Objective
Our primary objective is to identify microbes that prevent autoimmune diabetes in humans. Our secondary objective is to understand how these diabetes protective microbes educate the immune system to prevent autoimmune diabetes.
Background Rationale
Some people's genetics puts them at higher or lower risk for developing autoimmune diabetes. The most important gene for determining this risk is called the HLA or human leukocyte antigen. Decades ago, researchers discovered that people with certain versions of the HLA gene almost never developed autoimmune diabetes even if they had other important risk factors such as a relative with autoimmune diabetes. Although we have known about these protective genes for a long time, we have not understood how they work to prevent autoimmune diabetes. To better understand this remarkable genetic protection from autoimmune diabetes, I studied a mouse model of autoimmune diabetes. Similar to humans, a specific version of the HLA (called the MHC in mice) prevented the development of autoimmune diabetes. My research demonstrated that the MHC gene prevented autoimmune diabetes by helping the natural microbes that live within us (called our intestinal or gut microbiome) develop diabetes protective-microbes. In essence, protective genes work to promote the development of microbes that educate the immune system to prevent autoimmune diabetes. This education of the immune system occurs at very young age around the time the mice (and we think babies) transition from milk to solid food. We have developed an novel approach to identify diabetes-preventative microbes by using the natural antibodies that people make against their own intestinal microbes that educated their immune system. So far, we found a microbe that we think has high-potential to educate the immune system and prevent autoimmune diabetes. Next steps are to validate this microbe in humans and identify additional microbes that may all work together to prevent diabetes.
Description of Project
Some people's genetics puts them at higher or lower risk for developing autoimmune diabetes. The most important gene for determining this risk is called the HLA or human leukocyte antigen. Decades ago, researchers discovered that people with certain versions of the HLA gene almost never developed autoimmune diabetes even if they had other important risk factors such as a relative with autoimmune diabetes. Although we have known about these protective genes for a long time, we have not understood how they work to prevent autoimmune diabetes. To better understand this remarkable genetic protection from autoimmune diabetes, I studied a mouse model of autoimmune diabetes. Similar to humans, a specific version of the HLA (called the MHC in mice) prevents the development of autoimmune diabetes. My research demonstrated that the MHC gene prevents autoimmune diabetes by helping the natural microbes that live within us (called our intestinal or gut microbiome) develop health-promoting microbial communities in the gut. In essence, protective genes work to promote the development of microbes that educate the immune system to prevent autoimmune diabetes. This education of the immune system occurs at very young age around the time that mice (and we think babies) transition from milk to solid food.
At this point, the important next step is to identify in diabetes-protective microbes in humans. We think that humans with HLA genes that prevent autoimmune diabetes will be enriched in diabetes-preventative microbes. There are thousands of microbes that live in our intestines which makes it very difficult to identify the microbe or microbes that prevent autoimmune diabetes. We have developed a novel approach to identify diabetes-preventative microbes by using the natural antibodies that people make against their own intestinal microbes that educated their immune system. Using this approach, we have begun to identify diabetes-protective microbes in mice. So far, we have identified one very promising microbe. This microbe has recently been associated with protection from autoimmune diabetes in people. We will then use what we learn in the mice to help target our search for diabetes-protective microbes in humans. We have partnered with an ongoing study of healthy human babies to obtain the necessary intestinal microbes and natural antibodies to help us find diabetes-preventative microbes. We will also study patients at high risk for developing autoimmune diabetes. Our long-term goal is be able to give young people, whose genes put them at high risk for autoimmune diabetes, diabetes-protective probiotics to help educate their developing immune system and prevent autoimmune diabetes.
Anticipated Outcome
We anticipate that this proposed study will identify microbes from human children that prevent autoimmune diabetes.
Relevance to T1D
There are currently no effective approaches to prevent type 1 diabetes. Our research goal is to identify microbes that prevent type 1 diabetes in mice and humans. We anticipate that our proposed study will identify microbes from human children that prevent type 1 diabetes. Once we identify diabetes-preventative microbes and we can begin to test whether they can be given to "at risk" people to lower their risk of developing type 1 diabetes.