How a Specific Gut Bacterium May Cause Type 1 Diabetes

Diabetes, the broad term for a handful of diseases that prevent the body from properly regulating blood sugar levels, was first documented over 3,500 years ago in ancient Egypt—yet experts still aren’t sure exactly how it develops, although scientists are almost certain that there’s no single trigger. Indeed, two primary forms of the condition are already known: types 1 and 2. Type 1 diabetes, which tends to have a more sudden onset, has proven particularly enigmatic, as people can develop the condition at different ages, and unlike type 2, it seems to be more closely linked to genetic and other predispositions than to diet and lifestyle.

Now, research published July 25 in PNAS may have revealed a key piece of the puzzle. The presence of the bacterium Parabacteroides distasonis in the gut microbiome causes type 1 diabetes in a mouse model and seems to predict the onset of the disease in humans. This is likely because the microbe produces a peptide similar enough to part of an insulin molecule that it can lead to the production of insulin-targeted antibodies, priming the immune system to launch an attack against insulin and the cells that produce it. Thus, the researchers have identified a microbial culprit for doctors to examine as they look for new ways to screen for and perhaps eventually prevent the disease.

It’s well established that the immune systems of people with type 1 diabetes attack insulin and the pancreatic cells that produce it. The team hypothesized that this autoimmune response may actually be an attempt to assail a foreign entity that’s structurally similar to insulin, which then goes awry. So they screened existing databases for sequences of peptides known to be produced by gut bacteria, keeping an eye out for structural similarities to insulin. After that screen identified over 50 candidates.

Researchers gradually narrowed the list based on the peptides’ degree of similarity to insulin and ability to activate insulin-attacking CD8+ T cells taken from a human patient with diabetes.

The team then moved to a mouse model, testing their short list of candidates by injecting mice with one of the peptides or with insulin and measuring their immune cells’ response. Out of all the possible peptides, only one, called hprt4-18 (which had already shown to be produced by P. distasonis), activated an immune response from CD8+ T cells in mice. The team then began another experiment in which they fed the bacterium to mice, seeding their gut microbiomes, in order to see how it affected disease progression. The specific mouse model used is fated to eventually develop type 1 diabetes,  but not as quickly as they did in this experiment. By the time they were 12 weeks old, mice colonized with P. distasonis showed clear signs of type 1 diabetes while controls, who were otherwise identical, did not. Scientists were able to accelerate the disease onset by just giving this vector.

Further investigation revealed that the newly diabetic mice had increased counts of CD8+ T cells and other immune cells implicated in type 1 diabetes such as dendritic cells and macrophages.

https://www.pnas.org/doi/abs/10.1073/pnas.2120028119