microbiome
playing a facilitating role between stress response, inflammation, and depression, and
anxiety is emerging. Future research is needed to firmly establish the microbiome's
causal role, to further elucidate the mechanisms by which gut microbes influence
brain function and mental health, and to possibly develop treatments that improve
mental health through microbiotic targets.

KEYWORDS
anxiety, depression, gut microbiome, inflammation, stress

1 | I NTRO D U C TI O N a variety of techniques, such as 16S ribosomal RNA gene sequence

1.1 | The human gut microbiome
The gut microbiome is the collection of microorganisms, mainly bac‐
teria, that reside within the gastrointestinal (GI) tract in the human
host (Backhed, Ley, Sonnenburg, Peterson, & Gordon, 2005). These
microbes are estimated to outnumber human cells (Sender, Fuchs,
& Milo, 2016) and have orders of magnitude more genes than their
human host (Qin et al., 2010). The implications of the gut micro‐
biome for human health are so vast that the Human Microbiome
Project (HMP) has begun to analyze the human microbiome by using
and taxonomic profiling, metagenomic sequencing of whole commu‐
nity DNA, and alignment of the assembled sequences to the refer‐
ence microbial genomes (Proctor, 2016). One of the main goals of the
HMP is to uncover a human microbiome reference genome that can
be used to characterize dysbiosis and could allow the association of
it with a variety of conditions, both normal and pathological (Proctor,
2016). This is no small task as the composition of the microbiome is
affected by several factors including birth mode (i.e., natural vs. ce‐
sarean), infant feeding method, social and outdoor exposure, and an‐
tibiotic use, which may, in turn, affect risk of allergies and infections
(Bloomfield et al., 2016). The composition of the gut microbiome also

J Neuro Res. 2019;97:1223–1241. wileyonlinelibrary.com/journal/jnr

© 2019 Wiley Periodicals, Inc. | 1223

1224 | PEIRCE and ALVIÑA
Significance
A myriad of recent studies has revealed that the gut micro‐
biome, or the community of microorganisms (mostly bac‐
teria) that reside in the human gut, seems to be intimately
interwoven with mental health. More specifically, both the
function of the Central Nervous System and its stress‐trig‐
gered dysfunction, have emerged as targets of gut microbi‐
ome imbalance. Here, we review seminal insights and recent
advances outlining this gut–brain relationship and elucidat‐
ing mechanisms underlying this link. We also delineate ap‐
proaches for improving mental health by treating the gut
microbiome.
correlates with host genetic variation in immunity‐related pathways
(Blekhman et al., 2015). For instance, the host cytokine production
is linked to the metabolic activity of gut microbes (Schirmer et al.,
2016), which further suggests an intimate relationship between the
gut microbiome and the immune system.
The gut microbiome appears to significantly interact with the
nervous system through the gut–brain axis, a communication channel
between the central and enteric nervous system (Carabotti, Scirocco,
Maselli, & Severi, 2015). Gut microbes thereby have the potential to
influence brain activity and ultimately, mental health (Rogers et al.,
2016). Since recognizing that gut microbes play an important role
in human health, efforts have been made to improve the microbi‐
ome composition using probiotics and prebiotics (Schrezenmeir & de
Vrese, 2001). Probiotics are consumed microorganisms intended to
alter the host gut microbiome and provide health benefits, whereas
prebiotics are consumed dietary fibers meant to improve health by
feeding and promoting a balanced intestinal microbial ecosystem (de
Vrese & Schrezenmeir, 2008).
1.2 | Mental health trends: Focus on
depression and anxiety
Mental health is a growing concern in the United States and world‐
wide as rates of common mental disorders such as depression and
anxiety have increased over the past several decades (Friedrich,
2017; Jorm, Patten, Brugha, & Mojtabai, 2017). The prevalence of
depression in the United States increased significantly between
2005 and 2015, most markedly among youth (Carrellas, Biederman,
& Uchida, 2017; Weinberger et al., 2018). Moreover, the increase
in depressive symptoms have contributed to a surge in the number
of adolescent deaths by suicide between 2010 and 2015 (Twenge,
Cooper, Joiner, Duffy, & Binau, 2019). This increase in suicide rates
is common to adults as well (Curtin, Warner, & Hedegaard, 2016;
Hedegaard, Curtin, & Warner, 2018), particularly those living in rural
areas with greater social isolation and limited access to proper men‐
tal health care (Kegler, Stone, & Holland, 2017). Furthermore, the
projection is similarly morose for young adults with elevated anxiety.
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Between 2010 and 2015, college students throughout the United
States have reported increased prevalence of depression, general‐
ized anxiety, and social anxiety (Xiao et al., 2017). These increased
rates of mental health issues have been accompanied by lackluster
treatments. Across four developed countries including the United
States, rates of mood and anxiety disorders and symptoms have in‐
creased between 1990 and 2015 despite increased treatment and
medication (Jorm et al., 2017). Across 21 countries surveyed by the
World Health Organization, roughly one tenth of responders had
an anxiety disorder, yet approximately only one fourth of those af‐
flicted received treatment, and most of the treatments were deemed
inadequate (Alonso et al., 2018). The rising trend of mental afflic‐
tions across the world indicates a dire need for novel treatment ideas
that may include microbiome‐mediated means.
1.3 | Gut microbiome influence on
depression and anxiety
With the advent of improved molecular and metagenomic tools,
human and animal studies have provided increasing evidence sug‐
gesting a strong link between the gut microbiome composition and
the development of mental disorders such as depression and anxiety
(Bastiaanssen, Cowan, Claesson, Dinan, & Cryan, 2019; Jiang et al.,
2018; Rogers et al., 2016; Tognini, 2017). First, it is known that a variety
of bacterial phyla cohabitate in the human gut, with over 1,000 distinct
bacterial species (Human Microbiome Jumpstart Reference Strains
Consortium et al., 2010). More than 70% of the microbiome comes
from the two most prominent phyla Firmicutes and Bacteroides, while
Proteobacteria, Actinobacteria, Fusobacteria, and Verrucomicrobia
are present in reduced numbers (Eckburg et al., 2005). However, we
are only starting to fully understand the implications of this microbial
diversity for human health and disease. Regarding mental health spe‐
cifically, a few studies are beginning to show interesting trends. For in‐
stance, patients diagnosed with major depression disorder (MDD) have
a different fecal microbiome composition compared to healthy con‐
trols: MDD patients showed increased Bacteroidetes, Protobacteria,
and Actinobacteria, and less Firmicutes. Further, among genus these
patients showed increased Enterobacteriaceae and Allistipes, and less
Faecalibacterium, the last of which inversely correlated with the se‐
verity of the depression (Jiang et al., 2015). Interestingly, in this study,
no differences were observed between the gut microbiome of female
or male MDD patients although sex differences have been reported
in healthy individuals (more on sex‐dependent differences will be dis‐
cussed on Section 33.2).
Similarly, fecal microbiota of patients suffering from general‐
ized anxiety disorder (GAD) showed a much lower prevalence of
five genera: Faecalibacterium, Eubacterium rectale, Lachnospira,
Butyricicoccus, and Sutterella (Jiang et al., 2018). These genera
could be relevant to mental health due to their documented pro‐
duction of short‐chain fatty acid (SCFA) compounds (van de Wouw
et al., 2018). Reduced SCFA production in GAD patients could re‐
sult in intestinal barrier dysfunction (Morris et al., 2017) that could
compromise proper immune responses and ultimately contribute to

