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doi: 10.1111/joim.12508
Introduction
The human body is home to several distinct
microbial ecosystems colonizing all mucosal linings of the body [13]. Most studies have focused
on the gut microbiota, which is a dynamic
ecosystem shaped by a number of factors such
as genetics, diet and environment [4]. The adult
gut microbiota is dominated by taxa belonging to
two phyla, Bacteroidetes and Firmicutes [5], but
the relative proportions of these phyla differ
between populations (Fig. 1). Despite harbouring
bacterial genera from just a few phyla, the gut
microbiota shows a tremendous diversity at
lower taxonomic levels, for example species and
strains [5], which renders an individuals microbiota unique. However, a core gut microbiota
encompassing 160 bacterial taxa has been iden-
2016 The Association for the Publication of the Journal of Internal Medicine
339
T. Arora & F. B
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HMP
Bacteroidetes
Firmicutes
Proteobacteria
Verrucomicrobia
Actinobacteria
Others
Others 0.3%
0.4%
Akkermansia 0.9%
Others 0.2%
Escherichia 0.8%
Sutterella 1.1%
Others 2.6%
Butyrivibrio 1.5%
Roseburia 1.5%
Dialister 2.3%
Faecalibacterium 3.5%
75.7%
20.5%
Ruminococcus 3.7%
Bacteroides 51.1%
Eubacterium 6.9%
Others 6.6%
Alisitpes 12.3%
Prevotella 5.7%
MetaHit
Bacteroides 21.8%
Alisitpes 8.6%
Others 0.5%
2.1%
Akkermansia 2.3%
Others 1.0%
Escherichia 1.0%
Sutterella 0.6%
45.8%
Prevotella 11.8%
Others 6.2%
Butyrivibrio 3.0%
46.8%
Others 3.6%
Roseburia 3.9%
Dialister 4.0%
Eubacterium 14.7%
Faecalibacterium 5.7%
Ruminococcus 6.0%
2016 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2016, 280; 339349
Fig. 1 Quantitative
comparison of faecal microbiota
in two healthy populations.
Relative taxonomic abundance
data from 139 healthy
individuals in the Human
Microbiome Project (HMP)
Consortium and 99 healthy
individuals in the
Metagenomics of human
intestinal tract (MetaHIT)
Consortium (25 patients with
inflammatory bowel disease
were excluded) representing
American and European
populations, respectively, were
extracted from http://
huttenhower.sph.harvard.edu/
metaphlan and analysed using
the metagenomic phylogenetic
analysis (MetaPhlAn) pipeline
[104]. The inner pie chart
indicates the proportions of
major phyla found in healthy
human gut. The outer pie chart
indicates the percentage of
major genera in the respective
phyla.
T. Arora & F. B
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Fiber
Protein/fat
Bacte roides
Pr evotella
a
in
is
a
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2016 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2016, 280; 339349
T. Arora & F. B
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a similar level of food intake compared to conventionally raised animals [5254]. The increased
resistance to obesity in GF mice may in part be
attributed to elevated levels of Angptl4 as discussed above [31]. Furthermore, phosphorylation
of AMP-activated kinase (AMPK) was increased in
GF mice [52]. However, it is still not clear whether
the increased phosphorylation of AMPK is a cause
of reduced adiposity or contributes to the lean
phenotype. Because the calorie-rich western diet
used in this study [52] is lacking in fermentable
fibre, the gut microbiota is also likely to contribute
to metabolic disease through additional pathways
other than harvesting nutrients from a polysaccharide-rich diet.
Obesity increases the risk of multifactorial diseases such as type 2 diabetes. Recently, we and
others found that type 2 diabetes in humans was
associated with a reduced abundance of butyrateproducing bacteria and an increased abundance of
Lactobacillus sp. [5658]. Moreover, computational
models based on the gut metagenome were able to
predict type 2 diabetes-associated phenotype in
patients with impaired glucose tolerance [57],
suggesting that the gut microbiome may constitute
a novel biomarker for prediction of type 2 diabetes.
Vancomycin treatment in patients with metabolic
syndrome reduced the abundance of Gram-positive bacteria, such as butyrate-producing bacteria;
this was associated with reduced insulin sensitivity, suggesting that the decreased levels of butyrate-producing bacteria observed in patients with
Bacteria and bacterial products have been associated with cardiovascular disease (CVD), and
atherosclerotic plaques contain bacterial DNA
and cells [64, 65]. Interestingly, we found that
several of the bacterial taxa observed in atherosclerotic plaques were also present in the oral cavity or
the gut of the same individuals [64], highlighting
the possibility that the microbial communities at
these sites may be a source of bacteria in the
plaque, which may contribute to plaque stability
and development of CVD. Metagenomic sequencing
of the stool microbiota from these subjects revealed
that the microbial ecology was altered in patients
with unstable plaques (e.g. patients with stroke),
associated with reduced levels of taxa belonging to
the genus Roseburia and increased capacity of the
microbiome to produce pro-inflammatory peptido 2016 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2016, 280; 339349
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glycans and reduced production of anti-inflammatory carotenes [66]. Thus, the gut microbiome of
patients with CVD may be producing more proinflammatory molecules.
