Some of the workhorses that keep the immune system in check are tiny proteins on the surface of cells encoded by a set of guardian genes - human leukocyte antigen (HLA) in humans and major histocompatibility complexes (MHC) in mice.

Scientists have long known that certain common variants of the HLA/MHC genes protect against a range of autoimmune diseases, notably type 1 diabetes. Yet how these genes and the tiny cell proteins they regulate yield their immune-modulating effects has remained shrouded in mystery. Now, a study in mice led by scientists at Harvard Medical School reveals that at least one of these genes has a protective influence that is powerfully shaped by the trillions of intestinal bacteria collectively known as the gut microbiota.

The team’s experiments, published in the Proceedings of the National Academy of Sciences journal, show that despite harboring the powerful guardian gene, mice developed severe inflammation of the pancreas - a precursor to type 1 diabetes - after receiving antibiotics shortly after birth or if raised in a sterile environment.

The new findings demonstrate that gut bacteria are potent catalysts of autoimmunity and pancreatic cell function and that perturbations in the gut microbiota can precipitate diabetes. The results also open up avenues for immune-modulating therapies targeted at maintaining the delicate bacterial balance of the gut microbiota.

“We believe that our results not only offer a clue into a longstanding mystery but also raise the possibility that substances or environmental influences that alter the intestinal balance can modulate the effects of a powerfully protective gene and shape disease risk,” said Diane Mathis, who led the study together with Christophe Benoist, both professors in the Department of Microbiology and Immunobiology at Harvard Medical School.

The researchers caution that there are important physiological differences between mice and humans and emphasize that further studies are needed to elucidate precisely how gut bacteria affect gene activity and the risk for an autoimmune attack on the pancreas.

However, the scientists say their results highlight the role of the gut in proper immune function and point to the existence of a critical window in the proper development of the gut microbiome - a time during which the intestines get populated with a variety of bacteria.

“Our findings need to be borne out in further experiments,” Mathis said. “However, our results powerfully illustrate the notion that early antibiotic exposure can modulate disease risk and that avoiding or at least minimizing antibiotic treatment in infants and pregnant women during critical periods of development may be a good idea.”