PEIRCE and ALVIÑA
brain dysfunction. We will review in detail mechanisms that compro‐
mise immune system in the gut.
1.4 | Resident gut microbes support the brain and
immune system
Experimentally, a common approach for uncovering the role of the gut
microbiome has been to raise murines in a germ‐free (GF) environment,
and then compare their characteristics with conventionally raised
counterparts. The most notable differences are seen in the brain and
the immune system, both particularly relevant in addressing anxiety
and depression‐like behaviors. Moreover, both depression and anxiety
disorders are heavily influenced by stress pathways such as the hypo‐
thalamus–pituitary–adrenal (HPA) axis, which can be strongly modified
by the gut microbiome composition (Luo et al., 2018; Sudo et al., 2004).
Studies of GF murines revealed important differences in the de‐
velopment and function of the brain when compared with conven‐
tionally raised animals. For instance, a seminal study reported that GF
male mice have an overreactive HPA axis leading to increased concen‐
trations of corticosterone and adrenocorticotropic hormone (ACTH)
following a stressful stimulus (Sudo et al., 2004). These findings have
been replicated several times (Clarke et al., 2013; Luo et al., 2018; K.
A. Neufeld, Kang, Bienenstock, & Foster, 2011; K. M. Neufeld, Kang,
Bienenstock, & Foster, 2011); and have been expanded to GF male
rats (Crumeyrolle‐Arias et al., 2014). Furthermore, an in‐depth epigen‐
etic study reported that gene expression in the brain of GF male mice
was significantly different from controls, the most notable differences
were observed in the hippocampus, cortex, striatum, and cerebellum
(Heijtz et al., 2011). These alterations in the hippocampus and cortex
are likely to contribute to differences in HPA axis activity (Bellavance
& Rivest, 2014). Likewise, different levels of neurotransmitters in the
brain of GF male rats have been reported: elevated norepinephrine,
dopamine, and serotonin turnover in the striatum, whereas decreased
dopaminergic turnover was reported in the frontal cortex, hippocam‐
pus, and striatum of GF rats (Crumeyrolle‐Arias et al., 2014). Other
findings in GF mice include decreased expression of brain‐derived
neurotropic factor (Arentsen, Raith, Qian, Forssberg, & Heijtz, 2015;
Clarke et al., 2013; Heijtz et al., 2011; Sudo et al., 2004) and nerve
growth factor‐inducible protein A in several brain regions along with
increased expression of the plasticity‐related proteins synaptophysin
and PSD‐95 in the striatum (Heijtz et al., 2011). Overall, there are
significant changes in the brain of murines who develop without a
normal gut microbiome, particularly in regions involved in the stress
response. Increasing evidence suggests that these changes in brain
development can be detrimental for mental health. It is important to
note that only male rodents were used for these studies.
1.5 | Germ‐free murines reveal an important
role for resident microbes in host immune system
development
Experiments on GF murines have also uncovered important roles
for the gut microbiome in shaping the host immune system and its
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| 1225
responses to infection or stress. For example, GF mice have an under‐
developed mucosal immune system compared with conventionally
raised mice (Macpherson & Harris, 2004; Mazmanian, Liu, Tzianabos,
& Kasper, 2005). Further, GF murines exhibit a far less effective im‐
mune response to carefully administered infection (Inagaki, Suzuki,
Nomoto, & Yoshikai, 1996; Nardi et al., 1991; Strauch et al., 2005)
and endotoxin challenge (Clarke et al., 2013). A significant defect is
that GF mice have fewer regulatory T cells (Tregs) with reduced anti‐
inflammatory capacities (Ostman, Rask, Wold, Hultkrantz, & Telemo,
2006; Strauch et al., 2005). An especially notable finding related to
neuroinflammation is that GF mice display global defects in their
microglia, which exhibit an immature phenotype and an impaired
innate immune response (Erny et al., 2015). A later study demon‐
strated that atypical gene expression in the microglia of GF mice in‐
volving endotoxemia recognition and inflammation can be observed
even prior to birth (Thion, Ginhoux, Ginhoux, & Garel, 2018). These
studies demonstrate an often‐overlooked role that resident gut mi‐
crobes can play in promoting the development of the host immune
system. Taken together, these findings and the behavioral abnor‐
malities reported in GF murines, a clear picture of the impact of the
gut microbiome in shaping the immune and nervous system starts
to emerge.
2 | S TR E S S A N D D I S O R D E R E D
I N FL A M M ATI O N C A N R E S U LT I N
D E PR E S S I O N A N D A N X I E T Y
Many human and animal studies have shown that physiological path‐
ways involving inflammatory and stress responses likely play an impor‐
tant role in the etiology of depression and anxiety (Bekhbat & Neigh,
2018; Benatti et al., 2016; Dantzer, O'Connor, Freund, Johnson, &
Kelley, 2008; Dantzer, O'Connor, Lawson, & Kelley, 2011; Derry, Padin,
Kuo, Hughes, & Kiecolt‐Glaser, 2015). Here, we discuss key findings.
2.1 | Stress‐induced inflammation is involved
in depression
The role of inflammation in depression has been documented in sev‐
eral studies (Kim, Na, Myint, & Leonard, 2016; Leonard, 2018; Miller
& Raison, 2016). A systematic review of genetic contributions to
depression revealed several gene variants involved in both immune
activation and depression (Barnes, Mondelli, & Pariante, 2017).
According to the “pathogen host hypothesis,” these depression
risk alleles promote pathogen–host defense interactions that were
adaptive in an ancestral infection‐ridden environment; public health
measures that increased hygiene and reduced infections, meanwhile,
have rendered this pathogen host defense mainly maladaptive as it
now contributes to depressive symptoms such as withdrawal behav‐
ior (Raison & Miller, 2013). Using murine models, abnormal behav‐
ior has been associated with pro‐inflammatory cytokines also seen
in depressive patients (Dantzer et al., 2008). Studies have reported
increased pro‐inflammatory cytokine levels in some depressive

