Neuroscience and Biobehavioral Reviews 70 (2016) 300–312

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Review

What’s bugging your teen?—The microbiota and adolescent mental

health
Karen-Anne McVey Neufeld a , Pauline Luczynski a , Clara Seira Oriach a,b ,
Timothy G. Dinan a,b , John F. Cryan a,c,∗
a
APC Microbiome Institute, University College Cork, Ireland
b
Department of Psychiatry, University College Cork, Ireland
c
Department of Anatomy and Neuroscience, University College Cork, Ireland

a r t i c l e i n f o a b s t r a c t

Article history: Human adolescence is a time of enormous developmental change, second only to infancy and early child-
Received 4 March 2016 hood in terms of brain shaping and growth. It is also a period in life when the young adult is faced with
Received in revised form 4 June 2016 distinct environmental challenges and stressors. Interestingly, we now know that these external sources
Accepted 6 June 2016
of stress all have an impact on the intestinal microbiota. Given that there is now a significant body of
Available online 7 June 2016
knowledge indicating a role for the microbiota-gut-brain axis in development and function of the brain,
and potentially the emergence of psychiatric illnesses, we need to draw our attention to the intestinal
Keywords:
microbiota in the adolescent. As psychiatric illnesses frequently first manifest during the teenage years it
Adolescence
Microbiota-gut-brain axis
may be that the intestinal bacteria are playing an as yet unidentified role in disease pathogenesis. Iden-
Development tifying a role for the microbiota in psychiatric illnesses opens up an exciting opportunity for therapeutic
Psychiatric illnesses advances via bacterial manipulation. This could prove to be a beneficial and novel avenue for treatment
Early life challenges of mental illnesses in the developing teen.
Probiotics © 2016 Elsevier Ltd. All rights reserved.
Hypothalamic-pituitary-adrenal axis
Brain plasticity
Critical windows

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
2. Microbiota-gut-brain axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
3. Brain development – focus on adolescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
3.1. Structural brain development in adolescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
3.2. Brain function in adolescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
3.3. Stress responsivity in adolescence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .303
4. Enteric nervous system – focus on development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
5. Microbiota development – focus on adolescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
6. Adolescent mental health – what role could bacteria be playing? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
6.1. Stress-resilience and microbiota . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
6.2. Diet, alcohol and exercise – effects on the microbiota . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
7. Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
8. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

Abbreviations: ACTH, adrenocorticotropic hormone; AH, afterhyperpolarization; BDNF, brain-derived neurotrophic factor; CNS, central nervous system; ENS, enteric
nervous system; GF, germ-free; HPA, hypothalamic-pituitary-adrenal; IBS, irritable bowel syndrome; MIA, maternal immune activation; PUFA, polyunsaturated fatty acid;
VPA, valproic acid.
∗ Corresponding author at: APC Microbiome Institute, University College Cork, Ireland.
E-mail address: j.cryan@ucc.ie (J.F. Cryan).

http://dx.doi.org/10.1016/j.neubiorev.2016.06.005
0149-7634/© 2016 Elsevier Ltd. All rights reserved.
 K.-A. McVey Neufeld et al. / Neuroscience and Biobehavioral Reviews 70 (2016) 300–312
1. Introduction
As a society, we are well aware of the many and varied external
sources of pressure adolescents face; from possible drug and alco-
hol exposure, to social issues involving peers, to changing habits
related to eating and sleeping, to balancing workload and the seem-
ingly inevitable associated stress. What we are likely less aware of
is that teenagers face additional developmental influence from the
inside – in the form of the commensal intestinal microbiota. In fact,
we now know that collectively extrinsic factors and the internal
microbial environment work in concert to exert defining effects on
host anatomy, physiology and behavior (Cryan and Dinan, 2012;
McVey Neufeld et al., 2013; Borre et al., 2014; De Palma et al., 2014;
McVey Neufeld et al., 2016). In addition, emergence of psychiatric
illness is often first seen during the adolescent period when envi-
ronmental stressors frequently peak (Paus et al., 2008; O’Connor
and Cryan, 2014). Intriguingly, for all of the external influencing
factors listed above, lasting effects on the gut bacteria have been
identified, leading to the hypothesis that mental illness emerging
during adolescence could in part be mediated by the commensal
intestinal microbiota (see Fig. 1).
The human gut houses 100 trillion bacteria, and the impact of
our synergistic coexistence with these bugs on human develop-
ment and function is only beginning to be appreciated (Backhed
et al., 2005; Frank and Pace, 2008). A recent study examining the
variation in microbiota in healthy adults has identified a human
core microbiota that is globally observed, and is made up of 17
bacterial genera (Falony et al., 2016). In this review we will intro-
duce the concept of the microbiota-gut-brain axis, a bi-directional
axis of communication with broad implications for human physiol-
ogy, health and disease. We will focus on the developing adolescent
brain, its fragile balance between plasticity and vulnerability, and
the role that this axis, and the intestinal microbiota particularly,
may play in both its normal, healthy development and the patho-
physiology of the psychiatric illnesses that frequently first manifest
during this critical window. We will discuss studies examining the
use of both pre- and pro-biotics; the latter are live bacteria that con-
fer health benefits to the host and which only transiently inhabit the
gut, and prebiotics are the indigestible foods (primarily carbohy-
drates), that selectively promote the growth of certain gut bacteria,
thereby providing indirect health benefits to the host (Gibson and
Roberfroid, 1995; Roberfroid, 2007). Finally, we will propose poten-
tial lines of inquiry for future research on therapeutics aimed at
the treatment of psychiatric illnesses via the intestinal commensal
microbiota.
2. Microbiota-gut-brain axis
The existence of a gut-brain axis has been acknowledged for
decades, with both clinical and basic research identifying this bidi-
rectional axis of communication as fundamental for both normal
gastrointestinal function but also to the frequently co-morbid psy-
chiatric and bowel diseases (Mayer, 2000). In the last decade, the
concept of this axis has been extended to the “microbiota-gut-brain
axis”, a reflection of our increased understanding of the impor-
tance of the trillions of bugs residing and working in the human
gut (Rhee et al., 2009; Bercik, 2011; Cryan and O’Mahony, 2011).
Our relationship with the commensal bacteria is mutualistic – the
bugs benefit from a rich and protected habitat, while we humans
benefit as bacteria breakdown otherwise indigestible food prod-
ucts, providing us with previously inaccessible nutrients. We also
gain as these beneficial bacteria provide a biofilm through which it
is difficult for pathogenic bacteria to gain access. However, we are
beginning to understand that this mutually beneficial relationship
has further far-reaching consequences for optimal human health
301
and well-being than previously considered, and that the benefits of
a synergistic relationship with bacteria can extend to human men-
tal health. Most interestingly, we now know that the microbiota
influence the expression of host behavior and likely play a role in
pathophysiology of psychiatric disease (Foster and McVey Neufeld,
2013).
