Dr Aleksandar Kostic Explains the Relationship Between the Gut Microbiome and T1D

There is some kind of a strong signature we are getting at both in human and mouse studies, said Aleksandar Kostic, PhD, an assistant professor of microbiology at Harvard Medical School. Kostic's research on microbiome antigens as a vaccination strategy in type 1 diabetes was presented at the American Diabetes Association's 81st Scientific Sessions.

Transcript:

Can you introduce yourself and describe the work you do?

I'm Aleksandar Kostic, an assistant professor of microbiology at Harvard Medical School. My lab is based at Joslin Diabetes Center, where we have an active interest in the role of the microbiome in diabetes, both immune interactions and metabolic interactions.

How has the gut microbiome come to be considered a component that drives inflammatory processes leading to type 1 diabetes (T1D)?

There's many different sources of data and they come from many different places. I think, to me, what is correlated data but still, I think, very strong data, is the rapid increase in incidence of T1D around the world in recent decades, an event that has been happening at the same time as we are experiencing a drastic drop in overall diversity of our microbiome. This is correlated with with a more industrialized lifestyle, which means a change in diet, a change in amount of activity or exercise, and what is considered to be general improvements in things like sanitation, for example, and use of antibiotics, better cleanliness, generally, around us, which has had a positive impact in terms of infectious diseases. It's always hard to say this in the middle of a pandemic, but we have, in the grand scheme of things, made a lot of progress in infectious disease compared to where we were 100 years ago because of all these developments. At the same time, the incidence of not just T1D, but other autoimmune diseases and other immune mediated diseases like allergies are really increasing rapidly. So it is possible that there is some some kind of a connection here.

Another thing to note on a correlative epidemiological standpoint, is geography. If you look at where T1D has its highest incidence, geographically, it's correlated with with gross domestic product (GDP) of countries. It's high in North America and Europe and in Japan, or Australia, for example. It's very low in South America and Africa, and in poorer regions of Asia. Which again, correlates with a difference in lifestyle, and this access to sanitation, and this idea that maybe those microbes that people in a more non-industrial lifestyle have access to, could somehow be protective against diabetes.

I have been involved in several large consortia projects headed out of Helsinki, the DIABIMMUNE Consortium, where they did really amazing work collecting many different kinds of samples from children at high risk genetically for developing T1D, including blood samples, and a lot of different dietary information. But really importantly, also stool samples when they collect these from the children from when they're born until they're 3 years old. Then, it compares children living in Helsinki, which happens to be one of the highest rates of T1D in the world, to other parts of Europe, namely Russian Karelia, just across the border, which, genetically people there are quite similar. But the incidence is more than 6 times lower in Russian Karelia. It turns out the microbiome is in fact very different in these kids in the first year of life in the Russian Karelians, where there's a lower incidence.

Counterintuitively, you see a more inflammatory microbiome early on in life, which we think is important to train the immune system. These kinds of exposures to many different kinds of microbes, including those that cause inflammation is an important part of immune education so that later on in life, when you're bombarded with a very strong case of the flu or some other pathogen, it doesn't send your immune system haywire. Maybe it's a little bit more tolerant to those kinds of kinds of triggers. So, that's the human data.

On the mouse side, there have been some great studies. One thing that we know, we can we can actually raise mice completely devoid of any microbes in germ free isolators. We know that their incidence of diabetes is much higher than in controls, with with a normal mouse microbiota, the onset is faster. What's really cool, there have been several studies now showing that you can do fecal microbiota transplants from mice and transfer incidence of T1D in this way. This is all in non-obese diabetic (NOD) mice. For example, the incidence of diabetes in male NODs is much lower than females. You can transfer the stool from male mice into germ-free female mice and have their incidence of diabetes be as low as male mice. So there's something here, right? The mechanistic understanding at this point is really not evolved yet. But there is some kind of a strong signature that we're getting at both in human studies and in mouse studies of an important role that the microbiome is playing in T1D incidence.