1226 | PEIRCE and ALVIÑA
patients compared to healthy controls (Duivis, Vogelzangs, Kupper,
Jonge, & Penninx, 2013; Lamers et al., 2013). Longitudinal studies,
meanwhile, reported that high levels of pro‐inflammatory cytokines
predict future risk for depression (Gimeno et al., 2009; van den
Biggelaar et al., 2007). Further, experiments that initiate an immune
response induce feelings of depression (Eisenberger et al., 2010;
Harrison et al., 2009; Reichenberg et al., 2001; Strike, Wardle, &
Steptoe, 2004; Wright, Strike, Brydon, & Steptoe, 2005), while anti‐
inflammatory drugs further enhance recovery in patients with de‐
pression (Mendlewicz et al., 2006; Muller et al., 2006). Thus, the link
between inflammatory state and depressive mood is supported by
several lines of evidence and suggests that influencing inflammation
can indirectly affect mental health.
The stress response has been shown to be altered in some cases
of depression. In fact, a link between depression and hyperactive
HPA axis has been reported in several conditions (Juruena, Cleare,
& Pariante, 2004; Pariante, 2003; Varghese & Brown, 2001). For in‐
stance, patients with depression have higher amounts of corticotro‐
pin‐releasing hormone (CRH) in their cerebrospinal fluid and release
less ACTH in response to a CRH signal (Varghese & Brown, 2001).
A murine model of depression–anxiety has similar overproduction of
CRH indicating a hyperactive HPA axis (Park et al., 2013). Furthermore,
several studies have suggested that inflammation mediates stress‐in‐
duced depression (Aschbacher et al., 2012; Koo, Russo, Ferguson,
Nestler, & Duman, 2010; Pace et al., 2006; Zhang et al., 2015).
2.2 | Stress‐induced inflammation is involved
in anxiety
In addition to depression, inflammation has been implicated in anxi‐
ety. Studies of clinically diagnosed anxious patients have reported
increased levels of pro‐inflammatory cytokines compared to healthy
individuals (Duivis et al., 2013; O'Donovan et al., 2010; Pitsavos
et al., 2006). Moreover, activating an immune response has been
shown to increase anxiety behaviors in rats (Sominsky et al., 2013)
and human subjects (Reichenberg et al., 2001). At a mechanistic
level, stress‐induced interleukin (IL)‐6 activity has been shown to
alter gene expression in monocytes and cause anxiety‐like behav‐
ior in mice (Niraula, Witcher, Sheridan, & Godbout, 2019). Although
more research is needed, observational and experimental studies
support the overall notion that inflammation is involved in anxiety.
The link between stress and anxiety in humans is perhaps the
least concrete of the psychophysiological connections made so far.
A comprehensive review of this topic finds that the link between
anxiety and a hyperactive HPA axis is inconclusive, in part because
co‐morbid depression may confound analyses and because HPA axis
alterations may be a transient state (Faravelli et al., 2012). Several mu‐
rine models of anxiety display increased HPA axis activity (Landgraf,
Wigger, Holsboer, & Neumann, 1999; Park et al., 2013), and exper‐
iments perturbing the stress response in mice result in anxiety‐like
behavior (Barbosa Neto et al., 2012; Flandreau, Ressler, Owens, &
Nemeroff, 2012; Niraula et al., 2019). Stress seems to be relevant in
murine models, but its role in human anxiety is still undefined.
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3 | S E X D I FFE R E N C E S I N R ATE S O F
D E PR E S S I O N A N D A N X I E T Y
Females show higher rates of anxiety and depression compared
to males (Albert, Pruessner, & Newhouse, 2015; Songtachalert,
Roomruangwong, Carvalho, Bourin, & Maes, 2018). This can in part
be explained by sex hormones and their differential effects on gut
microbiome as well as differences in immune cells (including micro‐
glia), discrepant stress, and immune responses between males and
females, and sociological factors.
3.1 | Sex hormones differentially affect
microglia, the gut microbiome, and immune status
The higher rates of depression and anxiety observed in females
may be in part explained by sex hormones, as androgens seem to
have anxiolytic properties whereas estrogens have been found to
enhance HPA activity (Maeng & Milad, 2015; Turner‐Cobb, Osborn,
Silva, Keogh, & Jessop, 2010). Furthermore, rates of depression in fe‐
males correlate with hormonal changes, particularly with low levels
of estrogen that occur throughout the life cycle (Albert et al., 2015).
These low estrogen periods may involve heightened neuroinflam‐
mation as estrogen seems to have anti‐inflammatory effects on mi‐
croglia (Hanamsagar & Bilbo, 2016). The microglial cells themselves
display sex‐dependent differences, as they express more inflamma‐
tion‐related genes in adult female mice compared to males (Thion,
Low, et al., 2018). Furthermore, female mice have higher amounts of
mature microglia compared to age‐matched males (Hanamsagar et
al., 2017). However, when immuno‐challenged, only microglial cells
in males showed accelerated maturation (Hanamsagar et al., 2017).
These changes may be related to inflammation‐associated conditions
such as depression and anxiety that tend to emerge early during de‐
velopment and are more prominent in females compared to males
(Hanamsagar & Bilbo, 2016; Hanamsagar et al., 2017). Similarly, in a
model of microembolic stroke in rats, microglial activation was ob‐
served in both females and males, but only males displayed larger
branches in activated microglial cells concurrent with anxiety‐like
behaviors (Nemeth, Reddy, Bekhbat, Bailey, & Neigh, 2014).
Sex hormones also mediate sex differences in gut microbiome
composition which may exert adverse inflammatory and psychologi‐
cal effects (Yurkovetskiy et al., 2013). For instance, adult women have
been shown to have fewer Bacteroidetes in their gut microbiome
compared to age‐matched men, while Firmicutes and Actinobacteria
were not statistically different between sexes (Dominianni et al.,
2015). This study also showed a strong effect of body mass index
(BMI) on gut microbiome composition, especially in women. Namely,
higher BMI was correlated with even fewer Bacteroidetes com‐
pared to a normal BMI (Dominianni et al., 2015). Lower levels of
Bacteroidetes have also been observed in fecal microbiota from
patients diagnosed with clinical depression (study combining age‐
matched females and males) (Naseribafrouei et al., 2014), and in
obese humans and murine models (Cani et al., 2009; Graessler et al.,
2013). Furthermore, the documented sexual dimorphism observed

PEIRCE and ALVIÑA
in a mouse model of Type I diabetes was attributed to differences
in gut microbiome composition between males and females, dif‐
ferences that could be reversed in a GF environment or castrating
males (Yurkovetskiy et al., 2013).
In sum, sex hormones differentially affect males and females by
altering both their gut microbiome composition and their immune
status, particularly microglial cells.
3.2 | Sex differences in stress and immune
responses: More research is needed
The existing evidence concerning sex differences in stress and im‐
mune responses is mixed. Some studies indicate a greater sensitivity
of women to stressful and inflammatory conditions, for instance sys‐
temic inflammation impairs mood and affective behavior in women
more than men (Moieni et al., 2015); also women seem to exhibit
more robust stress responses and more potent immune responses
compared to men (Bekhbat & Neigh, 2018), and women show greater
activation of the enzyme indole 2,3‐dioxygenase (IDO), which me‐
tabolizes tryptophan (Trp) through the kynurenine (Kyn) pathway,
and increased levels of anxiogenic Trp catabolites (Trycats) follow‐
ing immune activation (Songtachalert et al., 2018). On the contrary,
other studies have shown that men display greater sensitivity to
stressful and inflammatory conditions: women resolve local inflam‐
matory responses more rapidly than men (Rathod et al., 2017), social
isolation causes more mortality in men mediated by greater immune
activation (Moieni & Eisenberger, 2018), and adult men seem to
respond to typical psychological stressors with a greater increase
F I G U R E 1 Bidirectional communication between the gut microbiome and the CNS is affected by stress. Stress (a) activates the HPA axis
and results in increased intestinal permeability (b). Intestinal permeability lets bacterial endotoxins leak out of the gut lumen (c) and enter
blood circulation. (d) Endotoxins initiate peripheral inflammation. The immune response then spreads to the CNS (e) and neuroinflammation
compromises mental health. Stress primes microglial cells (f) as part of the neuroinflammatory response. See main text for details
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| 1227
in cortisol compared to age‐matched women (Kudielka, Buske‐
Kirschbaum, Hellhammer, & Kirschbaum, 2004). Meanwhile, a meta‐
analysis failed to observe any significant differences between men
and women in how acute psychological stress affects inflammatory
markers (Steptoe, Hamer, & Chida, 2007).
Women's higher rates of depression and anxiety may in part be
explained by situational as well as biological factors: women are
more prone to a variety of inflammation‐inducing factors such as
prior depression, somatic symptomatology, interpersonal stress‐
ors, childhood adversity, obesity, and physical inactivity that then
cause mood and behavioral changes (Derry et al., 2015). From a so‐
ciological point of view, traditional gender roles may play a part as
caregiving is associated with increased stress in women, and the dif‐
ference in stress levels between men and women has decreased as
more women have entered the workforce (Mayor, 2015). However,
women continue to have a greater risk of depression compared to
men in more liberal, economically developed countries, meaning tra‐
ditional gender roles may be only a small piece of the puzzle (Alonso
et al., 2018; Rai, Zitko, Jones, Lynch, & Araya, 2013).
4 | A PL AU S I B LE S TR E S S–
I N FL A M M ATI O N–D E PR E S S I O N/A N X I E T Y
D I S O R D E R PATH WAY
The mechanisms that connect psychological stress to systemic and
neural inflammation to mood disorders such as depression and anxi‐
ety are beginning to be uncovered (Figure 1). Psychological stress can

