The irritable bowel syndrome (IBS). This is particularly

The area
where Gut microbiota live in is heavily balanced. Any perturbation to this
environment, known as dysbiosis is
commonly linked to pathogenesis of gastrointestinal (GI) diseases, in
particular irritable bowel syndrome (IBS). 
This is particularly true as the gut microbiome is said to regulate
immunity.

There is now growing evidence that there exists a
bidirectional interaction between the central nervous system (CNS) and the
immune system through a number of direct and indirect pathways. Involved in
this are various systems such as the immune, endocrine (hypo-
thalamic–pituitary–adrenal (HPA) axis, autonomic and enteric nervous systems.

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All these listed systems go in to form what is known as the
microbiota-gut-brain (MGB) axis, a key feature in this essay.

An extensive number of
neuro/immune active substances that come from the intestinal lumen are able to
pass through the gut mucosa, be distributed in the blood, make their way
through the blood-brain barrier (BBB) and then go on to affect the CNS. The
amazing thing about gut microbiota is their ability to actually synthesise and
emulate a number of host signalling molecules that include catecholamines, his-
tamine, acetylcholine, ?-aminobutyric acid, 5-hydroxytryptamine (5-HT
serotonin) and melatonin. Many of these neuroactive molecules play an active
role in human behaviour especially serotonin, which is important in the
regulation of peristalsis or the modulation of sensation.

There are a number of key
communication pathways involved in relaying messages from the gut microbiota to
the brain. With this complex communication network in place between the gut and
the brain, and the movement of information across the gut-brain-axis, one can’t
help but wonder if these microbes also influence the brain’s chemistry. There
are numerous pathways and mechanisms by which microbes and the CNS interact
with each other and directly influence the behaviour of the host as a result.

This may be through the sympathetic and parasympathetic divisions of the
autosomal nervous system, and the neuroimmune and neuroendocrine systems that
are activate by stress and stress related disorders.  In the (Rieder et al.,
2017)following
discussion, we wish to discuss a number of these pathway including the vagus
nerve, fatty acids and tryptophan.

Vagus Nerve

The vagus nerve (sometimes
referred to as the tenth (X) cranial nerve) conveys afferent and efferent
sensory information to the CNS. It is also responsible for carrying information
to the brain due to the direct link from the gut to the brain. A number of
studies have shown that primary afferent pathways through the vagus nerve
facilitate communication between the gut microbes and the CNS (Goehler et al.,
2008).

These studies have recognised the induction of c-FOS in the vagal sensory
neuron and post vagotomies as possible neural mechanisms of the said
interactions. Expression of c-FOS and the upregulation of neuronal c-FOS mRNA have
been said to be indicative of recent neuronal activity. Surprisingly, animals
that have been infected with pathogenic Campylobacter
jejuni and Citrobacter rodentium
had increased levels of c-FOS in their vagal sensory ganglia and visceral
sensory nuclei in a few regions of the brain in comparison to animals which
hadn’t been infected suggesting a link between GI pathogenic challenges and
brain region implicated by anxiety (Goehler et al.,
2008).  Further studies in rats were carried out in
the area of vagotomy, where rats were infected with Salmonella typhimurium in order to mimic the conditions of a
natural bacterial infection. The role the vagal nerve pathway plays were
further highlighted in the transmission of gut immune signals to the CNS. On
the compromisation of the vegal pathway, the expression of c-FOS in those
neurons were attenuated (Goehler et al.,
2008)

 

Metabolites obtained from
digestion and microbial fermentation of dietary and nutritional component may
play a huge role on brain processes. By manipulating the make-up of the gut
microbiota there is a direct knock on effect on the availability and regulation
of fatty acids and tryptophan. Taking into consideration the important roles of
these metabolites in human health, they are also important mediators of the gut-brain
axis. (Rieder et al.,
2017)

 

Fatty Acids

The brain is saturated
with fatty acids that help monitor several processes including
neurotransmission, neuroinflammation and cell survival. Microbial derived short
chain fatty acids have powerful anti-inflammatory properties and they are the
main metabolites of the gut bacteria. To be exact species of Bifidobacterium, Roseburia, Eubacterium,
Lactobacillus and Faecalibacterium,
all of which are found in the gut microbiota produce hexonate, butyrate,
propionate and acetate. These listed fatt acids have been shown to influence
intestinal permeability and decreasing colonic pH. Short chain. Fatty acids
also have arole to play in the release of neuropeptides such as YY (PYY) and
glucagon like peptides (GLP-1) (Kuwahara, 2014). On the release of these
peptides, they can influence the regulation of energy homeostasis by the
activation of the primary afferent vegal pathways. Taking into consideration
the influence that microbial-derived short chain fatty acids found in the gut
have on energy metabolism, it signifies a potential mechanism by which the gut
microbiota influences human behaviour. (Rieder et al.,
2017)