Despite the fact that the concept of a microbiota-gut-brain axis
is now well established both pre-clinically and clinically, exact
mechanisms by which communication occurs are still under inves-
tigation. A number of systems are involved in this highway of
information transfer, likely working in parallel to transmit infor-
mation between the microbiota and the brain, with neural (both
autonomic and enteric), immune, and endocrine pathways all
engaged in the constant crosstalk (Cryan and Dinan, 2012; Foster
and McVey Neufeld, 2013; El Aidy et al., 2015; Mayer et al., 2015).
The enteric nervous system (ENS) is a dedicated nervous system
housed with the gastrointestinal wall that exists from the esopha-
gus to the anus. While the ENS makes connections to the extrinsic
nervous system, it is also capable of operating independently of
the spinal cord and brain (Costa et al., 2000). Both the ENS and the
vagal nerve have proven to be important in transmitting informa-
tion regarding the intestinal microbiota from the gut to the brain,
which is unsurprising when we consider that the first neural point
of contact for the gut bacteria is the approximately 500 million
neurons housed within the ENS and extending the full length of
the gastrointestinal tract (Furness, 2006; Blackshaw et al., 2007).
Pre-clinical studies carried out in mice have shown that the vagal
nerve can be necessary for microbiota-gut-brain communication,
but these findings seem to be dependent on the bacterial species
in question. Both vagal dependence (Lyte et al., 2006; Bercik et al.,
2011b; Bravo et al., 2011) and independence (Bercik et al., 2010,
2011a) have been demonstrated in rodent studies incorporating
bacterial treatments with vagotomy.
The immune system is unquestionably involved in microbiota-
gut-brain communication, but again the degree to which it is
necessary for the transmission of specific information seems to
depend upon the bacterial species under investigation. Early work
has demonstrated that sub-clinical doses of pathogenic bacteria
administered to mice could increase anxiety-like behavior in the
absence of changes to peripheral cytokine levels (Lyte et al., 2006). A
more recent study in immunocompromised animals demonstrated
that B and T cell deficient Rag1 knockout mice, which have altered
neurological and gut function, show normalization of some deficits
following probiotic treatment (Smith et al., 2014).
Research using germ-free (GF) mice, animals raised and main-
tained in the total absence of bacteria, has provided perhaps the
most persuasive evidence for a role of the microbiota in brain-gut
signalling. GF animals show significantly altered immune, gastroin-
testinal, digestive, and metabolic function (for review see Luczynski
et al., 2016). Moreover, the absence of microbes during develop-
ment dramatically affects the brain-gut axis and central nervous
system (CNS) circuitry and wiring, although exact mechanisms
whereby these changes occur remain unknown. Indeed, GF ani-
mals show anxiolytic-like behavior (Diaz Heijtz et al., 2011; Neufeld
et al., 2011; Clarke et al., 2013), reduced sociability (Desbonnet
et al., 2014; Arentsen et al., 2015) and learning deficits (Gareau
et al., 2011). GF mice also demonstrate heightened hypothalamic-
pituitary-adrenal (HPA) axis reactivity following exposure to a
stressor (Sudo et al., 2004), with stress hyperresponsivity known
to induce CNS change. Most recently, it has been shown that GF
animals have differences in brain structure, with hypermyelina-
tion observed in the prefrontal cortex (Hoban et al., 2016), and
also marked differences in microglial cells (Erny et al., 2015). GF
mice have more microglia throughout the brain compared to con-
trol mice, and these cells are clearly abnormal, with longer, more
complex processes. In addition, the microglia of GF mice do not dis-
302 K.-A. McVey Neufeld et al. / Neuroscience and Biobehavioral Reviews 70 (2016) 300–312
Fig. 1. The microbiota-gut-brain axis in adolescence. This bidirectional axis is generally healthy and functioning, but environmental factors frequently encountered by the
developing teen – such as drugs of abuse, alcohol, altered nutrition and sleep, and stress all have known effects on the intestinal microbiota. Here we propose that these
environmentally induced alterations to the microbiota may be playing a role in psychiatric disease pathogenesis, particularly in relation to those disorders that often first
manifest in the teenage years.
play activated morphology following a bacterial or viral challenge,
indicating that the lack of microbiota somehow impact the host’s
ability to mount appropriate immune responses both peripherally,
and in the CNS (Erny et al., 2015). Interestingly, antibiotic-treated
mice display an immature microglial profile similar to that of
GF mice (Erny et al., 2015). It is important to mention that the
GF model is often criticized for its lack of clinical relevance, as
humans are never in a GF state (Funkhouser and Bordenstein, 2013).
However, the use of GF animals in research is not to directly imi-
tate the human condition. Instead, the GF model allows the study
of the dysfunction which arises in the absence of any microbial
input on host physiology and behavior. As GF animals are not
exposed to microbes from conception on, they are perhaps not
the ideal model to study experimental questions regarding the
effect of altered microbial composition occurring later in life. For
these reasons, alternative models such as antibiotic treatment must
be explored further. Interestingly, many of the characteristics of
GF mice (ie reduced anxiety-like behaviour, cognitive dysfunc-
tion, social deficits, microglia activation deficits, BDNF expression
changes) also emerge after a sustained antibiotic-induced deple-
tion of the microbiota (Desbonnet et al., 2015; Erny et al., 2015;
Bercik, 2011).
From infancy to old age, diet is one of the most important factors
mediating the establishment and composition of the gut microbiota
(Power et al., 2014). Correspondingly, the microbiota is essential
for the optimal digestion and vitamin absorption of the food we
eat (Flint et al., 2012). As previously mentioned, there is strong evi-
dence linking the composition of the gut microbiota to behavioral
alterations. Given that the diet can affect the gut microbiota, host
nutrition is one of the most potent factors contributing to brain-gut
signaling and behavior (for review see Seira Oriach et al., 2016).
Clearly neural, immune and endocrine systems are all respon-
sive to changes in the intestinal microbiota and likely have
overlapping roles in communicating information from the gut to
the brain and vice versa, but we are still in the relative infancy of
understanding the exact mechanisms of activity for the microbiota-
gut-brain axis. Furthermore, there is little to no research on the
development of this axis over the lifespan, much less in the adoles-
cent. What is abundantly clear is that there is cross-communication
between the systems; the subsequent sections of this review will
detail what we know about adolescent development and changes
occurring centrally in the brain, as well as peripherally, in the
enteric nervous system and the gut microbiota.