1228 | PEIRCE and ALVIÑA
increase intestinal permeability and allow bacterial liposaccharides
(known as endotoxins) to enter blood circulation when an immune
response is initiated (de Punder & Pruimboom, 2015). This peripheral
inflammation then can spread to the central nervous system (CNS) in
various ways and thus affect mental health by promoting neurotox‐
ins and hindering neurotransmitters (Miller & Raison, 2016).
4.1 | Stress induces endotoxemia by increasing
intestinal permeability
Psychological stress has been shown to reliably induce pro‐inflam‐
matory cytokine production in murine models (Bailey et al., 2011;
Zhang et al., 2015) and in human subjects (Baumeister, Akhtar,
Ciufolini, Pariante, & Mondelli, 2016; Maes et al., 1998; Wright et al.,
2005). These inflammation changes may be explained by stress sig‐
nals that modify the immune system and the intestinal barrier. Stress
hormones mobilize immune cells throughout the body in prepara‐
tion for pathogen defense and wound healing (Dhabhar, Malarkey,
Neri, & McEwen, 2012). As the stress response increases intestinal
epithelial permeability to increase water and sodium availability, en‐
dotoxins may seep into circulation and initiate an immune response
termed “endotoxemia” (de Punder & Pruimboom, 2015). Stress has
indeed been found to increase intestinal permeability in several ani‐
mal models including rats (Maslanik et al., 2012; Meddings & Swain,
2000), mice (Yu et al., 2013), and pigs (Overman, Rivier, & Moeser,
2012), and humans (Vanuytsel et al., 2014).
4.2 | Peripheral inflammation causes central
inflammation
The long‐standing notion that the brain is “immune privileged” has
been updated by discoveries revealing that the brain's immune
system exists and is heavily regulated (Galea, Bechmann, & Perry,
2007). Many murine studies show that peripheral administration
of endotoxins causes global expression of pro‐inflammatory cy‐
tokines in the brain (Gatti & Bartfai, 1993; Laye, Parnet, Goujon,
& Dantzer, 1994; Quan, Stern, Whiteside, & Herkenham, 1999).
Several reviews have outlined the variety of pathways by which
peripheral inflammation can spread to the brain and initiate neuro‐
inflammation (Baganz & Blakely, 2013; Dantzer et al., 2008; Miller
& Raison, 2016), namely: (a) peripheral cytokines and pathogen‐
associated molecular patterns send inflammatory signals to the
brain via afferent nerves, (b) cytokines pass through permeable
sections of the blood–brain barrier (BBB), and (c) activated im‐
mune cells migrate into the brain. When it comes to mental health,
this central neuroinflammation may be especially insidious since it
may last up to 40 times longer than the initial peripheral immune
response (Qin et al., 2007). The timing of stress is of importance
as well: the stress pathway can be activated to counter an immune
response by exerting an anti‐inflammatory effect; however, stress
prior to an immune response primes microglia reactivity and pro‐
motes a pro‐inflammatory neuroimmune environment (Bellavance
& Rivest, 2014). The stress response that activates the immune
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system in preparation of pathogen defense and wound healing
can apparently misfire by instigating endotoxemia and long‐lasting
neuroinflammation.
4.3 | Neuroinflammation affects brain activity and
mental health
Once inflammation has reached the brain, it can have serious delete‐
rious consequences for mental health. First, activated microglia con‐
tribute to neural toxicity by releasing reactive nitrogen and oxygen
species that damage brain epithelial cells and compromise the BBB
(Kacimi, Giffard, & Yenari, 2011). These microglia are the resident
immune cells of the CNS that participate in neuroinflammation and
whose development and activity have repeatably been shown to re‐
spond to changes in gut microbiome composition (Erny et al., 2015;
Thion & Garel, 2018). Second, pro‐inflammatory cytokines activate
the enzyme IDO increasing the metabolism of Trp through the Kyn
pathway (Dantzer et al., 2008; Schwarcz, Bruno, Muchowski, & Wu,
2012). Several studies exploring endotoxin‐induced depressive‐like
behavior in murines suggest that IDO activation plays a causal role
in neuroinflammatory mood disorders by promoting the release of
these neurotoxins (Dobos et al., 2012; O'Connor et al., 2009; Parrott
et al., 2016; Smith et al., 2013; Walker et al., 2013; Wichers et al.,
2005). Third, synthesis of the monoamine neurotransmitters sero‐
tonin, dopamine, and norepinephrine is hindered during neuroin‐
flammation since pro‐inflammatory cytokines damage and divert
the activity of tetrahydrobiopterin, an essential enzyme co‐factor of
monoamine synthesis (Miller & Raison, 2016). Overall, neuroinflam‐
mation promotes a toxic environment unsuitable for proper brain
activity and likely harmful for mental health.
5 | PRO B I OTI C S A N D PR E B I OTI C S H AV E
C A PAC IT Y TO I M PROV E M E NTA L H E A LTH
Probiotics are consumable microbes intended to promote a healthier
microbiome; prebiotics, on the other hand, are dietary fibers that nour‐
ish commensal gut microbes (Schrezenmeir & de Vrese, 2001). A great
number of studies on both murines and humans have shown promise
for probiotics and prebiotics to improve the stress response, the in‐
testinal barrier, the immune response, and ultimately mental health.
5.1 | Probiotics and prebiotics dampen the
stress response
The administration of probiotics and prebiotics has shown beneficial
effects on the physiological stress response. For instance, colonizing
GF male mice with the strain Bifidobacterium infantis normalizes their
previously overreactive HPA axis in response to restraint stress and
returns their stress hormone levels to levels observed in control mice
(Sudo et al., 2004). Similarly, Lactobacillus (L) spp. probiotics ameliorate
overreactive HPA axis in mice facing maternal separation stress (Gareau,
Jury, MacQueen, Sherman, & Perdue, 2007). Further, administering