Tryptophan

Being an essential amino
acid and a precursor to a number of active biological agents, tryptophan plays
a large role in the local environment of the gut microbiota. It is directly
linked to the production of serotonin (which will be later discussed in this
essay). The production of serotonin heavily relies on the availability of
tryptophan and the rate limiting enzyme tryptophan hydroxylase. I order to
evaluate the antidepressant properties of tryptophan, rats were fed the
probiotic bacteria Bifidobacteium
infantis. (B. infantis). From this study it was found that rats that were
fed with B. infantis increased levels
of tryptophan and showed a reduction in depressive like behaviours after a
forced swim test (Desbonnet et
al., 2008)

The Kynurenine Pathway is
the main physiological pathway for tryptophan metabolism. Its dysregulation has
been linked to identified in many disorders of the brain and also the GI tract.

Kynurenine is able to be further metabolised into two unique products. The
first is able to produce some neurotoxic metabolites such as quinolone acid.  The second is able to produce neuroprotective
kynurenine acid. An increase in the conversion rate of plasma a Kynurenine to
kynurenic acid is thought to be neuroprotective and cause a reduction in stress
induced depression (Agudelo et al.,
2015).  The results of the Desbonnet et al study show
that pathway of metabolism of plasma kynurenine is to kynureninic acid (Desbonnet et
al., 2008). This
is because as trptophan levels increased in the animals that had been treated
with B. infantis, Kynureic acid also
showed increase. The inference that could be made from such results is that
certain  probiotics reserve the ability
to influence tryptophan metabolism and weaken the extent of strees induced
depression by increasing the conversion of peripheral kynurenine to kynurenic
acid. (Rieder et al.,
2017)

Nuerotransporters and Neuropeptides

The fact that many
bacteria  such as Escherichia, Lactobacillus, Enterococcus and Truchuris have the ability to produce neurotransmitters and
neuropeptides has been proven many times (Barrett, 2014). These neurotransmitters
include serotonin and brain derived neurotrophic factor (BDNF). Chemical
messengers that can transmit signals from one neuron to another target neuron,
gland or muscle is known as a neurotransmitter. Neuropeptides are small
proteins that are released from the brain in order to activate different
receptors that allow the neurons to communicate with each other. Neuropeptides
are very different from neurotransmitters in many ways as neuropeptides seem to
be linked with specific behaviours such as the role of oxytocin in maternal
behaviour and pair bonding. Neurotransmitters and neuropeptides are both said
to be neuronal signalling messengers. Any perturbation to this balance can have
a significant effect on the brain and behaviour.

 

Serotonin is a key Neurotransmitter when it comes
to mood regulation. The GI tract has a pivotal role in the sensing, secretion
and signalling of serotonin. This makes serotonin an important molecule in the
Brain-gut-microbiota pathway. Most of the production of serotonin takes place
in the gut by enterochromaffin (EC) cells. In a study carried out with germ
free mice it was noted that there was a threefold increase in serotonin levels
when these mice were colonised by gut microbiota. A very key thing to note is
that decreased levels of serotonin precursor, tryptophan has been linked to
depression.

As previously stated most
of the 5-HT synthesised and released by humans is produced by a subset of
enteroendocine cells called enterochromaffinn cell found in the intestinal
mucosa.  The release of 5-HT from the EC
cells has been proven to mediate many of the GI functions such as peristalsis, one’s
perception of pain and vasodilation through activation of the 5-HT receptors on
intrinsic and extrinsic afferent nerve fibres. Serotonin-selective reuptake
transporter (SERT) which is mainly responsible for 5-HT uptake in the brain is
expressed by practically all epithelial cells of the intestinal mucosa (FIG). The serotonin transporter is a
member of a family of neurotransporters known as neurotransmitter sodium symporter
(NSS). As all the cells in the lining of the intestines seem to express SERT,
its main purpose is to act as a selective sponge to remove 5-HT from the interstitial
space after its release by the EC cells. By carrying out its purpose by
inactivating the 5-HT by the rapid reuptake into the epithelial cells of the
intestinal mucosa. The SERT acts as critical molecule in actions in the
intestines and the regulation of 5-HT availability locally.

 

Brain derived neutrophic factor (BDNF)

BDNF is a protein that supports
the survival of neurons and signals the growth and differentiation of new
synapses and neurons. It is normally expressed in the CNS. There is believed to
be a link between chronic depression associated with low levels of BDNF. A
number of treatments (such as antidepressants) have been able show a
significant increase in the levels of BDNF expressed in the brain. What is most  surprising about all this is that BDNF mRNA
and protein levels are linked to the gut-brain axis. Particularly, the
microbiota of the intestines have been observed to increase levels of
hippocampal BDNF in some pathogen free mice after they a been treated with faecal
transplant and antimicrobials (Bercik et al.,
2011).  Where the mice was infected with Truchuris muris there was a decrees in
the levels of hippocampal BDNF mRNA observed. Amazingly after treatment with B. longum the level of BDNF returned to
normal.