3. Brain development – focus on adolescence
From an evolutionary point of view, the physiological changes
associated with adolescence are thought to prepare the young adult
to leave the safety of home and thus gain independence from care-
givers (Burnett et al., 2011; Spear, 2011). Refinement in social and
cognitive abilities during adolescence also facilitates this transi-
tion into adulthood (Burnett et al., 2011; Spear, 2011; Crone and
Dahl, 2012; Spear, 2013). Until recently, it was thought that the
brain was finished developing at puberty. However, it is now clear
that adolescence is a robust transitory period characterized by neu-
roanatomical change and maturation. These structural changes to
the brain map onto behaviours commonly associated with ado-
lescence, such as stress responsivity, cognitive function, reward
sensitivity, and social cognition (Burnett et al., 2011; Spear, 2013).
3.1. Structural brain development in adolescence
In the late 1960’s and 70’s research on post-mortem human
brains revealed that certain regions, namely the frontal cortex, con-
tinue to develop morphologically beyond early life and even the
pubertal period (Huttenlocher, 1979; Huttenlocher et al., 1982;
Benes, 1989). The two most salient structural alterations in the
adolescent frontal cortex are changes in synaptic connectivity
and axonal myelination. The frontal cortex is involved in exec-
utive function, cognition, and memory (Miller and Cohen, 2001;
Tamminga and Buchsbaum, 2004). As such, it is unsurprising that
this neuroanatomical development during adolescence occurs in
parallel with dramatic changes in identity, self-consciousness, and
cognitive flexibility (Burnett et al., 2011).
Early in postnatal life, the brain generates many new synaptic
connections between neurons in a process known as synapto-
genesis (Rakic et al., 1994; Huttenlocher and Dabholkar, 1997).
This proliferation of synapses is then followed by a period of
synaptic elimination or pruning. Synaptic pruning is an experience-
dependent process in which the neural wiring in the brain is
fine-tuned: frequently used connections are strengthened and
scarcely used connections are eradicated (Holtmaat and Svoboda,
2009). Although the exact mechanisms underlying this process
remain to be elucidated, it is understood that resident microglia
in the brain regulate the elimination of certain synapses and the
strengthening and maintenance of others (Hua and Smith, 2004;
Schafer et al., 2012). Moreover, recent evidence has implicated
immune signaling, specifically activation of the complement sys-
tem, in the elimination of synapses during postnatal development
(Sekar et al., 2016). In sensory regions, synaptic density is highest
in the first months of life after which time neural connections begin
to be pruned, reaching adult levels before or around adolescence
(Cragg, 1975; Huttenlocher et al., 1982; Bourgeois and Rakic, 1993).
Structural development in the prefrontal cortex however, follows a
strikingly different time course. Here, there is a proliferation in neu-
ral connectivity during childhood and again in puberty, followed
 K.-A. McVey Neufeld et al. / Neuroscience and Biobehavioral Reviews 70 (2016) 300–312
by a post-pubertal period of stability and a subsequent elimination
and reorganization of synaptic connections (Huttenlocher, 1979;
Bourgeois et al., 1994; Woo et al., 1997). Therefore, during the tran-
sition from adolescence to adulthood, prefrontal cortical synapses
are systematically pruned resulting in a net decrease in synaptic
density in this brain area.
The second defining change in brain structure in the post-
pubertal period relates to myelination. During neural development,
oligodendrocytes produce a layer of myelin, which wraps around
axons. This process forms an insulating sheath, which increases
the speed at which neurons can transmit information. By the
first few years of life, axons in the sensory and motor cortices
are already fully myelinated (Yakovlev and Lecours, 1967). In
contrast, myelination continues in the frontal cortex well into ado-
lescence (Benes, 1989). This increase in myelination accelerates the
speed and efficiency of neural communication across distant brain
regions, impacting the functional connectivity of the adolescent
brain (Markham and Greenough, 2004; Fair et al., 2008).
Non-invasive brain imaging has provided further evidence of
the ongoing morphological development of the frontal cortex of
adolescents. Cortical gray matter volume progressively increases
in the frontal and parietal lobes throughout childhood, peaking in
puberty, and then begins to decrease (Pfefferbaum et al., 1994;
Giedd et al., 1996; Reiss et al., 1996; Giedd et al., 1999; Sowell
et al., 2001; Sowell et al., 2003; Giorgio et al., 2010). In contrast,
white matter volume in these brain areas consistently increases
throughout childhood and adolescence (Giedd et al., 1999; Barnea-
Goraly et al., 2005). These changes in gray and white matter are
thought to be due to the aforementioned changes in synaptic prun-
ing and myelination (Blakemore and Choudhury, 2006; Paus et al.,
2008; Tau and Peterson, 2010). The concomitant loss of gray matter
and increase in white matter during adolescence is potentially due
to increased axonal myelination (Sowell et al., 2003; Paus et al.,
2008). Another interpretation is that changes in gray matter vol-
ume reflect alterations in synaptic connectivity: that the increase
and decrease of gray matter before and after puberty are a result of
synaptic proliferation and elimination, respectively (Huttenlocher
and Dabholkar, 1997; Paus et al., 2008; Tau and Peterson, 2010).
3.2. Brain function in adolescence
Developmental immaturities in cognitive control, attentional
regulation, and response inhibition have been widely attributed to
the delayed maturation of the frontal cortex (Casey et al., 2008;
Spear, 2013). Although adolescents can generally perform well
on cognitive tasks, performance deficiencies emerge when task
demands increase or when emotions are heightened (Liston et al.,
2009). These results can perhaps be explained by the decrease
in frontal brain activity and the increase in the involvement of
emotional centres in adolescents when emotions or stress are par-
ticularly high (Casey et al., 2008). The development of the frontal
cortex in adolescence is therefore thought to underlie the delay
in maturation of the ‘top-down’ control systems controlling sub-
cortical ‘bottom-up’ systems, which mediate emotions and reward
(Casey et al., 2008; Spear, 2013).
Novel stimuli, risky situations, and drugs of abuse feed into
the brain’s reward circuitry, which is critical for seeking natural
rewards essential for survival (Nesse and Berridge, 1997). Ado-
lescents typically (Galvan et al., 2006; Cohen et al., 2010; Van
Leijenhorst et al., 2010), although not always (Bjork et al., 2004),
show altered striatal responses to rewards. Moreover, reward seek-
ing peaks in mid-adolescence and then gradually decreases into
adulthood (Steinberg et al., 2009; Cauffman et al., 2010). Although
multiple factors impact risk-taking during adolescence, impulsive
behavior is likely a key mediator (Pfefferbaum and Wood, 1994).