PEIRCE and ALVIÑA
Lactobacillus rhamnosus significantly reduces corticosterone levels in
mice subjected to stress‐induced hypothermia or the elevated plus
maze test; this attenuated stress response was accompanied by region‐
dependent alterations in ɣ‐aminobutyric acid (GABA) receptor subunit
expression throughout the brain (Bravo et al., 2011). Daily adminis‐
tration of Lactobacillus helveticus NS8 to adult specific pathogen‐free
(SPF) rats reduced plasma corticosterone and ACTH levels in response
to chronic restraint stress compared to a selective serotonin reuptake
inhibitor (SSRI) (Liang et al., 2015). Pretreating mice with the probiotics
L. helveticus and B. infantis dampens the stress response during water
avoidance stress as well as maintains hippocampal neurogenesis and
hypothalamic plasticity (Ait‐Belgnaoui et al., 2014). Prebiotic treatment
consisting of fructo‐ (FOS) and galactooligosaccharides (GOS) lowers
corticosterone release in mice exposed to chronic psychosocial stress
in part by modulating hippocampal and hypothalamic gene expres‐
sion (Burokas et al., 2017). In healthy medical students, L. casei intake
significantly alleviates academic stress‐induced rises in cortisol levels
(Kato‐Kataoka et al., 2016). Taken together, these findings indicate that
the intake of probiotic strains or prebiotic mixes has a potentially sig‐
nificant effect on the regulation of the stress response in both murines
and humans. However, although this evidence is compelling more re‐
search is needed to validate results obtained in animal models.
5.2 | Probiotics and prebiotics decrease intestinal
permeability
Probiotic and/or prebiotic administration can have important effects
on the integrity of the intestinal epithelial barrier, including decreas‐
ing its permeability and thus inhibiting endotoxemia. For instance,
administering Lactobacillus farciminis to mice suppresses partial re‐
straint stress‐induced hyperpermeability of the colon and thereby
prevents endotoxins from entering circulation (Ait‐Belgnaoui et al.,
2014). Mice undergoing water avoidance stress display increased
intestinal permeability but treating them with L. farciminis can help
maintaining the barrier integrity and confers epithelial and mucosal
barrier strengthening (Da Silva et al., 2015, 2014). Pretreatment with
probiotics L. helveticus and Bifidobacterium longum also restores tight
junction (TJ) barrier integrity in mice facing water avoidance stress
(Ait‐Belgnaoui et al., 2014). Prebiotics decrease intestinal permeabil‐
ity and improve TJ integrity in obese mice, thereby limiting metabolic
endotoxemia (Cani et al., 2009). Administering prebiotics to rats with
acute pancreatitis significantly improves intestinal barrier function
(Zhong et al., 2009). Treatment with Lactobacillus plantarum is shown
to improve paracellular sealing between epithelial cells by increasing
expression of scaffold protein zonula occludens (ZO)‐1 and trans‐
membrane protein occludin near TJ structures (Karczewski et al.,
2010). These beneficial effects have also been observed in humans.
A mix of L. rhamnosus and Lactobacillus reuteri reduces small intestinal
permeability in children with eczema (Rosenfeldt, Benfeldt, Valerius,
Paerregaard, & Michaelsen, 2004). Providing a probiotic fermented
milk drink to patients with irritable bowel syndrome (IBS) decreases
their small bowel permeability (Zeng et al., 2008). Athletes taking
a multispecies probiotic have decreased intestinal permeability as
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| 1229
evidenced by less zonulin in their feces (Lamprecht et al., 2012).
Therefore, as seen in a plethora of murine and human studies, there
is a handful of bacterial species along with some useful prebiotics
that decrease intestinal epithelial permeability and thereby lower
the risk of endotoxemia and uncontrolled inflammation.
5.3 | Probiotics and prebiotics decrease
inflammation
Resident gut microbes can have a significant effect on limiting the in‐
flammatory response in both murines and humans. B. infantis adminis‐
tration decreases inflammatory cytokine production in rats following
a forced swim test (Desbonnet, Garrett, Clarke, Bienenstock, & Dinan,
2008). Mice subjected to early life maternal separation (MS) have
enhanced peripheral IL‐6 production after the forced swim test, but
those given B. infantis had a normalized immune response comparable
to that of non‐MS mice (Desbonnet et al., 2010). Giving L. farciminis
to mice suppresses stress‐induced neuroinflammation during partial
restraint stress (Ait‐Belgnaoui et al., 2014). L. helveticus administration
prevents the negative mental effects of an inflammatory diet in mice
(Ohland et al., 2013). Daily L. helveticus NS8 intake also improves IL‐10
levels in adult SPF rats facing chronic restraint stress in comparison
to a SSRI (Liang et al., 2015). FOS/GOS prebiotic treatment lowers
pro‐inflammatory cytokine levels in mice exposed to chronic psycho‐
social stress (Burokas et al., 2017). A more in‐depth study discovered
that providing male young adult and middle‐aged mice with FOS‐inulin
for 12 weeks prevented stress‐induced peripheral inflammation and
microglial activation concomitant with changes of the gut microbiome
and SCFA profile (van de Wouw et al., 2018). Furthermore, IBS pa‐
tients treated with B. infantis showed alleviation of their symptoms
and a balanced ratio of anti‐inflammatory to pro‐inflammatory cy‐
tokines (O'Mahony et al., 2005). L. reuteri has an anti‐inflammatory
effect on human epithelial cells in part by upregulating an anti‐inflam‐
matory molecule, NGF, and by inhibiting inflammatory NF‐kB activity
(Ma, Forsythe, & Bienenstock, 2004). Athletes taking a multispecies
probiotic have lower pro‐inflammatory TNF‐α levels (Lamprecht et al.,
2012). In sum, probiotics and prebiotics decrease inflammation in both
murines and humans, likely by boosting intestinal barrier integrity and
by presenting anti‐inflammatory signals to immune cells.
5.4 | Probiotics and prebiotics improve
anxiety and depression
Administration of probiotics and prebiotics has been shown to dimin‐
ish the stress response during difficult tasks, improve the integrity
of the intestinal barrier, and decrease inflammation. There is consid‐
erable evidence suggesting that these improvements among other
effects may contribute to decreased anxiety‐ and depression‐like
behaviors in murines. L. rhamnosus administration reduces stress‐in‐
duced anxiety‐ and depressive‐like behaviors in mice (Bravo et al.,
2011). B. longum reduces anxiety‐like behavior during the marble
burying test and reduces depressive‐like behavior during the tail sus‐
pension test in a mouse model of heightened anxiety (Savignac, Kiely,

