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For body physiology to function properly, interplay between
organ systems is essential. Dysfunction in one organ or organ system can lead
to abnormal bodily functions, and subsequent pathology. Abnormal functioning in an organ system can have a knock-on
effect in another organ system, and lead to further dysbiosis. The
brain-gut-microbiota axis is one such example of systems in balance. It is a
well-established bidirectional communication network between the central
nervous system, the gastrointestinal tract, and the gut microbiota1.

The gut microbiota is a collection of billions of micro-organisms that colonise
our gastrointestinal tract. While the relationship between the CNS and
gastrointestinal tract is relatively well established in scientific literature,
the role of the gut microbiota in regulating brain and gut behaviour is now
becoming an area of interest. Recent research shows the number of gut microbiota
match the number of cells in our body, if not slightly outnumber them2,
and contain as much as 150 times as many genes as in our human genome2.

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It is logical, therefore, to assume it is a significant mediator on both the
central nervous system, and the gastrointestinal tract

 

There
is a wealth of information describing many direct and indirect pathways through
which the gut microbiota influences both the central nervous system and the
gastrointestinal tract. Studies3 show that the gut microbiota is
essential for normal gut motility, and barrier permeability. The immune system,
through the release of pro-inflammatory cytokines, can alter the gut
microbiota. The hypothalamic-pituitary-adrenal axis and cortisol secretion also
influence the gut microbiota composition4. Cortisol can change gut
permeability, and alter the absorption of nutrients and short-chain fatty acids5.

The gut microbiota, through the anaerobic metabolism of dietary fibre, release
short chain fatty acids (butyrate, proprionate, and acetate), which are an
important energy source for humans6.

 

Another
mechanism of action through which the gut microbiota influence the central
nervous system is through neurotransmitter modulation, particularly via
regulation of tryptophan metabolism.

1.1  Tryptophan

 

Tryptophan
is an essential amino acid sourced in the diet. In the host, it exists in two
circulating forms; a free form and an albumin-bound form. Tryptophan can be
metabolised down two pathways; about 10% of circulating tryptophan takes part
in serotonin synthesis7, while most of it is metabolised to
kynurenine. This kynurenine pathway of tryptophan metabolism is mediated by the
enzymes tryptophan 2,3-diogygenase (TDO) and indoleamine 2,3-dioxygenase (IDO).

These two enzymes make up the first and rate limiting step of kynurenine
synthesis, and are stress and immune mediated, respectively. Under pro-inflammatory
and stress conditions, IDO and TDO activity is upregulated by cytokines and
cortisol. This increases the metabolism of tryptophan down the kynurenine
pathway.

 

This increase
in kynurenine synthesis has potentially negative down-stream effects in two
ways; firstly, it decreases the amount of tryptophan available for serotonin
synthesis. Secondly, it increases kynurenine metabolites- quinolinic acid, which
has neurotoxic effects at increased levels, and kynurenic acid, which, although
it has neuroprotective effects against quinolinic acid toxicity8, can induce cognitive impairment when
abnormally elevated9.

 

Research
has been carried out previously to understand the microbial regulation of
tryptophan. Studies have established that the gut microbiota is essential for
normal brain development and behaviour, and affects tryptophan synthesis. For
example, Clarke et al10 have shown that male germ free mice have
increased plasma tryptophan concentrations compared to their conventionally
colonised controls. It has also been shown in the same study that plasma kynurenine:
tryptophan ratios (used as a marker for IDO and TDO activity) were decreased in
both male and female germ-free cohorts compared to conventionally colonised
controls.

 

Korecka
et al11 looked at the mechanisms behind the regulation of tryptophan
availability and metabolism. They measured the levels of expression of several
hepatic genes involved in tryptophan metabolism, and compared them to the
expression of the same genes in conventionally colonised mice. They found
reduced levels of IDO in the livers
of germ-free mice as compared to conventionally colonised controls. They also
found reduced levels of AhR and AhRR, two genes upon which the
downstream metabolites of kynurenine act. However, they neglected to assess TDO
activity. TDO is the key hepatic enzyme involved in tryptophan metabolism, and
may be one of the mechanisms through which the gut microbiota influence
tryptophan.

1.2  Butyrate

 

Butyrate
is a short chain fatty acid produced by anaerobic metabolism of dairy products
and fibre by the gut nicrobiota. It is partly absorbed in the intestine,
travels via the enterohepatic circulation to the liver, and is processed here,
where it may affect metabolic processes in hepatocytes, and subsequently
regulate host physiology12. For example, butyrate stimulates
serotonin secretion from enterochromaffin cells in the gut, thus stimulating
gut motility13.

 

While
not directly exerting an effect on the brain, butyrate influences CNS
functioning indirectly, for example via the immune system or the enteric or
vagal nervous system14.

Butyrate
has also been shown to exert significant effects on CNS functioning when
administered at high levels, namely increasing neuronal plasticity and
improving long term memory function14.

 

Korecka
et al showed that butyrate could marginally induce the expression of AhR and AhRR in germ free mice11. Therefore, we decided to also
supplement our mice with butyrate, to determine the influence it may have on the
genes selected for this study. We also supplemented conventionally colonised
mice with butyrate, to observe the influence it has on basal gene expression
levels. 

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