Broad Institute. US: In one of the largest longitudinal studies of the microbiome to date, researchers from the Broad Institute of MIT and Harvard, Massachusetts General Hospital (MGH), and the DIABIMMUNE
Study Group have identified a connection between changes in gut
microbiota and the onset of type 1 diabetes (T1D).
The study, which
followed infants who were genetically predisposed to the condition,
found that onset for those who developed the disease was preceded by a
drop in microbial diversity – including a disproportional decrease in
the number of species known to promote health in the gut. These
findings, published by Cell, Host & Microbe, could help pave the way for microbial-based diagnostic and therapeutic options for those with T1D.
The human microbiome, which consists of the trillions of microorganisms
(bacteria, viruses, and other assorted “bugs”) that reside in our
bodies, has become an area of growing interest to the medical community
as researchers have begun to probe the role it plays in human health and
disease. While most bugs in our microbiome are harmless, and even
beneficial, changes in the microbiome (and in the interactions microbial
species share with their human hosts) have been linked to various
disease states, including diabetes and Inflammatory Bowel Disease (IBD).
To explore the possible connection between changes in the microbiome and type 1 diabetes, a team led by Ramnik Xavier,
an Institute Member of the Broad and Chief of Gastroenterology at MGH,
followed 33 infants (out of a much larger cohort of Finnish and Estonian
children) who were genetically predisposed to T1D. From birth to age 3,
the team regularly analyzed the subjects’ stool samples, collecting
data on the composition of their gut microbiome.
In the handful that developed T1D during this period, the team observed
a 25% drop in community diversity (in other words, in the number of
distinct species present in the microbiome) one year prior to the onset
of the disease. They also noted that this population shift included a
decrease in bacteria known to help regulate health in the gut, along
with an increase in potentially harmful bacteria that are known to
promote inflammation. The findings are further evidence of a previously
identified link between inflammation of the gut and type 1 diabetes.
“We know from previous human studies that changes in gut bacterial
composition correlate with the early development of type 1 diabetes, and
that the interactions between bacterial networks may be a contributing
factor in why some people at risk for the disease develop type 1
diabetes and others don’t,” said Jessica Dunne, Director of Discovery
Research at JDRF, which
funded the study. “This is the first study to show how specific changes
in the microbiome are affecting the progression to symptomatic T1D.”
Previous studies have shown that transferring microbiota from mice that
were predisposed to autoimmune diabetes (the mouse equivalent of T1D)
to mice that were not predisposed increased the prevalence of autoimmune
diabetes in mice that were otherwise unlikely to develop the disease.
Studies in humans have also shown an association between T1D and the
bacterial composition of the gut. However, those studies were
retrospective, meaning they were conducted after the patients developed
the disease, making causality difficult to prove.
“This study is unique because we have taken a cohort of children at
high risk of developing type 1 diabetes and then followed what changes
in the microbiome tip the balance toward progression to the disease,”
Xavier said.
Aleksandar Kostic, a postdoctoral fellow in Xavier’s lab and first
author of the study, agreed, calling the study “a compelling piece of
evidence pointing toward a direct role of the microbiome in type 1
diabetes.”
Since the study also followed infants who did not ultimately develop
type 1 diabetes, the researchers were also able to gain insights into
the normal development of the microbiome during infancy. They found
that, while the species of bacteria present in the gut microbiome vary
greatly between individuals, the composition of the microbiome is
generally stable within the individual over time.
Moreover, using metabolomic analysis (looking at the metabolites – the
tiny molecules produced during metabolism – in subject stool samples),
the researchers were also able to see that, while bacterial species
varied between individuals, the biological functions served by the
various species in the microbiome remained consistent over time, and
from person to person.
“Whether the bacterial community is very small, as it is in early
infancy, or if it’s larger as it is later in life, the community is
always serving the same major functions regardless of its composition.
No matter which species are present, they encode the same major
metabolic pathways, indicating that they’re doing the same jobs,” Kostic
said.
By revealing patterns in the development of the microbiome in healthy
individuals, and in those progressing toward T1D onset, the findings may
ultimately have diagnostic or therapeutic implications. In terms of
diagnostics, understanding how the microbiome shifts prior to the onset
of disease could ultimately help clinicians spot early microbial
features of T1D.
As for therapeutics, Xavier, who is also the Kurt Isselbacher Chair in Medicine at Harvard Medical School and Co-Director of the Center for Microbiome Informatics and Therapeutics at MIT,
says that knowing which species are absent and which are flourishing in
the gastrointestinal tract of children with T1D may help make it
possible to slow progression of the disease after onset by revealing
ways to manipulate the microbiome and, in turn, microbiome-induced
immunoregulation.
The next step, he says, is to broaden the sample pool to determine what
factors in the environment and in the microbiome might be making Finns –
who are at exceptionally high risk of T1D – more predisposed to the
disease than other populations. That includes revisiting the hygiene
hypothesis, which holds that a lack of childhood exposure to microbiota
and other potentially infectious agents may hinder the development of
the immune system and increase susceptibility to immunological
disorders.
The researchers are also examining the metagenomic data gathered in the
study to determine what biological pathways the microbiota are acting
upon – or what metabolites they may be producing – that could be
contributing to disease.
The study was funded by JDRF and supported by the European Union
Seventh Framework Programme and The Academy of Finland Centre of
Excellence in Molecular Systems Immunology and Physiology Research.
Other researchers who worked on the study include: Dirk Gevers, Heli
Siljander, Tommi Vatanen, Tuulia Hyötyläinen, Anu-Maaria Hämäläinen,
Aleksandr Peet, Vallo Tillmann, Päivi Pöhö, Ismo Mattila, Harri
Lähdesmäki, Eric A. Franzosa, Outi Vaarala, Marcus de Goffau, Hermie
Harmsen, Jorma Ilonen, Suvi M. Virtanen, Clary Clish, Matej Orešič,
Curtis Huttenhower, and the DIABIMMUNE Study Group under the leadership
of Mikael Knip.
About the Broad Institute of MIT and Harvard
The Eli and Edythe L. Broad Institute of MIT and Harvard was launched
in 2004 to empower this generation of creative scientists to transform
medicine. The Broad Institute seeks to describe all the molecular
components of life and their connections; discover the molecular basis
of major human diseases; develop effective new approaches to diagnostics
and therapeutics; and disseminate discoveries, tools, methods, and data
openly to the entire scientific community.
Founded by MIT, Harvard, and its affiliated hospitals, and the
visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad
Institute includes faculty, professional staff, and students from
throughout the MIT and Harvard biomedical research communities and
beyond, with collaborations spanning over a hundred private and public
institutions in more than 40 countries worldwide. For further
information about the Broad Institute, go to http://www.broadinstitute.org.
About JDRF
JDRF is the leading global organization focused on type 1 diabetes
(T1D) research. JDRF’s goal is to progressively remove the impact of T1D
from people’s lives until we achieve a world without T1D. JDRF
collaborates with a wide spectrum of partners and is the only
organization with the scientific resources, regulatory influence and a
working plan to bring life-changing therapies from the lab to the
community. As the largest charitable supporter of T1D research, JDRF is
currently sponsoring more than $450 million in charitable research in 17
countries. For more information, please visit www.jdrf.org
Papers cited:
Kostic, A. et al. The dynamics of the human infant gut microbiome in development and in progression towards type 1 diabetes. Cell, Host & Microbe. Online: February 5, 2015. DOI: 10.1016/j.chom.2015.01.001