In fact, impulsivity is associated with increased risk-taking and
303
adolescents typically behave more impulsively, as measured by
delayed discounting (Olson et al., 2007). These changes in reward
responsivity could be due to altered dopaminergic signalling in
reward-relevant subcortical regions. Indeed, there are profound
changes in both dopamine levels and the expression of its receptor
in areas implicated in reward seeking during adolescence in the rat
(Tarazi and Baldessarini, 2000).
Social interactions with peers take on a significant importance
in adolescence, with adolescents spending up to one third of their
waking time interacting with peers during the academic year
(Csikszentmihalyi et al., 1977; Spear, 2000). These experiences are
thought to help develop the social skills necessary to achieve inde-
pendence from the home environment (Spear, 2000). However, this
is also a time in which adolescents can conform to their peers and
develop antisocial behaviors such as stealing, aggression, trespass-
ing and cheating (Berndt and Keefe, 1979; Cairns et al., 1989). While
it is impossible to tease apart all of the factors influencing the devel-
opment of social cognition during adolescence, pubertal hormones
and neurodevelopment both are likely to play major roles (Spear,
2000; Blakemore, 2008; Burnett et al., 2011; Spear, 2013; Brizio
et al., 2015). Although there has been relatively little research into
the neural circuitry underlying the development of social cognition
in adolescence, imaging studies have provided evidence that there
exists a network of brain areas associated with social cognition,
and in particular the ability to mentalize (Frith and Frith, 2003;
Burnett et al., 2011; Brizio et al., 2015). This network is thought
to be the neural substrate for recognizing another person’s mental
state, including emotions, desires and beliefs (Frith and Frith, 2003).
This ‘social brain’ includes the prefrontal cortex and the amygdala,
amongst other structures (Blakemore, 2008), and the develop-
ment of social cognition in adolescence may be related to the
continued neurodevelopment of these brain regions (Blakemore
and Choudhury, 2006; Paus et al., 2008; Tau and Peterson, 2010;
Goddings et al., 2014, see Kilford et al., 2016).
Although most of the research on adolescent brain function has
focused on the cortex, limbic regions are also involved in medi-
ating the emotional changes which occur during this period. The
amygdala, in particular, is a key mediator of emotion and fear
(LeDoux, 2007). To investigate the neural correlates of the height-
ened emotionality and peer focus of adolescents, developmental
studies often assess amygdalar activation in response to emotional
social stimuli (Spear, 2013). Adolescents sometimes (Monk et al.,
2003; Hare et al., 2008), but not always (Pine et al., 2001), display
an increase in amygdala activity in response to emotional face cues.
These findings can potentially explain the reduced capacity to make
rational decisions in stressful or emotional situations (Dahl, 2004;
Spear, 2013). Interestingly, social peers are effective in provoking
these heightened emotional states during adolescence, with ado-
lescents engaging in more risk-taking behaviour than adults when
tested in the presence of peers (Gardner and Steinberg, 2005). These
results are particularly important given that adolescents often par-
ticipate in risky behaviours in social situations (Steinberg, 2008).
3.3. Stress responsivity in adolescence
Changes in endocrine signalling are a hallmark of adolescent
development. Although the majority of studies have investi-
gated gonadal hormones, recent attention has focused on the
development of HPA axis signalling and stress reactivity dur-
ing adolescence (for reviews see Romeo and McEwen, 2006;
McCormick and Mathews, 2007; Romeo, 2010; Eiland and Romeo,
2013; see Romeo et al., 2016). Our current knowledge of these
pubertal stress responses has largely been gleaned from rodent
models. During puberty, gonadal hormones increase considerably,
while basal levels of stress hormones remain comparatively sta-
ble (Pignatelli et al., 2006). In contrast, stress-induced release
304 K.-A. McVey Neufeld et al. / Neuroscience and Biobehavioral Reviews 70 (2016) 300–312
of corticosterone is prolonged in pre-pubertal versus adult rats
(Goldman et al., 1973; Vazquez and Akil, 1993; Romeo et al., 2004).
Importantly, this elongated stress hormone release is not influ-
enced by the different gonadal hormonal backgrounds of rats in
these two stages of development (Romeo et al., 2004). Adult rats
habituate to repeated responses to the same stressor; however,
pre-pubertal males, but not females, show heightened HPA axis
signalling in response to a repeated stressor (Romeo et al., 2006).
In agreement with these results, pre-pubertal rats exposed to a
stressor display increased anxiety- and depressive-like behaviours
(Vidal et al., 2007; Leussis and Andersen, 2008; McCormick
et al., 2008). Taken together, these data clearly indicate that HPA
axis signalling and stress reactivity undergo significant change
during adolescence; however, there remains a paucity of informa-
tion describing the mechanisms underlying these developmental
alterations.
4. Enteric nervous system – focus on development
While there is admittedly little information on ENS changes
specific to adolescence, we do know that it continues to be sig-
nificantly plastic well into adulthood (Galligan et al., 1989; Giaroni
et al., 1999). Moreover, evidence shows that the ENS is receptive to
changing intestinal microbial status, with altered neuronal physi-
ology observed in response to bacteria, as well as changes observed
in mRNA gene expression in adult enteric neurons after introduc-
tion of bacteria. Work examining GF mice that have been colonized
with commensal intestinal microbiota in adulthood shows that
intracellular recordings taken from sensory neurons residing in
the gut wall, the so-called afterhyperpolarization (AH) neurons,
are different from those obtained from adult GF animals. Specif-
ically, AH neurons are less excitable in GF mice, whereas if the
mouse has been “conventionalized” in adulthood with bacteria,
neurons respond with normal levels of excitability when com-
pared to controls (McVey Neufeld et al., 2013). These same neurons
respond with increased excitability when exposed to probiotic Lac-
tobacillus rhamnosus (JB1) (Kunze et al., 2009). Interestingly, these
sensory neurons have been shown to form a nicotinic synapse with
vagal afferents leading to the brain (Perez-Burgos et al., 2014),
and similarly, mixed mesenteric afferent recordings from adult
conventionalized-GF mice show levels of activity comparable to
controls, whereas recordings from these nerves in GF mice again
demonstrate reduced excitability (McVey Neufeld et al., 2015).
Mixed nerve recordings also show increased activity after expo-
sure to probiotic JB-1 (Perez-Burgos et al., 2013). Levels of mRNA
gene expression of calcium binding protein calbindin in the enteric
neurons are also similar when comparing conventionalized-GF gut
tissue to that of controls, whereas GF animals show significantly
less expression compared to both (McVey Neufeld et al., 2015).
