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Gut instincts
low sample size and heterogenous methods
between studies. In humans there is currently
limited data on how the gut microbiota is
altered in diabetes and atherosclerosis.
Could you discuss your work with germfree animal models? What are some of the
benefits of this method compared to other
techniques?
© MARKUS MARCETIC
Could you begin by summarising the
objectives of your research and what gaps in
understanding it seeks to address?
Recent evidence has suggested that the large
amount of bacteria in the human gut, which
contains 150-fold more genes compared with
our own genome, may impact on our health.
My group has taken a translational approach
to investigate the role of the gut microbiota in
metabolic diseases such as obesity, diabetes,
and atherosclerosis.
In order to study whether the microbial
community or its functional capacity
(metagenome) is altered in these metabolic
diseases we assess the metagenomes of
well-phenotyped patients using nextgeneration sequencing. By rederiving
genetically engineered mice as germ-free we
are delineating the molecular mechanisms by
which the gut microbiota causes disease.
What evidence have you observed to date to
suggest a link between gut microbiota and
metabolic diseases?
Our initial findings that germ-free mice are
resistant to developing diet-induced obesity
have now been corroborated by several other
investigators around the world. Furthermore,
we noted that the gut microbiota was altered
in obese mice. Direct evidence that the
‘obesogenic’ microbiota transmit disease
has been demonstrated through microbiota
transplants into germ-free mice.
The evidence in humans has been more
controversial but several of the main groups
of bacteria appear to be altered in obesity.
One important limitation so far has been a
The major benefit of the germ-free mouse
model is that we can exactly control the
microbial composition in these mice as well
as test causality. For example we can test if
the microbiota from a patient contributes to
disease development, whereas the healthy
microbiota does not. Furthermore, we are
currently setting up simplified microbiota
which allows us to study the microbe-microbe
interactions as well as the host-microbe
interactions.
How easily translatable are the results from
your animal models to humans? Are there
any specific factors you must take into
account?
treatments. Another caveat that needs to be
overcome is to determine when treatment
would be successful, or if the gut microbiota
may act preventively or perhaps serve as a
diagnostic marker.
Does your research have any potential in
elucidating and treating any other diseases?
The gut microbiota has been implicated
in several inflammatory and autoimmune
diseases, for example, allergy, inflammatory
bowel disorder, Crohn’s and asthma. Similar
approaches to ours can be utilised to decipher
the gut microbiota as a therapeutic target.
ASSOCIATE PROFESSOR FREDRIK BÄCKHED
In a bid to advance understanding of the mechanisms behind metabolic diseases,
Associate Professor Fredrik Bäckhed discusses the progress of his research
project, which uses germ-free mice to study the role of microbiota in the gut
Have there been any particularly notable
successes from your research so far, which
you would like to highlight?
Our research has demonstrated that the gut
microbiota affects host metabolism through
several distinct but complimentary signalling
pathways. Delineating the relative impact of
these will reveal important biomarkers for
future human studies.
This research field is less than 10 years old and
upcoming experiments will demonstrate how
well we can translate our findings from mice to
humans. One important challenge to control
for is the resilience in an individual’s microbiota,
addressing questions such as whether we can
alter an existing microbiota in adults.
What difficulties do you foresee in targeting
gut microbiota to regulate a person’s
metabolism?
I think that one of the most important factors
to overcome is that the gut microbiota is quite
resilient to manipulations. It will be challenging
to test whether it is sufficient to add missing
strains to the microbiota of patients or whether
we need to develop strategies to reduce the
original microbiota.
What progress still needs to be made
before your research can be developed
into treatments for patients suffering from
metabolic disorders?
As this is a new field of research, there is still
much work to be undertaken. However, the
concept of probiotic may work and if it turns
out that metabolic diseases can be corrected by
the addition of specific probiotics, this should
be relatively rapid. However, due to the large
intra-individual variability in gut microbiota it
is likely that we will have to design personalised
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ASSOCIATE PROFESSOR FREDRIK BÄCKHED
Unravelling the human gut
With obesity now reaching epidemic proportions, the ‘Microbial Regulation of the Metabolic Syndrome’ project
is discovering how microbial communities in the gut might play a part in this and other metabolic diseases
METABOLIC SYNDROME IS
prevalent
worldwide and obesity and its associated diseases
are at the heart of this phenomenon. Obesity has
increased dramatically during recent decades in
both developed and developing countries, and
consequently, it is now considered to be one
of the most serious public health problems of
the 21st Century. Although genetic factors can
determine the propensity of an individual to
become obese, the recent increase in obesity
probably reflects environmental and lifestyle
changes where dietary change is a major
contributor. Altered dietary intake not only
affects our energy balance but also has a major
impact upon gut microbial composition, and
this can promote obesity and increase the risk of
developing metabolic diseases. Research in this
BACTEROIDES THATAIOTAOMICRON
BACTERIUM IN A MOUSE GUT
fermentation of dietary polysaccharides that our
own enzymatic repertoire is not able to degrade.
