Early life infections raise the risk of beta cell autoimmunity

A new paper in Diabetologia does not support the hypothesis that exposure to viral infection in the first year of life may trigger beta cell autoimmunity and type 1 diabetes. Instead, the study finds that it is bacterial infections that increase this risk, possibly through an effect on the gut microbiome. Dr Susan Aldridge reports.

The incidence of type 1 diabetes has been on the increase in many countries around the world. And, although we now have immunotherapy with teplizumab to delay onset by a few years, it’s not likely to be available to all for some time – if ever. So primary prevention is crucial. The problem is that the cause – or causes – of type 1 diabetes remain unknown.

Genetic predisposition is significant, but lifestyle and environmental factors also play a part. For instance, there is a marked difference in incidence of type 1 diabetes between the Russian and Finnish parts of the Karelia region, even though the populations share a similar genetic background. Also, migrants tend to show a type 1 diabetes incidence that is similar to that in their new country. The influence of lifestyle and environment is encouraging, as these factors can be modified, with the potential to reduce the incidence of the condition.

There are many environmental factors that might contribute to type 1 diabetes and there is evidence suggesting that exposure to infections in early life might be one of them. Studies have pointed to enterovirus infections, suggesting they may trigger the autoimmune process that leads to type 1 diabetes or accelerate the disease process once it is underway. These infections might also attack the pancreas and, indeed, signs of persistent enterovirus infection have been detected in the newly diagnosed. As well as enteroviruses, upper respiratory viruses have also been implicated as a risk factor for type 1 diabetes. Bacterial infections could also be involved, possibly by affecting the gut microbiota.

So far, however, we don’t have a clear picture of the role of infection in triggering type 1 diabetes. Therefore, Johnny Ludvigsson of Linköping University, Sweden, and colleagues have carried out a study of infections occurring in the first year of life and their link to the subsequent development of type 1 diabetes.

Early life infection and type 1 diabetes

The researchers studied children in the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study. This was an international double-blind, multicentre trial,  looking at whether weaning to a hydrolysed infant formula compared with a cow’s milk formula had any impact on the incidence of type 1 diabetes. Of the 2159 participants in TRIGR, 2059 were autoantibody negative and free of diabetes at the end of their first year, and had information on infections during that year. So these children entered the study.

Autoantibody tests were carried out at regular intervals and infections reported by parents were also recorded. These were classified as: upper respiratory, gastrointestinal, urinary tract, middle ear, pneumonia and other. And depending on antibiotic use and other clinical information, the infections were further classified as bacterial or viral. Of the participants, 41.7% developed at least one type of diabetes-related antibody, 11.7% developed multiple antibodies and 6.6% developed type 1 diabetes. When it came to infections, 48.0% had one to three infections, 18.8% four to six infections and 6.5% had seven or more infections during the first year of life. The researchers then had to match these two sets of data to explore the relationship between number of infections and the development of antibodies or type 1 diabetes.   

They found that children who developed at least one diabetes-related antibody had more infections during the first year of their life than those who did not have any infections. Narrowing this down to the type of infection, those with at least one, or with multiple antibodies, and those who went on to develop clinical diabetes were more likely to have had an unspecified bacterial infection.  Finally, timing – children who had had their first viral infections between the ages of six and 12 months were less likely to have multiple antibodies or to go on to type 1 diabetes than those who had had no infections.

Focus on bacterial infections

So, exposure to bacterial infections in the first year of life seems to be a marker for later development of both diabetes-related autoantibodies and type 1 diabetes. The researchers think that the bacteria may affect immune balance, while antibiotic treatment could upset the gut microbiome, which could also influence immunity in a way that promotes type 1. One previous study on a nationwide birth cohort showed that antibiotic treatment during the first two years of life did not increase the risk of type 1 diabetes. However, another nationwide study found the opposite. Bacterial infections could also cause damage to the pancreas.

This new study also does not support the hypothesis that it is viral infections during the first year of life that trigger the autoimmune process underlying the development of type 1 diabetes. In fact, the finding that infants who had their first viral infection after the age of six months were less likely to develop diabetes-related antibodies or diabetes supports the hygiene hypothesis –  which argues that exposure to viruses is protective, helping to develop the immune system.

As this study was exploratory, the researchers caution that it needs confirmation by other studies. To this end, it would be worthwhile including questions about exposure to bacterial and viral infections in early life when taking a history on diagnosis of type 1 diabetes.

To read this paper, go to: Kordonouri O, Cuthbertson D, Belteky M, Aschemeier-Fuchs B, White NH, Cummings E, Knip M, Ludvigsson J. Infections in the first year of life and development of beta cell autoimmunity and clinical type 1 diabetes in high-risk individuals: the TRIGR cohort. Diabetologia 9 September 2022.

https://pubmed.ncbi.nlm.nih.gov/36083343/

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.