Again, this illustrates that ENS tissue in the adult mouse is plastic
and responds to changes in intestinal luminal status, and given that
activity of these sensory AH neurons is transmitted to the brain via
the vagal nerve this could then provide an avenue whereby infor-
mation regarding the bacterial contents of the gut can be conveyed
to the brain. While these results are from adult mouse tissue, it
is entirely reasonable to assume that adolescent tissue would be
similarly plastic and responsive to bacterial input, indicating that
information travelling via the microbiota-gut-brain axis would be
altered in adolescence depending on environmental, and subse-
quent microbial, changes. This confirmation of previous findings of
extended plasticity in the ENS (Galligan et al., 1989; Giaroni et al.,
1999), compared to what has been reported in terms of central
nervous tissue plasticity in response to adult commensal conven-
tionalization, is very exciting. Not only does it indicate a potential
target of action for microbial based therapies that could extend into
adulthood, it also provides a viable route for information to travel
from the intestinal microbiota to the brain.
5. Microbiota development – focus on adolescence
The advent of next-generation microbial sequencing technology
has changed what we know about the constituent bacteria in the
human gut and how it changes over the course of life (Dominguez-
Bello et al., 2011; Forde and O’Toole, 2013). It was largely believed
that the fetus existed in a sterile environment, but while we now
know that we were incorrect in thinking that the human is GF while
in utero, it is still understood that colonization of the gut primarily
occurs during birth and the subsequent immediate postnatal period
(Funkhouser and Bordenstein, 2013). A variety of factors are known
to influence this early pattern of bacterial colonization, including
mode of delivery, (i.e. vaginal vs Caesarean), location of birth (i.e.
hospital vs homebirth), formula vs breastfeeding, and whether the
mother or infant undergoes any antibiotic treatment in early life
(Stark and Lee, 1982; Penders et al., 2006; Adlerberth and Wold,
2009; Dominguez-Bello et al., 2010; Fallani et al., 2010; Le Huerou-
Luron et al., 2010; Roger et al., 2010; Bezirtzoglou et al., 2011;
Hussey et al., 2011; Azad et al., 2013; Prince et al., 2014; Arboleya
et al., 2015; Mueller et al., 2015).
Following the immediate postnatal period, we also now have
more reliable information regarding the bacterial composition of
the infant gut. In comparison to the adult, the infant microbiota is
much more simple and unstable (Fouhy et al., 2012; Borre et al.,
2014). Over the course of the child’s lifetime we see changes in
the resident intestinal microbiota, with by and large less species
diversity than that of an adult (Ringel-Kulka et al., 2013). How-
ever, as the child enters into the adolescent period the outwardly
observable growth and change underway is mirrored inside the
intestine. In a study examining bacterial diversity across the life-
time, researchers examined 3 age cohorts; young children (prior
to 7 years), young adults and the elderly. In so doing, the investi-
gators were able to track microbial changes with increasing age,
corresponding to gradual decreases in the number of aerobic and
facultative anaerobic bacteria, and increases in anaerobic species
(Hopkins et al., 2002). A high-throughput analysis of distal gut
microbiota comparing that of adolescents and adults found that
while there was a significantly higher amount of Bifidobacterium
and Clostridium genera in the younger cohort, actual species num-
ber was similar in the two age groups (Agans et al., 2011). A more
recent study has compared the microbiota of pre-adolescent chil-
dren to that of adults and found that again, the younger cohort
had higher numbers of Bifidobacterium, while adults demonstrated
more Bacteroides (Hollister et al., 2015). In addition, the authors
note that they also observed differences in microbiota profiles from
a functional perspective, with the microbiota found in children
enriched in functions related to growth and development, while the
adult’s microbial communities demonstrated higher functionality
associated with inflammation and obesity (Hollister et al., 2015). It
should be noted that more studies are needed in order to examine
the development and change of intestinal microbiota over the lifes-
pan; those that have been done to date focus on the extremes of age
(i.e. composition of microbiota during infancy and in the elderly),
and instead we need more information that is reflective of bacterial
diversity over the normal, gradual transitions of maturation.
One of the more obvious changes associated with puberty
relates to sexually dimorphic development. After a relatively quies-
cent period in juvenility, the hypothalamic-pituitary-gonadal axis
reactivates in adolescence, and continues to be active throughout
adulthood (Marceau et al., 2015). This increased release of gonadal
hormones during adolescence exerts organizational and activa-
tional effects on the physical, behavioral, and emotional aspects
 K.-A. McVey Neufeld et al. / Neuroscience and Biobehavioral Reviews 70 (2016) 300–312
of development (Romeo, 2003). In particular, the brain under-
goes sexual differentiation during puberty and adolescence, with
ovarian and testicular hormones mediating the feminization and
masculinization of the brain, respectively (for review see Juraska
et al., 2013). Intriguingly, changes in gut microbiota in mice also
seem to follow a sexually divergent trajectory (Jasarevic et al.,
2016). Sex-related differences in the adult intestinal profiles of mice
are abolished when male mice undergo castration (Yurkovetskiy
et al., 2013). However, the mechanisms by which testosterone may
be affecting the commensal microbial community is still unclear.
Conversely, it appears that early-life microbial exposure itself can
influence gonadal hormone levels the risk of autoimmune dis-
ease (Markle et al., 2013). Female non-obese diabetic mice are
more susceptible to type 1 diabetes than males. However, colo-
nization of female GF non-obese diabetic mice with the microbiota
of males conferred protection against diabetes pathology through
a testosterone-dependent mechanism (Markle et al., 2013). Taken
together, these findings suggest that the microbiota and gonadal
hormones bidirectionally modulate each other. Given the resur-
gence of gonadal hormone signaling in adolescence, more research
is clearly needed to determine how these hormones impact the
microbiota and vice versa.
Admittedly, we are still far off from an exhaustive list of changes
that occur over the developing lifespan in the colonizing intestinal
microbiota, but it is still quite clear that the bacteria in the gut nat-
urally diversify throughout life and respond to physiological and
environmental cues varying from individual to individual. As men-
tioned previously, we know that the intestinal microbiota alter in
response to many of the environmental stressors known to par-
ticularly affect teens. Diet and sleep variations, exposure to drugs
of abuse and alcohol, stress and extended antibiotic usage all affect
the composition of the constituent microbiota. Given that teenagers
can be exposed to any combination of these stressors over the
adolescent period we are left questioning what role changes in
intestinal microbial status may have on the development of ado-
lescent psychiatric disturbances.
6. Adolescent mental health – what role could bacteria be
playing?