However, the gut microbiota is also a source of
proinflammatory molecules that are essential for
attracting immune cells to the gut.
PREVIOUS RESEARCH
Many research consortia worldwide have
embarked on defining and cataloguing the
normal human gut microbiota and have revealed
that they contain at least 150-fold more genes
than we have in our own genome, suggesting that
less than 1 per cent of the genes in the human
body are encoded by human DNA. Accordingly,
there is a need to increase the understanding of
this second dominating genome.
Until recently, understanding of the gut
microbiota was limited. However, advances in
non-culture based analysis have revolutionised
the identification and classification of new
species. The gut microbiota is composed of
around 200 prevalent bacterial species and up
to 1,000 less common species, and is dominated
by bacteria belonging to three major groups:
Firmicutes, Bacteroidetes and Actinobacteria.
Several factors such as diet, genetic background
and immune system status affect the
composition of the microbiota.
THE LINK TO METABOLIC DISEASES
field is still in its early stages, and the ‘Microbial
Regulation of the Metabolic Syndrome’ project,
led by Associate Professor Fredrik Bäckhed, is at
the forefront. The project has been uncovering the
ways in which gut microbiota could affect obesity
and obesity-associated diseases, and the group’s
research is adding to the accumulating evidence
that there are direct relationships between diet,
gut microbiota and metabolic disease.
Bäckhed’s project group and other researchers
are now beginning to delineate how the gut
microbiota contributes to metabolic diseases
by developing genetically engineered germ-
THE GUT MICROBIOTA
The human gut is home to a vast amount of
bacteria – the microbiota – that have co-evolved
with us and established a finely tuned symbiosis.
The gut microbiota functions at the intersection
between host genotype and diet to modulate
host physiology and metabolism. The metabolic
activities performed by these bacteria resemble
that of an organ. The majority of bacteria
live in the colon where they are essential for
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INTERNATIONAL INNOVATION
A MOUSE INTESTINAL VILLI
WALLENBERG LABORATORY GROUP
© GUNNEL ÖSTERGREN-LUNDÉN
free animal models to study the role of the gut
microbiota in disease progression. Germ-free mice
were found to be leaner than conventionally raised
counterparts and moreover, they did not develop
diet induced obesity. Colonisation of germ-free
mice with a normal microbiota increased the
amount of body fat by about 50 per cent and
reduced insulin sensitivity. Jeffrey Gordon’s group
used shotgun metagenomic analysis of the gut
microbiome – the collection of genes encoded
by the gut microbiota – in obese and lean mice
and revealed an enrichment of genes involved in
energy harvest in the obese mice. Bäckhed’s future
studies hope to reveal how well these findings can
be translated from mice to humans.
For now, the emerging picture implies there
are several distinct microbially regulated
mechanisms which contribute to metabolic
disease: “Our research has demonstrated that the
gut microbiota affects host metabolism through
several distinct but complimentary signalling
pathways,” Bäckhed explains. “Delineating the
INTELLIGENCE
MICROBIAL REGULATION OF THE
METABOLIC SYNDROME
Changing the gut microbiota towards a healthy
composition can improve human health and prevent
disease development
relative impact of these will reveal important
biomarkers for future human studies.”
THE GNOTOBIOTIC FACILITY
The project’s most recent findings have identified
microbial DNA originating from the mouth
and the gut in human atherosclerotic plaques.
Evidence suggests that bacteria directly promote
development of atherosclerosis and supports
the hypothesis that the gut microbiota may be
an appropriate therapeutic target for treating
metabolic diseases.