1230 | PEIRCE and ALVIÑA
Dinan, & Cryan, 2014). B. breve intake reduces anxiety‐like behav‐
ior during the elevated maze test in the same anxious mouse strain
(Savignac, Tramullas, Kiely, Dinan, & Cryan, 2015). Mice fed with a
diet composed of one‐half refined carbohydrate and one‐third fat
(called inflammatory diet) have increased anxiety‐like behavior and
memory deficits but L. helveticus administration relieves these ef‐
fects (Ohland et al., 2013). Likewise, daily L. helveticus NS8 treatment
improves anxiety‐like and depressive‐like behavioral dysfunctions in
adult SPF rats facing chronic restraint stress in comparison to a SSRI
(Liang et al., 2015). Chronic intestinal inflammation induces anxi‐
ety‐like behavior in mice but B. longum treatment counteracts the
pro‐anxiety effect (Bercik et al., 2010). Administration of prebiotic
GOS and polydextrose to rats prevents anxiety‐like and depressive‐
like behaviors that typically occurs following inescapable tail shock
stress (Mika et al., 2017). FOS and GOS treatments have antidepres‐
sive and anxiolytic effects on mice exposed to chronic psychosocial
stress (Burokas et al., 2017). Further, an excellent study showed
that administering L. helveticus and B. longum to rats for two weeks
decreases anxious‐like behavior during the conditioned defensive
burying test (Messaoudi et al., 2011). In summary, there is substan‐
tial evidence supporting the notion that probiotics and prebiotics do
indeed exert antidepressive and anxiolytic effects in murines.
Similar benefits of probiotic and prebiotic treatments can be
observed in human studies. For instance, the L. helveticus and B.
longum probiotic mix given to healthy human volunteers for one
month alleviated psychological distress in comparison to a control
group, matching the positive results seen in rats (Messaoudi et al.,
2011). High intake of prebiotic trans‐GOS given to patients with
IBS for 12 weeks significantly improved subjective global assess‐
ment scores and anxiety scores compared to placebo treatment
(Silk, Davis, Vulevic, Tzortzis, & Gibson, 2009). In a study of healthy
adult volunteers consuming a probiotic‐containing milk drink daily
for 3 weeks, those initially in the bottom third on the depressed/
elated dimension reported significantly improved mood compared
to placebo (Benton, Williams, & Brown, 2007). Healthy human sub‐
jects receiving a multispecies probiotic show a significantly reduced
overall cognitive reactivity to sad mood compared to those receiving
a placebo (Steenbergen, Sellaro, Hemert, Bosch, & Colzato, 2015).
Furthermore, two meta‐studies investigating the efficacy of probi‐
otics on counteracting depression reported an overall improvement
of depressive symptoms following probiotic administration with low
risk of side effects (Huang, Wang, & Hu, 2016; Wallace & Milev,
2017). Overall these studies indicate that there is a significant po‐
tential for probiotic and prebiotic treatments to improve anxiety and
depression in human subjects.
6 | G U T M I C RO B I O M E /I N FL A M M ATI O N ‐
D E R I V E D M EC H A N I S M S TH AT C A N
I N FLU E N C E D E PR E S S I O N A N D A N X I E T Y
Given that stress and inflammation play direct and indirect roles
in modulating brain function and that the gut microbiome affects
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both the stress and the immune system, it is useful to illuminate the
mechanisms by which the gut microbiome may exert its antidepres‐
sive and anxiolytic effects (Figure 2). Microbial effectors include
SCFAs and Trycats, as well as microbial‐associated molecular pat‐
terns (MAMPs). These factors among others affect intestinal bar‐
rier integrity, immune system activity, and vagal nerve stimulation to
improve depression and anxiety.
6.1 | SCFAs improve immune status and
gastrointestinal health
The gut microbiome can ferment host‐indigestible carbohydrates
into SCFAs such as acetate, propionate, and butyrate (Miller &
Wolin, 1996). Microbiome‐derived SCFAs modulate gastrointestinal
cells in different conditions. For instance, SCFAs bind to colonic epi‐
thelial cells to promote cytokine and chemokine production during
immune response (Fukuda et al., 2011; Kim, Kang, Park, Yanagisawa,
& Kim, 2013; Singh et al., 2014; Singh et al., 2010). SCFAs also pro‐
mote gut homeostasis in noninflammatory conditions (Povoleri et al.,
2018) and promote serotonin production in enterochromaffin cells
(Reigstad et al., 2015). SCFAs bolster barrier integrity in intestinal
epithelial colon cells and decrease permeability (Kelly et al., 2015;
Mariadason, Barkla, & Gibson, 1997; Peng, Li, Green, Holzman, &
Lin, 2009; Suzuki, Yoshida, & Hara, 2008) thereby preventing micro‐
bial endotoxins from entering circulation and initiating an immune
response. In addition, SCFAs affect the development of a variety of
immune cells: they inhibit dendritic cell development from bone mar‐
row stem cells (Singh et al., 2010), enhance T cell differentiation into
anti‐inflammatory Tregs (Singh et al., 2014; Smith et al., 2013), and
regulate microglia maturity and function (Erny et al., 2015). SCFAs
also affect immune cell activity: butyrate downregulates expression
of pro‐inflammatory mediators in macrophages during an immune
response (Chang, Hao, Offermanns, & Medzhitov, 2014), promotes
the expression of anti‐inflammatory IL‐10 in macrophages and intes‐
tinal dendritic cells, and enhances the anti‐inflammatory activity of
Tregs (Singh et al., 2014). Hence, by bolstering the intestinal epithe‐
lial barrier and then promoting an anti‐inflammatory phenotype in
immune cells, the gut microbiome defends against stress‐induced
endotoxemia and limits mood‐altering neuroinflammation.
6.2 | Trycats lower inflammation and bolster the
intestinal barrier
The gut microbiome metabolizes dietary Trp into Trycats (Gao et al.,
2018). These microbiome‐derived Trycats are agonists of aryl hy‐
drocarbon receptors (AHRs), ligand‐dependent transcription factors
expressed on immune cells and intestinal epithelial cells (Stockinger
et al., 2014). There are several ways in which Trycats affect intesti‐
nal integrity and immune activity through AHR binding. Microbe‐
derived Trycats bind to AHR on innate lymphoid cells and induce
the release of IL‐22 to promote antimicrobial peptide production
and pathogen defense (Qiu et al., 2012; Romani et al., 2014; Zelante
et al., 2014). Trycats activate AHRs on T cells and dendritic cells to
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PEIRCE and ALVIÑA | 1231