Many psychiatric disorders first become evident during the
adolescent years. Symptoms of anxiety, depression, psychosis,
substance abuse and eating disorders often manifest at this crit-
ical window of development (Paus et al., 2008; Sturman and
Moghaddam, 2011; Jaworska and MacQueen, 2015), with a large
scale National Comorbidity Study conducted in the United States
from 2001 to 2003 demonstrating that the peak age of onset for
psychiatric disease is 14 years (Kessler et al., 2005). We are now
beginning to understand that this is because the pathophysiology
underpinning these disorders is strongly linked to the types of brain
development that are occurring during this time. Even in healthy
adolescents without clinical psychiatric illness, we see changes to
behavior related to increased risk taking (Spear, 2000; Steinberg,
2008), sensation seeking (Giedd, 2009) impulsivity (Steinberg,
2010) and emotional instability (Spear, 2000). Alterations to these
neurodevelopmental pathways can occur due to the particular
types of environmental challenges that the adolescent typically
faces, and intriguingly the intestinal microbiota have likewise been
demonstrated to be affected by these challenges.
The links between the importance of a stable gut microbiota
and human health have been most clearly illustrated in disorders
primarily affecting peripheral systems such as irritable bowel syn-
drome (IBS) (Salonen et al., 2010; Tana et al., 2010; Jeffery et al.,
2012; Wu, 2012), obesity (Ley et al., 2006; Turnbaugh et al., 2009;
Tremaroli and Backhed, 2012), type 2 diabetes (Qin et al., 2012;
305
Vrieze et al., 2012; Karlsson et al., 2013), and cardiovascular disease
(Koren et al., 2011; Howitt and Garrett, 2012; Karlsson et al., 2012;
Tuohy et al., 2014; Hansen et al., 2015). Clinical studies linking psy-
chiatric disorders with intestinal microbiota have been slower in
coming, but a significant body of preclinical literature now exists.
Preclinical work has either focused on administering beneficial (i.e.
probiotic), or pathogenic bacteria to a host, or manipulating the nor-
mal commensal intestinal microbiota of a host (as in antibiotic or GF
studies). Studies infecting mice with subclinical doses of pathogenic
bacterial strains like Campylobacter jejuni and Citrobacter rodentium
have shown induction of anxiety-like behavior and learning deficits
in the absence of overt inflammatory responses (Lyte et al., 1998;
Lyte et al., 2006; Goehler et al., 2008; Gareau et al., 2011). Alter-
nately, administering probiotics, which are live organisms known
to confer health benefits on the recipient when ingested in ade-
quate amounts, have been demonstrated to have a beneficial effect
on brain function and behavior. Both Bifidobacteria and Lactobacil-
lus genera have demonstrated anxiolytic effects in both humans
and mice (Bravo et al., 2011; Messaoudi et al., 2011b), and the Lac-
tobacillus strains particularly have been shown to normalize HPA
axis reponsivity, reverse stress-induced colonic motility, as well as
confer cognitive benefits in mice (Savignac et al., 2015). Several
rodent studies have shown that bacterial strains can ameliorate
stress hyperresponsivity, cognitive dysfunction, visceral hypersen-
sitivity and anxiety-like behaviour in studies of chemically-induced
colitis, infection, and early life adverse events (Gareau et al., 2007;
O’Mahony et al., 2009; Bercik et al., 2010; Bercik et al., 2011b).
There are still remarkably few studies examining the
microbiota-gut-brain axis over the course of development. The
information that we do have can be gleaned from those studies
examining the impact of colonizing adolescent GF mice with nor-
mal commensal bacteria, as well as those looking at the result
of antibiotic treatment in otherwise healthy juvenile rodents. As
previously described, GF mice have an abnormal behavioural and
physiological profile and distinct alterations in HPA axis activity
(Luczynski et al., 2016). Specifically, GF mice show anxiolytic-like
behavior, decreased social preference and discrimination, and cog-
nitive deficits (Sudo et al., 2004; Diaz Heijtz et al., 2011; Neufeld
et al., 2011; Clarke et al., 2013; Desbonnet et al., 2014). In addi-
tion, they show lifelong stress hyperreactivity, and significantly
increased plasma adrenocorticotropin hormone (ACTH) and cor-
ticosterone after stress exposure (Sudo et al., 2004). Interestingly,
it has been demonstrated that if GF mice are colonized with com-
mensal bacteria by the adolescent period (in mice roughly equal
to 4 weeks of age), their stress hyperresponsivity can be reversed.
This is not true however, if the bacteria are introduced in adulthood.
This finding is highly provocative, because it indicates that there is a
critical window of development, up to and including adolescence,
whereby the gut bacteria can program central stress circuitry. A
critical component of all of the psychiatric illnesses that often first
appear in adolescence is dysregulation of stress circuitry. It is there-
fore compelling to note that these same circuits are responsive to
changes in gut microbial status at this window in development.
Antibiotic studies have proven a useful source of information
in unraveling the role of the microbiota-gut-brain axis in behavior.
Administering antibiotics to rodents in order to deplete the micro-
biota has resulted in a reduction in anxiety-like and exploratory
behavior that reverses after a two-week washout period (Bercik
et al., 2011a). In addition, feeding adult mice an antibiotic cock-
tail has recently been shown to result in cognitive dysfunction
as observed in the novel object recognition test, with associated
changes to mRNA gene expression of brain-derived neurotrophic
factor (BDNF) in both the hippocampus and prefrontal cortex
(Frohlich et al., 2016). A more recent study examining the effects
of antibiotics particularly during the adolescent period in mice
found significant changes to adult behavior, brain neurochemistry,
306 K.-A. McVey Neufeld et al. / Neuroscience and Biobehavioral Reviews 70 (2016) 300–312
and intestinal microbial content when compared to that of con-
trols (Desbonnet et al., 2015). At weaning (3 weeks of age) mice
were given an antibiotic cocktail in drinking water over a 4 week
period, and then behavior was assessed in adulthood. Antibiotic
treated mice showed anxiolytic-like behavior, altered cognitive
function in the novel object recognition test in that antibiotic
treated mice were unable to successfully discriminate between
a novel object and a familiar, and social behavior dysfunction
in the social transmission of food preference test. Treated mice
also showed significantly increased serum tryptophan and reduced
kynurenine levels. In the brain, antibiotic treatment resulted in
significantly reduced hippocampal BDNF mRNA, and reduced vaso-
pressin mRNA in the hypothalamus. Alterations were also observed
in brain monoamines and monoamine metabolites (Desbonnet
et al., 2015). This important study is the first to show that antibiotic
treatment during adolescence in mice can result in long term alter-
ations to brain function and gene expression, and clearly indicates
that more work in this area is warranted.
