The
metabolic
syndrome
is
known
to
have
a
direct
and
indirect
impact
on
endogenous
metabolism.
Additionally,
there
is
emerging
evidence
of
an
obesity-­‐associated
microbiome
with
the
potential
to
influence
caloric
extraction
from
the
diet
and
host
energy
metabolism.
However,
the
nature
of
the
shift
in
relative
contributions
of
bacterial
phyla
in
obesity,
and
the
question
of
whether
the
observed
shift
in
microbiome
is
more
associated
with
a
high-­‐fat
diet
than
genetically
induced
obesity
per
se,
are
still
yet
to
be
fully
elucidated.
This
thesis
seeks
to
explore
the
relationship
between
obesity
progression
and
the
co-­‐evolution
of
the
intestinal
microbiota,
via
profiling
of
host
fluid
and
tissue
metabolites,
and
faecal
bacteria.
The
obese
Zucker
rat
is
characterised
predominantly
by
obesity,
insulin
resistance
and
dyslipidaemia,
and
serves
as
an
animal
model
of
metabolic
syndrome.
The
effect
of
mixed-­‐
strain
housing
of
obese
(fa/fa)
and
lean,
(+/+)
and
(fa/+),
Zucker
rats
on
the
evolution
and
development
of
the
microbiome
and
metabolic
phenotype
of
the
animals
over
the
course
of
ten
weeks
was
investigated
via
1H
NMR
spectroscopy
of
biofluids,
faeces
and
tissue
extracts,
and
metagenomic
profiling
of
the
intestinal
microbiota
via
pyrosequencing
of
faecal
samples.
The
collected
data
sets
were
evaluated
and
interrogated
using
a
combination
of
multivariate
and
univariate
statistical
analyses
to
gain
a
comprehensive
understanding
of
how
age,
genotype
and
cage
environment
affect
endogenous
metabolism
and
metabolic
cross-­‐talk
between
the
host
and
intestinal
microbiota.
The
nature
of
the
interaction
between
host
and
microbiome
remains
poorly
understood,
particularly
with
respect
to
the
development
of
obesity
and
metabolic
syndrome.
Here
for
the
first
time
I
have
adopted
a
complex
systems
biology
approach
using
multivariate
statistical
methods
(principal
components
analysis
(PCA)
and
orthogonal
projections
to
latent
structures
discriminant
analysis
(OPLS-­‐DA),
for
example)
to
identify
correlations
between
host
metabolism
and
faecal
microbial
composition
during
the
development
of
obesity.
Urinary
and
faecal
metabolite
changes
were
assessed
over
a
period
of
ten
weeks,
with
end
point
tissue
and
plasma
composition
assessed
at
14
weeks
of
age.
Urinary
metabolic
differences
were
apparent
at
week
five
and
trajectory
plots
illustrated
further
divergence
with
age
between
the
obese
and
lean
strains.
The
two
lean
strains
were
found
to
be
comparable
metabolically,
with
both
strains
exhibiting
a
similar
urinary
metabolite
trajectory
over
the
ten-­‐week
sampling
period.
The
analysis
of
faecal
extracts
demonstrated
clear
age-­‐related
variation
across
the
ten-­‐week
period,
however,
only
subtle
variation
relating
to
genotype
and
cage-­‐environment
were
observed.
Bacterial
profiling
showed
clear
age-­‐related
variation
in
the
relative
abundance
of
certain
phyla
and
bacterial
families
dominated
by
an
age-­‐related
three-­‐fold
increase
in
Bacteroidetes,
with
a
concomitant
decrease
in
Firmicutes.
Differences
relating
to
genotype
were
not
evident
at
either
the
phylum
or
family
level,
whereas
cage-­‐environment-­‐based
clustering
of
samples
was
clearly
apparent,
with
the
most
marked
differences
at
weeks
five
and
seven.
With
evidence
of
differences
in
urinary
metabolites
of
host-­‐microbiome
co-­‐metabolic
origin
found
between
the
obese
and
lean
animals,
and
no
perceptible
difference
in
the
intestinal
bacteria
of
the
two
phenotypes
based
on
compositional
profiling,
these
results
suggest
that
the
contribution
of
the
microbiota
to
host
metabolism
is
not
straightforward
but
merits
further
investigation.