F I G U R E 2 Gut microbiome–brain axis mechanisms that can influence CNS function. Short‐chain fatty acids (SCFAs), tryptophan
catabolites (Trycats) catabolites, and microbial‐associated molecular patterns (MAMPs) bolster the intestinal barrier (a) preventing
endotoxins from leaking through the intestinal epithelium. This results in reduced inflammation (b). The vagus nerve (c) communicates with
the gut epithelium, including enteroendocrine cells (gray), to exert antidepressive and anxiolytic effects. Probiotics and prebiotics (Pro/Pre),
and fecal microbiota transplants (FMT) have been shown to have beneficial effects on the gut microbiome (d) and mental health. See main
text for details

favor the differentiation of IL‐10‐producing Tregs cells in place of
pro‐inflammatory Th17 cells (Montagnoli et al., 2006; Quintana,
2013). At the neural level, these microbial‐produced Trycats bind
to AHRs on astrocytes to limit neuroinflammation (Rothhammer et
al., 2016). However, more research is needed to uncover the roles
of individual Trycats. Lactobacillus spp., especially L. reuteris, can
catabolize tryptophan into indole‐3‐aldehyde (Zelante et al., 2014),
which exerts anti‐inflammatory effects by increasing expression of
the IL‐10 receptor in intestinal epithelial cells (Alexeev et al., 2018).
Indole increases expression of genes involved in strengthening the
mucosal barrier, increasing mucin production, and decreasing intes‐
tinal permeability (Bansal, Alaniz, Wood, & Jayaraman, 2010). Indole
is also anti‐inflammatory by decreasing TNF‐α‐mediated activa‐
tion of NF‐kB, lowering expression of pro‐inflammatory chemokine
IL‐8, and increasing expression of anti‐inflammatory cytokine IL‐10
(Bansal et al., 2010). Indole‐3‐propionic acid improves intestinal bar‐
rier function and decreases TNF‐α expression by binding to the preg‐
nane X receptor on intestinal epithelial cells (Venkatesh et al., 2014).
Kynurenic acid has been reported to inhibit LPS‐induced release of
TNF‐α in peripheral immune cells (Bansal et al., 2010). Kynurenine
leads to AHR‐dependent Tregs differentiation from T cells (Mezrich
et al., 2010). Some resident microbes harbor the enzyme IDO, which
catabolizes Trp and is activated by pro‐inflammatory cytokines
(Morris et al., 2017). The IDO–AHR‐Treg axis has been proposed as
an evolutionary adaptation to maintain immune homeostasis along‐
side resident microbes; namely, inflammation‐activated IDO makes
Trycats lower inflammation by binding to AHRs and promotion of
Tregs activity (Zelante et al., 2014). Similar to SCFAs, Trycats pro‐
mote immune homeostasis by boosting the intestinal mucosal layer,
inducing Tregs differentiation, and tilting the balance of cytokines
toward an anti‐inflammatory state (Martin‐Subero, Anderson,
Kanchanatawan, Berk, & Maes, 2016).
6.3 | Microbial pattern recognition contributes to
immune and intestinal homeostasis
Hosts use pattern recognition receptors (PRRs) to keep track of resi‐
dent microbes by sensing their MAMPs (Chu & Mazmanian, 2013).
Toll‐like receptors (TLRs) are a version of PRRs present on immune
and epithelial cells that are used to maintain immune and intestinal
homeostasis (Kawai & Akira, 2006). TLR2 stimulation on intestinal
epithelial cells by gastrointestinal microbes enhances transepithe‐
lial resistance and preserves ZO‐1‐associated barrier integrity when
facing stress‐induced damage (Cario, 2008). This effect of the mi‐
crobiome is especially importance since stress‐induced intestinal
permeability is the first step toward brain‐harming neuroinflamma‐
tion. These intestinal epithelial cells also initiate a defense and re‐
pair program in response to microbial TLR2 recognition consisting

1232 | PEIRCE and ALVIÑA
of increased epithelial cell proliferation, secretion of IgA into the
gut lumen, and greater expression of antimicrobial peptides (Abreu,
2010). Intestinal Paneth cells run an antimicrobial program in re‐
sponse to enteric bacterial TLR sensing which decreases bacterial
penetration through the intestinal barrier and maintains gut ho‐
meostasis (Vaishnava, Behrendt, Ismail, Eckmann, & Hooper, 2008).
Bacteroides fragilis likely exerts many of its beneficial effects by ac‐
tivating immunomodulatory TLR2 pathways (Troy & Kasper, 2010).
It displays polysaccharide A (PSA) on its outer membrane, which
promotes a Th1/Th2 balance and induces Tregs cells to limit pro‐in‐
flammatory cytokine expression by Th17 cells and increase release
of anti‐inflammatory IL‐10 (Round et al., 2011; Shen et al., 2012; Troy
et al., 2010). In sum, commensal gut microbes activate TLR‐sensing
pathways using their MAMPs to improve intestinal epithelial integ‐
rity and to establish immune homeostasis.
6.4 | The vagus nerve mediates some
antidepressive and anxiolytic effects of probiotics
The vagus nerve is the principal component of the parasympathetic
nervous system and links the internal viscera to the CNS (Bonaz,
Sinniger, & Pellissier, 2016). Its afferent fibers can also sense periph‐
eral pro‐inflammatory cytokines and initiate the “cholinergic anti‐in‐
flammatory pathway” which activates the HPA axis to dampen down
the immune response (Borovikova, Ivanova, Nardi, et al., 2000;
Borovikova, Ivanova, Zhang, et al., 2000; Pavlov et al., 2009). Clearly,
the vagus nerve plays a versatile role in sensing enteric conditions
and, in turn, modulating neural transmission and hormone release.
Two probiotics have been shown to require an intact vagus nerve
to mediate their beneficial effects. First, mice with intestinal inflam‐
mation that normally exhibit anxiety‐like behavior show less anxious
displays when treated with B. longum for 1 week; this anxiolytic ef‐
fect was not observed in mice with a severed vagus nerve which
suggests that the parasympathetic vagal tone likely plays a causal
role in mediating central modulation of behavior (Bercik et al., 2011).
This probiotic effect has been confirmed in healthy human volun‐
teers where B. longum treatment reduced stress and anxiety while
enhancing memory performance (Allen et al., 2016). Second, chronic
treatment of L. rhamnosus in mice significantly reduces anxiety‐like
behavior in the elevated plus maze, decreases depressive‐like be‐
havior in the forced swim test, lowers stress‐induced corticosteroid
response, and induces region‐dependent alterations in GABA recep‐
tor subunit expression throughout the brain; however, mice with a
severed vagus nerve did not show these effects (Bravo et al., 2011).
Moreover, L. rhamnosus was found to increase the firing rate of vagal
afferents in the mesenteric nerve bundle, and this stimulation is re‐
quired for GABA modulation in the brain (Perez‐Burgos et al., 2013).
Taken together, these studies indicate that vagal afferents mediate
at least partially the antidepressive and anxiolytic effects of probi‐
otic strains by modulating neural transmission and perhaps influenc‐
ing neuroendocrine activity.
The vagus nerve's primary role in the gut–brain axis invites fur‐
ther study into its mechanisms of action. As of now, two probiotic
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species, B. longum and L. rhamnosus, are known to require an intact
vagus nerve for their beneficial effects on depression and anxiety
(Bercik et al., 2011; Bravo et al., 2011); the latter was later shown
to operate by increasing the firing rates of vagal afferents (Perez‐
Burgos et al., 2013). Recent studies have sought to characterize the
biochemical flow of information through the vagus nerve in other
contexts (Han et al., 2018; Kaelberer et al., 2018). Previously termed
enteroendocrine cells have been discovered to synapse onto vagal
nodose neurons and have been renamed neuropod cells (Kaelberer
et al., 2018). These neuropod cells detect and relay nutrient con‐
ditions in the gut, inviting the possibility that GI cells serve as an
intermediary between microbial signals and vagus nerve activity.
Vagal stimulation has also been shown to induce dopamine release
in the substantia nigra (Han et al., 2018). This may have implications
for mood disorders, especially since rats with lesions in the dopa‐
mine neurons of the substantia nigra exhibit depressive‐like behav‐
ior (Winter et al., 2007). Given that vagus nerve activity increases
GABA transmission in the brain when stimulated by L. rhamnosus
(Bravo et al., 2011) but can also induce neural dopamine release in
other circumstances (Han et al., 2018), future studies should explore
how different aspects of the vagus nerve mediate this relationship
between microbial signals in the gut and neurotransmitter activity
in the brain.
6.5 | Fecal microbiota transplants show promise
in the treatment of depression and anxiety
A novel biological treatment for disorders relating to unhealthy gut
microbiome are the fecal microbiota transplants (FMT) (Cohen &
Maharshak, 2017; Gupta, Allen‐Vercoe, & Petrof, 2016). FMT is a
procedure that transfers gut microbes from a healthy donor's fecal
matter into the recipient's intestinal tract to promote a healthier
microbiome. FMTs have been successful in treating Clostridium dif‐
ficile antibiotic‐resistant infections (Cohen et al., 2015), and have
shown promise for improving neurological and GI tract‐related dis‐
eases (Cohen et al., 2016). As we have reviewed here, several lines
of evidence support the notion that some neurological disorders and
GI conditions share a common etiology involving gut dysbiosis (i.e.,
unhealthy gut microbiome). First, patients with inflammatory bowel
disease (IBD) have higher rates of depression and anxiety compared
to healthy controls (Fond et al., 2014; Graff, Walker, & Bernstein,
2009; Mikocka‐Walus et al., 2007). Second, both patients with de‐
pression and IBD have significantly different gut microbiomes com‐
pared to healthy controls (Morgan et al., 2012; Zheng et al., 2016).
Third, use of antibiotics correlates with increased risk of subse‐
quent depression, anxiety, and IBD (Lurie, Yang, Haynes, Mamtani,
& Boursi, 2015; Mendall & Kumar, 1998). Lastly, a common mecha‐
nism involving activated immune‐inflammatory, oxidative, and ni‐
trosative stress pathways (including Trycats and gut‐brain axis) has
been proposed to explain the co‐morbidity of depression and IBD
(Martin‐Subero et al., 2016). Therefore, since the gut microbiome
appears to regulate immune activity through several mechanisms, it
is natural to question whether FMTs might be an effective method