The emergence of maladaptive behavior is modeled in rodents
that have been exposed to early life adverse events, such as stress
or immune challenge. While it should be noted that many of the
studies in early immune challenge come from the autism litera-
ture, and that autism is a disease that is primarily diagnosed and
evident from early childhood onwards, this body of work pro-
vides some excellent examples of studies worth examining that
show altered behaviour in adolescent rodents following early life
immune challenge which have implications for other disorders
such as schizophrenia (Harvey and Boksa, 2012). Injecting preg-
nant mice with valproic acid (VPA) results in pups developing
autistic-like behaviour, and intriguingly, altered social behavior is
later observed in adolescent offspring accompanied by changes to
commensal intestinal microbiota profiles (de Theije et al., 2014).
Similar studies of maternal immune activation (MIA) injected preg-
nant dams with either lipopolysaccharide or propionic acid, and
also demonstrated significant changes to social behaviour in ado-
lescent offspring. Marked changes in enteric bacteria were also
observed with both treatments (Foley et al., 2014). In a recent
study highlighting the potential role of intestinal bacteria in these
MIA-induced behavioural alterations, pregnant dams were injected
with the viral mimic Poly (I:C), and then subsequent pups were
fed the human commensal Bacteroides fragilis. Fed pups later
showed attenuated changes to gut permeability, social behavior
and anxiety-like behavior (Hsiao et al., 2013). Interestingly, MIA
treatment alters the expression of proteins associated with neu-
ronal development and synaptic transmission in the pre-pubertal
rat offspring (Forrest et al., 2012). MIA offspring display reduced
hippocampal myelination and axonal diameter in the juvenile, pre-
weaning stage, but not in adulthood (Makinodan et al., 2008). MIA
treatment also alters dendritic morphology in the prefrontal cor-
tex and hippocampus of offspring rats throughout development
(Baharnoori et al., 2009). Similarly, prenatal VPA exposure induces
neural remodelling in limbic regions in adult rats, but not in the
peri-pubertal period (Bringas et al., 2013).
6.1. Stress-resilience and microbiota
In this review, we have discussed how the microbiota regulates
the brain development and function, however, the inverse is also
true, and findings indicate that stressful experiences can in and of
themselves alter the composition of the gut microbiota (O’Mahony
et al., 2009; Bailey et al., 2011; Dinan and Cryan, 2012; De Palma
et al., 2015; Golubeva et al., 2015; Jasarevic et al., 2015; Bharwani
et al., 2016). These stressors can impact microbial composition not
only in early life but also in adulthood. Prenatal stress in mice alters
the composition of the intestinal microbiota of the offspring along
with gastrointestinal function, respiration, and stress responsiv-
ity (Golubeva et al., 2015). One potential mechanism explaining
these results is that stress alters the mother’s vaginal microbiome,
which then results in a decreased transmission of certain bacterial
strains to the offspring (Jasarevic et al., 2015). Rodent models of
stress in early life and adulthood also demonstrate altered com-
position of the microbiota, immune dysfunction, and changes to
sociability behaviours and stress reactivity (O’Mahony et al., 2009;
De Palma et al., 2015). Importantly, the degree to which animals
are affected by stress can be predicted by changes in the microbial
composition (Bailey et al., 2011; Golubeva et al., 2015; Bharwani
et al., 2016). These findings suggest that the microbiota could be
driving maladaptive responses to stress. Indeed, the microbiota
is required for the stress-induced induction of certain anxiety-
like and depressive-like behaviours (De Palma et al., 2015). This
raises the intriguing possibility that the composition of the micro-
biota could be a susceptibility factor for responses to various
stressful insults, particularly at vulnerable neurodevelopmental
time windows such as adolescence. In addition, this highlights the
importance of identifying and examining the various factors that
could be affecting the microbial profile of the adolescent gut.
6.2. Diet, alcohol and exercise – effects on the microbiota
Nutrition, among other numerous environmental factors, has a
profound impact on both neurodevelopment and the gut micro-
biota (Innis, 2008; Skinner et al., 2010; Burokas et al., 2015).
Specifically, nutritional challenges during vulnerable developmen-
tal periods can have a detrimental impact on development and can
induce functional and structural effects that persist throughout the
lifespan (Barker et al., 1993; Seckl and Meaney, 2004; Skinner et al.,
2010). Adequate nutrition is thus essential during adolescence in
order to support neurodevelopment and the establishment of the
gut microbiota (Borre et al., 2014). Remarkable growth and devel-
opment occur over the course of adolescence, and as such, there
is a great demand for calories and nutrients. In addition, adoles-
cence is characterized by an increased independence leading to
the establishment of food choices, which can highly augment the
risk of dietary deficiencies (Findlay, 2004) and excesses (Berall,
2002). More than ever before, adolescents have accessibility to a
huge amount of unhealthy food options. Westernization has driven
large modifications to dietary patterns with an increase in intake
of fats, particularly saturated and trans-fats, and refined sugars
observed globally. This shift in diet has been linked to a loss of gut
microbial diversity including fiber-fermenting bacteria (De Filippo
et al., 2010), and to the flourishing of a wide range of chronic dis-
eases (Maslowski and Mackay, 2011). Diets high in fat and sugar
have been shown to markedly alter the gut microbial composition
by decreasing the Bacteroidetes/Firmicutes ratio and Lactobacillales
numbers, which are associated with brain dysfunction and behav-
ioral changes (Pyndt Jorgensen et al., 2014; Bruce-Keller et al., 2015;
Magnusson et al., 2015). Dietary fibre is known to be vital to shaping
of the gut microbiota (De Filippo et al., 2010; Schnorr et al., 2014),
and there has been a great reduction in fibre intake in the Western
diet. Interestingly, intake of a low-fibre diet over several genera-
tions has been demonstrated to result in a considerable loss of gut
microbial diversity, which could not be restored by a dietary fibre
re-intervention (Sonnenburg et al., 2016). A global dietary shift
towards more Western-style foods has also led to a major decrease
in intake of essential omega-3 polyunsaturated fatty acids (PUFAs)
and an increase in omega-6 PUFAs (Simopoulos, 2011). A defi-
ciency in dietary n-3 PUFAs across consecutive generations of rats
resulted in significant behavioural deficits during adolescence that
were linked to dopamine neurotransmission (Bondi et al., 2014),
which may be related to changes in gut microbiota composition.
Several studies in mice have demonstrated the beneficial impact of
omega-3 PUFAs on gut microbiota (Yu et al., 2014; Kaliannan et al.,
 K.-A. McVey Neufeld et al. / Neuroscience and Biobehavioral Reviews 70 (2016) 300–312
2015), while high doses of omega-6 resulted in dysregulation of the
gut microbiota (Ghosh et al., 2013). Furthermore, supplementing
omega-3 PUFAs has been shown to restore the long-lasting micro-
bial alterations induced by an early life stressor (Pusceddu et al.,
2015). Similarly, polyphenols, which are bioactive compounds nat-
urally found in plants, present a potential to modulate the gut
microbiota, thus showing prebiotic-like activity (Qiao et al., 2014;
Tzounis et al., 2011; Cardona et al., 2013; Kawabata et al., 2013).