 

Stress anxiety and the
microbiota-gut-brain axis

Anxiety is conventionally
described as a psychological state of mind that is characterised by
apprehension or fear. It a listed among the most commonly experienced
psychiatric disorders with more that 350 million sufferers globally (Baxter et al.,
2013).

Mental health disorders such as these causes significant impairment to those
affected and millions annually in health care costs. The exact aetiology of
these disorders remains a mystery to us but a number of neurobiological
mechanisms have been suggested that vary from chemical imbalances in the brain
to stress, inflammation and illness. For example, a reduction in the key
neurotransmitters such as serotonin, norepinephrine and dopamine and
abnormalities in the neuroendocrine pathway. Pivotal biological responses concerned
with stress include the hypothalamic-pituitary-adrenal axis, autonomic nervous
system and also their intricate interactions with metabolism. There is now
evidence to support the idea of a bidirectional relationship between commercial
organisms that live in the gut and responsivity and the programming of the
stress system (Cryan & Dinan, 2012). This being said, the
gut microbiota may indeed play a significant role in the prevention and the
treatment of anxiety and depression by stress related autonomic and
neuroendocrine pathways.

 

 

Microbes and stress

Psychological stress is a
normal and integrated part of life adversely even the slightest change in
stress response has widespread psychobiological repercussions. Research in the
two fields of microbiology and neurobiology have shown natural barrier defences
like that provided by the commensal microbes can be altered by exposure to
psychological disorder. Chronic stress in adulthood has been demonstrated to
alter the make-up of the gut microbiota. In a study carried out by (Bailey et al.,
2011) mice
were exposed to a social disruption stressor. It was found that the microbiome
of mice exposed to the stressor differed to that of the stress free mice, with
significant decrease noted in the levels of Clostridium
and Bacteroides (Rieder et al.,
2017)

 

This however caused the
activation of the immune system signified by the increase in interleukin-6 and
C-C chemokine ligand 2 production. These levels of acute stress such as anxiety
increased the GI and BBB permeability by the activation of mast cells (MC’s).

These MC’s express high affinity receptors for corticotrophin-releasing hormone
(CRH).  The CRH is said to be directly involved with
Alzheimer’s disease and major depression.  A recent discovery about MC’s is their unique
ability to secret mitochondrial elements extracellularly, this include
DNA.  These elements are then
misunderstood by the body as being innate pathogens. This causes a rigorous
auto-inflammatory response, ultimately leading to inflammation and neuronal
damage and affecting the CNS.

In a subgroup of patients
suffering from depression, there is a reoccurring trait of low grade
inflammation. The source of this inflammation has yet to be discovered. An idea
is that a compromised intestinal barrier or what is referred to as leaky gut
might allow a microbiota driven proinflammatory state is widely accepted.

Normally, immune cells are discrete from gram negative bacteria in the gut.

This being said, a “leaky gut” will allow the translocation and activation of
inflammatory pathways performed by bacteria such as the enterobacteriaceae. It has been shown that in depression here is a
higher immunoglobulin (IgA and IgM) mediated responses against the
liposaccharide of certain gram-negative gut bacteria. It is also important to
note that depressed patients have significantly elevated TLR4 expression than
healthy controls which may be associated with bacterial translocation. After an
accidental outbreak of Escherichia coli O157:H7 into a town water supply, the long-term
health outcome were investigated and there was strong correlation found between
the outbreak and E. coli.. Again an
outbreak in Germany of shiga toxins producing E. coli O104mled to an increase in self-reported cases of
depression and anxiety after the first six months prior to infection. Till this
day, only two clinical studies have been carried out to investigate the
microbiota components of depressed patients. It was found that in the first
study there was a significant increase in the order bacteriodales and a drop in Lachnospiracea
in the group with depression. There was an increase in the genuses Oscillibactor and Alistipes species

 

Microbes and behaviour:

Aside from the role the
microbiota plays in physiology, its role on its host’s behaviour is now being
investigated. For example, gut microbiota has been investigated for eating
behaviours (Alcock et al.,
2014) Changes in the gut microbiota has been
linked with recoded changes in behaviour related to pain, mood and cognition (Borre et al.,
2014). The
extent of the gut microbiota was thoroughly investigated by Bercil et al where
they used germ free (GF) animals to examine changes in the gut microbial
communities in aiding neuropsychiatric disorders and IBD’s (Bercik et al.,
2011). Two
species of mice that were raised in GF conditions were colonised microbial
profiles from strains of their own or the and opposite strain.  It was recorded that the behavioural traits only
found in a particular stain was passed along with the microbiota. In support of
this study GF mice showed reduced levels of anxiety symptoms consistently in a
number of studies (Clarke et al.,
2013).These
various studies give us substantial evidence to believe the gut microbiota
plats a key role in behaviour.