PEIRCE and ALVIÑA
to promote mental health by improving immune status via the gut
microbiome. This viable biological treatment is especially important
since psychological therapy has brought few long‐term benefits to
people with co‐morbid depression and IBD (Gracie et al., 2017). In
addition, FMTs have shown to be much more effective than a related
biological treatment, probiotics, in restoring a healthy gut microbi‐
ome after antibiotic use (Suez et al., 2018). In support of the idea
that changing gut microbiome composition affects mental health, GF
mice receiving FMT from patients with depression exhibited more
depressive‐like behaviors compared to GF mice receiving FMT from
healthy control individuals (Zheng et al., 2016).
7 | CO N C LU S I O N S A N D FU T U R E
D I R EC TI O N S
The study of the gut microbiome–brain axis is revolutionizing our
understanding of the mechanisms underlying nervous system dis‐
orders such as depression and anxiety. However, there are cur‐
rently more open questions than answers. What is clear is that
the gut microbiome's role in modulating mental health deserves
increased attention from researchers and clinicians. Across the
developed world, rates of depression and anxiety are increasing
(Jorm et al., 2017). At the same time, increased rates of urbaniza‐
tion are bringing about concerns over public health infrastructure
and policies (Bloomfield et al., 2016). These two trends make more
sense when seen through the lens of the gut microbiome. Modern
urban lifestyles often decrease exposure to microbes early in life
and lead to an underdeveloped immune system prone to chronic
inflammation later in life, possibly serving as a risk factor for men‐
tal disorders such as depression and anxiety (Rook, Raison, &
Lowry, 2013). Similarly, urban environments with decreased green
space combined with heavily marketed fast foods can contribute
to gut dysbiosis, particularly among lower socioeconomic classes
(Logan, 2015). Indeed, urbanization is associated with decreased
gut microbiome complexity (Segata, 2015), an indicator of poor
microbiome health (Lloyd‐Price, Abu‐Ali, & Huttenhower, 2016).
Increased urbanization worldwide certainly demands increased
interest in the ways the gut microbiome can contribute to mental
health. Finally, the economic case for further study is incredibly
viable: investments in treatments for mental conditions such as
depression and anxiety are likely to bring very high rates of return
through increases in productivity and quality of life (Chisholm et
al., 2016).
In future studies, it is necessary to fully characterize the com‐
ponents of the gut microbiome–brain axis. In fact, one of the areas
that remains poorly explored is the enteroendocrine cells that com‐
municate with and activate the vagus nerve. Knowing how these
cells operate will allow us to then use that criteria to develop more
effective probiotic/prebiotic formulations, for example. On a related
note, electric vagus nerve stimulation has been shown to signifi‐
cantly improve mental health outcomes in patients with treatment‐
resistant depression compared to a control group (Aaronson et al.,
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| 1233
2017). Future studies could explore whether probiotics could stim‐
ulate vagal afferents and doing so they might parallel or reinforce
these antidepressive effects. Overall, as the primary link between GI
conditions and the brain, the vagus nerve merits further study into
its mechanisms and roles in mental health treatment.
Other areas to continue developing are the use of pre/probiotics
and FMTs. For example, antibiotic‐resistant C. difficile infection has
been shown to be effectively treated with FMTs (Cohen et al., 2015).
Recent findings also show promise for the treatment of other con‐
ditions such as diabetes, obesity, metabolic syndrome, and GI tract‐
related pathologies (Gupta et al., 2016). Therefore, considering that
the gut microbiome seems to have a strong influence over the GI
physiology it is logic to think that FMTs and pre/probiotic treatments
can be beneficial. As discussed here, several reports already have
shown promise, but more research is needed.
Lastly, several important questions remain unanswered (Foster
& McVey Neufeld, 2013). One of the most significant open ques‐
tions is related to sex‐dependent differences in gut microbiome
composition. Even though progress is being made in this regard,
this is imperative considering that females are most likely to suffer
from depression and anxiety than males. Likewise, we are just be‐
ginning to understand what role the gut microbiome plays during
brain development. Early life is a period of rapid change when the
developing brain is vulnerable to most internal and external influ‐
ences. Furthermore, many mental disorders can originate from early
exposure to stress and inflammation, therefore improving our un‐
derstanding of the gut microbiome influence at this stage will also
have a significant impact on diagnosis and possible treatments.
C O N FL I C T O F I N T E R E S T
The authors declare no conflict of interest.
AU T H O R C O N T R I B U T I O N S
Conceptualization, J.M.P. and K.A.; Writing—Original Draft, J.M.P.;
Writing—Review & Editing, J.M.P. and K.A.; Supervision, K.A.; Funding
Acquisition, K.A.
ORCID
Karina Alviña https://orcid.org/0000-0002-8369-0953
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inflammation and the gut microbiome in depression and
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