Some polyphenols have been shown to increase the growth of
Akkermansia muciniphila and decrease the proportion of Firmicutes
to Bacteroidetes (Roopchand et al., 2015), as well as increase the
growth of both Lactobacillus and Bifidobacterium (Qiao et al., 2014),
all of which are considered to be beneficial changes to the host.
As previously mentioned, adolescence is the time period in
which substance abuse and eating disorders typically first mani-
fest (Paus et al., 2008; O’Connor and Cryan, 2014). Indeed, alcohol
is a substantial dietary disruptor of the gut microbiota, which is
particularly important during adolescence due to sometimes high
levels of consumption. Several studies have demonstrated the dis-
turbance of intestinal microbial homeostasis by the consumption of
alcohol in both rodents and humans (Mutlu et al., 2009; Mutlu et al.,
2012; Iyer and Vaishnava, 2016). Moreover, the microbiota profiles
of patients with the eating disorder anorexia nervosa show reduc-
tions in bacterial diversity (Kleiman et al., 2015). Interestingly, the
levels of anxiety, depression, and eating disorder psychopathol-
ogy are associated with bacterial diversity (Kleiman et al., 2015).
Taken all together, it is apparent that diet is a key modulator
of the gut microbial composition, which can consequently influ-
ence brain function (Seira Oriach et al., 2016). It is therefore of
great importance to meet nutritional requirements during adoles-
cence, as diet-induced changes in microbiota could contribute to
the development of psychiatric disorders later in life.
Recently, it has been shown that exercise is also an important
modulator of intestinal microbial status, particularly during the
adolescent period. An intriguing study has shown that exposing
juvenile rats to a running wheel for 6 weeks resulted in increases in
beneficial microbial species in the gut, with increased Bacteroidetes
species and decreased Firmicutes observed. More alterations were
observed in bacterial genera of adolescent rats first exposed to 6
weeks of exercise than adult rats exposed for the same period of
time. In addition, introducing exercise during the adolescent period
resulted in a persistent increase in lean body mass, which was not
observed in the adult rat runners (Mika et al., 2015). The results of
this study are provocative, and indicate that more work needs to
be done in examining the effects of lifestyle choices on commen-
sal bacteria and particularly those aimed at the adolescent period,
as the opportunity for targeted interventions directed at intestinal
microbiota could be substantial.
7. Future directions
Given our rapidly growing understanding of microbiota-gut-
brain communication it is unsurprising that this axis is an attractive
target for the development of potential therapeutics for psychiatric
disease. Currently there is high global interest in the possibility of
using both and pre- and probiotics for the often refractory psy-
chiatric illnesses. “Psychobiotics” is the term proposed to refer
to the therapeutic potential of manipulating the intestinal micro-
biota for the treatment of these diseases (Dinan et al., 2013). To
date, most of the clinical studies examining the potential bene-
fits of probiotics have focused on patients suffering from IBS. IBS
is a functional bowel disorder with symptoms of altered bowel
habits, visceral hypersensitivity and often co-morbid anxiety and
depressive symptoms. Several different strains of bacteria have
been demonstrated to have ameliorative effects in patients suf-
307
fering from IBS (Niedzielin et al., 2001; Bauserman and Michail,
2005; Whorwell et al., 2006; Andriulli et al., 2008; Enck et al., 2008;
Enck et al., 2009; Hun, 2009; Williams et al., 2009; Francavilla et al.,
2010; Guglielmetti et al., 2011; Clarke et al., 2012; Cui and Hu, 2012;
Dapoigny et al., 2012; Didari et al., 2015). However, other work has
shown that probiotics may also have beneficial effects on mood in
healthy volunteers (Benton et al., 2007; Messaoudi et al., 2011b;
Messaoudi et al., 2011a; Mohammadi et al., 2015; Steenbergen
et al., 2015). Clearly the use of pre- and or probiotics in the treat-
ment of mood and mood associated disorders is a promising field,
and given these reports of improved symptoms in both clinical and
healthy populations, further study into bacterial-based therapeu-
tic interventions for psychiatric disease is warranted. As treatment
options focused around commensal bacteria would be low risk and
with few, if any, side effects, this seems an ideal avenue of pur-
suit for interventions particularly geared towards adolescents. In
addition, the relative plasticity of the adolescent brain could make
it more receptive to neurogenic benefits conferred by potential
psychobiotic therapy.
8. Concluding remarks
The fact that the adolescence is a second, vital, critical window
of brain development is something of a double-edged sword. On
the one hand, the brain is arguably at its most vulnerable, second
only to the developing infant brain in terms of dramatic changes in
structuring, wiring and function that is occurring subject to external
influence from the individual’s environment. This shaping and re-
wiring is happening simultaneously with a time when the teenager
is entering the world as an independent young adult, often fac-
ing previously unknown risks and challenges. Alternately, this can
be viewed as one of the most exciting periods of brain develop-
ment, an opportunity to harness the already naturally occurring
developmental change underway. The adolescent window provides
an opening for the introduction of potential therapeutics, partic-
ularly those designed to address those psychiatric illnesses that
frequently first appear in young adulthood. Indeed, there are many
examples of preventative measures directed at adolescents, those
designed in order to aid youth in navigating the various challenges
they so frequently face. It would therefore be prudent to consider
the potential for therapeutics aimed at the intestinal microbiota
in the young adult. Individuals at high risk for the development
of psychiatric disorders could be identified, and the potentially
preventative and/or ameliorative options of pre- and probiotics
could be considered as a safe and possibly extremely effective
way of improving teenage resiliency. The microbiota-gut-brain axis
presents an attractive target for the introduction of therapies that
may prove highly beneficial to the mental health of the developing
teen. As such, we need to turn our attention to the possibility that
microbial-based interventions could potentially improve teenage
mental resiliency. Given that we know the teenage years are ones in
which the young adult often experiences difficult to control stress-
ors, accompanied by less than optimal diet and sleep patterns, pre-
and probiotic based therapies could provide an avenue by which
to bolster teenage resiliency. An increased understanding of ado-
lescent nervous system development in general, and the teenage
microbiota-gut-brain axis in particular will aid us in identifying
exciting new treatment approaches for psychiatric illness in the
young and may direct us to novel therapeutic channels for difficult
to treat mental illness throughout life.
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