Studies on animal models
have shown increased stress induced memory dysfunction and anxiety in connection
to alterations in pathogenic bacteria such as
C. rodentium, T. muris and C. jejuni (Goehler et al.,
2008). For
example, C57BL/6 mice infected with C.

rodentium showed no signs of anxiety like behaviour at the height of the
infection at 10 days and even after clearance at 30 days. Nevertheless, after
exposure to acute stress, damage in the non spatial memory was obvious after
following infection. The induction of anxiety like behaviour has also been
observed in C. jejuni in just only
eight hours post infection with the activation of multiple areas of the brain
associated with anxiety like behaviour including the amygdala (Gareau et al.,
2011). Even
though it appears that C. rodentium and C. jejunii effect anxiety like
behaviour differently, these discoveries suggest that infection cause the
bacteria to be pathogenic.  

ADHD is normally
classified as a neurodevelopmental disorder that has common characteristics in
its suffers such as impulsiveness, hyperactivity and lack of attention. Recent
studies have been able to show that children and adults with food allergies,
asthma and eczema have associated behavioural problems which include ADHD (Chang et al.,
2013). The
role that gut microbiota play in allergens is particularly noticeable. A study
carried out in which patients with ADHD were put on the Kaiser- Permanente diet using elimination of salicylates,
artificial food flavours or colours, and the preservative butylated
hydroxytoluene. It was found that while on this diet there was a reduction of
hyperactivity in the children with ADHD(Schab & Trinh, 2004).

 

 

Gut Microbiota and medicine

Psycobiotics is a fairly new branch of medicine
that involves ingesting live microorganisms that can produce health benefits in
patients suffering from mood disorders. It is not normally seen as the first
line treatment as it may prove to be difficult to alter a populations eating
habits. Two main species involved in the branch of medicine are the lactobacillus and bifidobacteria species.  Their
ability to alter the brain-gut- microbiota axis has been prove to have a beneficial
effect on cognition, mood and anxiety (Dinan et al.,
2013). A
study was conducted in which 124 healthy adult volunteers were given a mix of
certain psycobiotics containing Lactobacillus
helveticus and Bifidobacterium longum.

By the end of the study it was observed that the volunteers showed less signs
of depression and anxiety (Dinan & Cryan, 2013). More studies have been
carried out on animal models to show the positive effects of probiotics with
altered behavioural phenotypes. It was able to reduce the vagal-dependent
activation of ?-aminobutyric acid receptors in response to psychological stress
(Desbonnet et
al., 2008).

Additional studies have found that when Citrobacter
rodentium is orally administered to CF-1 Mice, anxious like behaviour is
seen to increase for a period of about 7 to 8 hours after the initial infection
through the activation of vagal pathways (Lyte et al.,
2006).

However, at the time of
this review there has been no published scientific study with the clinical use
of psycobiotics in clinically depressed patients. This limits the scientific
accuracy of this method of treatment, and even when such treatment is available
has been tested, there are a number of variables that would need to be assessed
such as the patients’ lifestyle and their surroundings.(Vuillermin et
al., 2017)

 

 

Probiotics

Probiotics are known as
living microorganisms that can provide health benefits when consumed (Milani et al.,
2017). The highlighted
coloration and tight relationship between the gut microbiota and a number of
health conditions has caused led to amplified interest in the use of probiotics
to have a positive effect on the gut microbiota. Recent studies have emphasised
the potential of probiotics as a method of treatment and prevention of
diseases.  There are two main genera used
to modulate the diversity and composition of the gut microbiota. They are the
lactic acid producing bacteria Lactobacillus
and Bifidobacterium (Sherwin et al.,
2016). It has
recently been discovered that these probiotics may also have a role in
depression like symptoms, stress and anxiety. A study was carried out where 55
adult participants were randomly allocated either a probiotic mixture that
contained Bifidobacterium longum R0175
and Lactobacillus helveticus R0052 and
the other given a placebo for a period of 30 days. The participants were
examined after this period and it was found that those who had been given the
probiotic mixture showed lowered scores on the global severity index of the Hopkins
symptoms (HSCL-90) checklist. They also showed improved symptoms of anxiety and
depression (Messaoudi et
al., 2011)

The effectiveness of Bifidobacterium longum subsp. Infantis 35624
(B. infantis) in treating gastrointestinal disorders among 275 non patients
who reported discomfort and bloating. was recently studied.

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