A series of studies have identified a microbederived metabolite, trimethylamine (TMA), which
is efficiently converted to trimethylamine-N-oxide
(TMAO) by the liver, as a biomarker and potential
causative factor for CVD [17, 67, 68]. Plasma
levels of TMAO were increased in subjects with
cardiovascular events compared to controls [67],
and it was demonstrated that microbial metabolism of dietary choline and L-carnitine increased
the levels of TMA, which was converted to TMAO
[17, 68]. Individuals exposed to antibiotics were
unable to convert L-carnitine to TMA and subsequently to TMAO [17], demonstrating that the
microbiota is essential for production of these
metabolites and is able to adapt to the macronutrient composition in the diet. A causal relationship between these microbial metabolites and
CVD has been established by supplementation of
TMAO in mice deficient in Apoe, a common model
for studying atherosclerosis, which increased
atherosclerotic lesions. TMA lyases have been
identified [69] and accordingly drugs inhibiting
these bacterial enzymes are attractive for preventing CVD.
Microbial signalling affects host metabolism
The gut microbiota has a vast capacity to produce
molecules that can affect host metabolism. Some
of these metabolites are structural components
such as LPS, the major component of membranes
of Gram-negative bacteria, which is known to
increase in type 2 diabetes and activate the innate
immune system (Fig. 3) [70]. A direct link between
LPS and metabolic impairment was demonstrated
by administering LPS for 4 weeks to chow-fed mice
[38]. Further, it was demonstrated that this signalling requires the LPS receptor CD14 and that
microbial activation of the innate immune signalling cascade in adipocytes promotes secretion
of the chemokine CCL2 [37, 71], which subsequently promotes accumulation of macrophages in
adipose tissue. LPS levels increased in human
subjects with type 2 diabetes [72, 73] and was
associated with increased risk of developing diabetes [74]. Administration of LPS in humans
induced insulin resistance by triggering inflammatory reactions [75], whereas in mice it enhanced
levels of hepatic pro-inflammatory lipid mediators
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2016 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2016, 280; 339349
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Diet
Microbiota
Fiber
Structural
components
Bile acids
a) Butyrate, propionate
CA/
CDCA
c)
DCA/
LCA
b)
GPR43
GPR41
TGR5
d) LPS
tMCA
MCA
TLR4
TGR5
FXR
Energy
source
Ileum
HDAC
inhibition
Intestinal
gluconeogenesis
Metabolic
regulation
Proinflammatory
cytokines
FXR
GLP-1
release
Thermogenesis
Incretin effect
Appetite
Intestinal transit
Energy
expenditure
Steatosis
Macrophage
recruitment
and polarisation
Inflammation
Fig. 3 Microbial metabolites regulate metabolism in different tissues. Fermentation of dietary fibre by the gut microbiota
produces short-chain fatty acids (SCFAs) such as butyrate, which serves as an energy source and promotes histone
deacetylase (HDAC) inhibition in enterocytes. (a) Propionate and butyrate also stimulate intestinal gluconeogenesis
facilitating metabolic regulation. In an enteroendocrine cell, SCFAs through G-protein coupled receptor 41 and 43 (a) and
microbiota-derived secondary bile acid lithocholic acid (LCA) and deoxycholic acid (DCA) through bile acid receptor TGR5 (b)
promote glucagon like peptide-1 (GLP-1) release, which enhances incretin response, suppresses appetite and reduces
intestinal transit. (b) LCA and DCA promote thermogenesis in brown adipose tissue (BAT) which increases energy
expenditure. (c) The gut microbiota promotes deconjugation of taurobetamuricholic acid (tbMCA), a natural farnesoid X
receptor (FXR) antagonist, which alleviates intestinal and hepatic FXR repression thus reducing bile acid synthesis and
altering fatty acid (FA) metabolism. (d) Lipopolysaccharide (LPS) a pro-inflammatory molecule derived from Gram-negative
bacterial membranes promotes macrophage recruitment and polarization in white adipose tissue inducing inflammation
through Toll-like receptor 4 (TLR4).
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2016 The Association for the Publication of the Journal of Internal Medicine
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