VITAL PARTNERSHIPS
Bäckhed’s research is based on a number of
interdisciplinary partnerships, including that with
his mentor and long-time collaborator Jeffrey
Gordon (Washington University, St Louis) who
was recently awarded an honorary doctorate at
the University of Gothenberg. He is working with
clinicians Göran Bergström, Björn Fagerberg and
Malin Werling at Sahlgrenska University Hospital
in Gothenburg to collect well-characterised
samples from defined patient cohorts. Ruth
Ley of Cornell University and Rob Knight of the
University of Colorado have been instrumental
in setting up analyses of microbial ecology.
Wolfram Ruf (Scripps Institute, La Jolla) has been
an important collaborator on understanding
the mechanisms by which the gut microbiota
modulates postnatal angiogenesis in the gut. Jens
Nielsen of Chalmers University in Gothenburg
has provided systems biology and analysis of
metagenomes. Matej Oresic of VTT Technical
Research Centre of Finland has been a long-term
collaborator on metabolomics and lipidomics
to determine the impact of the gut microbiota
on the host metabolome. And in Belgium,
Patrice Cani and Nathalie Delzenne of the
THE GNOTOBIOTIC FACILITY
Catholic University of Louvain in Brussels have
offered their expertise on understanding dietary
manipulations and metabolic inflammation and
the enteroendocrine system.
TREATING METABOLIC DISEASE
Bäckhed believes that changing diet and exercise
is the best way to improve an individual’s
metabolic status: “However, this is easier in
theory than in practice and requires significant
involvement from dieticians,” he points out.
“Currently, the only therapy that causes
prolonged weight loss is bariatric surgery, which
can result in some adverse effects such as nausea
and psychological issues that impact on the
patient’s quality of life. Of course, there are also
risks associated with surgery. Accordingly, novel
methods are required to improve metabolic
health in the population.”
A large proportion of Bäckhed’s future research
will be directed towards understanding the
interactions between specific bacteria in the
human gut and the host on a molecular level,
and investigating the impact of this signalling in
humans. The project group is also continuing to
develop a platform for metabolic phenotyping
of germ-free mice, which will be essential for
understanding how the gut microbiota regulates
host metabolism and physiology.
Understanding the signature of a ‘healthy gut’ and
changing the gut microbiota towards a healthy
composition can improve human health and
prevent disease development. However, much
work is still required to define the composition of
a normal gut microbiota and the means by which
it can be altered into a more health-promoting
state and thereby prevent disease.
OBJECTIVES
This research aims to understand the
intricate host-microbial cross-talk in the
human gut using a translational approach
of well-phenotyped patients and advanced
gnotobiotic mouse models focusing on
microbial regulation of host metabolism.
The team will especially examine how
the gut microbiota contributes to obesity
and associated metabolic diseases such as
diabetes and atherosclerosis.
KEY COLLABORATORS
Ruth Ley, Cornell University, Ithaca, U.S. •
Rob Knight, UC Boulder, Colorado, U.S. • Jens
Nielsen, Chalmers, Gothenburg, Sweden •
Matej Oresic, VTT, Finland • Patrice Cani;
Nathalie Delzenne, Catholic University of
Louvain, Brussels, Belgium • Björn Fagerberg,
MD; Göran Bergström, MD; Malin Werling,
MD, Sahlgrenska University Hospital,
Gothenburg, Sweden • Jeffrey Gordon,
Washington University, St Louis, U.S. • Wolfram
Ruf, Scripps Institute, La Jolla, U.S. • Professor
Gunnar Hansson, University of Gothenburg
FUNDING
The project is funded by the Swedish
Research Council, Heart Lung Foundation,
and Diabetes Foundation as well as by EU
Seventh Framework Programmes TORNADO
and ETHERPATHS
CONTACT
Associate Professor Fredrik Bäckhed
Wallenberg Laboratory
Bruna stråket 16
Sahlgrenska University hospital
SE 413 45 Göteborg
Sweden
T +46 31 342 7833
F +46 31 823 762
E [email protected]
FREDRIK BÄCKHED received a PhD from
Karolinska Institutet, Sweden in 2002
and performed his postdoctoral training
at Washington University, St Louis where
he identified the gut microbiota as an
environmental factor that regulates adiposity
and obesity. He was recruited to University of
Gothenburg and Center for Cardiovascular and
Metabolic Research in 2006. Dr Bäckhed has
received several prestigious awards; he was
named as ‘one of 101 super talents’ (number
12) in Sweden by Veckans Affärer 2010, and has
been elected to the Young Academy of Sweden
hosted by the Royal Academy of Sciences (2011).
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