Gut Feeling: the Microbiome and the Immune System

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Aleksandar D. Kostic, Ph.D.,

The onset of type 1 diabetes is mysterious, but one thing is for sure: some environmental factor triggers the immune system attack on beta cells. This environmental trigger is a longstanding mystery that research at Joslin Diabetes Center is beginning to unravel. Aleksandar D. Kostic, Ph.D., is studying how the colonies of bacteria that line our digestive systems, also known as the microbiome, could start a chain reaction that leads to autoimmunity and type 1 diabetes.

There are key pieces of evidence to support Dr. Kostic’s idea that the microbiome is linked to the onset of type 1 diabetes. The first involves non-obese diabetic (NOD) mice. These mice are genetically similar to people who are prone to type 1 diabetes. Not every NOD mouse will get diabetes, just like not every person with high-risk genetics will develop the disease. But curiously, the rate of diabetes onset for these mice varies from lab to lab: ninety percent of the mice in one lab will contract diabetes whereas only sixty percent will in a lab on the other side of the country.

At first, researchers blamed differing genetics between mouse populations. “But then when people transfer the mice from one center to the other, the mice take on the same rate of incidence as the facility that they go to,” says Dr. Kostic. “Then it seemed obvious that it’s some kind of environmental effect.”

When groups of these mice from various centers around the country were studied in a germ-free isolator, they developed diabetes at an astounding rate. “They get it really early on, they get very much more…severe inflammation in the pancreas, and it happens much earlier,” he says. This seems to support the hygiene hypothesis, or the idea that children (or in this case, mice) who are raised in too-sterile environments have a higher likelihood of immune system problems down the line.

Researchers then transplanted microbiomes from mice with no genetic risk of developing diabetes into these germ-free NOD mice.

With the new microbiome, the NOD mice appeared to be protected from developing type 1 diabetes. “And at a pretty steep level of protection against disease,” he says. “There’s something about the bacteria in the gut that you can remove and add and change and this somehow changes the incidence of diabetes.”

For his postdoc research, conducted at the Broad Institute of MIT and Harvard, Dr. Kostic explored whether or not the same held true in humans. He collaborated with a group at the University of Helsinki in Finland. (Finland has the highest incidence of type 1 diabetes in the world). Dr. Kostic’s collaborators screened newborns in hospitals in the Helsinki area for genetic risk factors associated with type 1 diabetes. Babies in the highest risk group were enrolled in a study which involved collecting stool samples each month for the first three years of life. Of this group of 400 children, four developed early-onset type 1 diabetes before turning 3 years old.

“We looked at what happened in the microbiome in these four cases that was different from the children that didn’t develop disease,” he said. “And what we saw was that there was this big shift in the microbiome that happened about a year prior to clinical diagnosis of type 1 diabetes.”

The children who developed type 1 diabetes had a reduction in the number of different species of bacteria in their guts. More importantly, the dominant species called Ruminococcus gnavus in the new microbiomes were known to increase gut inflammation.

But what triggered that shift in the first place? It’s an ongoing question that Dr. Kostic started to explore as part of a group studying diabetes along the Finnish-Russian border. People on the Finnish side of the border have a sixfold higher incidence of type 1 diabetes than those on the Russian side. The two cultural groups are genetically similar, but their lifestyles are worlds apart.

“The Finnish tend to be more urban, live a more modern lifestyle whereas the Russian Karelians tend to be more rural and live a more traditional lifestyle, [meaning] that they live on farms with exposure to farm animals and soil and to the natural environment [and eat] generally less processed foods,” says Dr. Kostic.

These differences are reflected in their gut microbes. The microbiomes of the Russian children include a bacteria called Bifidobacterium known to help educate the immune system, whereas the Finnish have bacteria called Bacteroides that has been shown to suppress immune system action. These important differences could account for the disparity in diabetes diagnosis and could again be explained by the hygiene hypothesis.

“This sets into motion a much more hyper-responsive immune system that hasn’t been exposed to many of these environmental antigens before. So when they get exposed to something, they react much more severely,” says Dr. Kostic. “This goes back to the point where when you have that severe immune reaction in someone that’s genetically predisposed to type 1 diabetes then you have a higher likelihood of developing type 1 diabetes.”

Dr. Kostic plans to use these observations to guide his work in his new Joslin lab. He will transplant microbiomes isolated from people with type 1 diabetes into the mice, including the early microbiomes from the children in Finland who eventually developed diabetes.

“For an infant it’s pretty easy to see what your exposures are, how your gut gets colonized. It’s direct contact with the mother and whatever other environmental contact you have in your first year. [In many cases] there’s nothing else going into the gut except for breastmilk,” he says. “So at least in that way it’s fairly easy to just think about ways for us to dissect this question in the lab in the coming years.”

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