Researchers at Joslin Diabetes Center and Boston College have identified a species of human gut bacterium, Parabacteroides distasonis, which makes a protein containing a sequence of amino acids that mimics the insulin peptide targeted by the immune system in type 1 diabetes (T1D).
The team’s analysis revealed that the immune cells that target the insulin peptide in T1D cross-react with the similar sequence from the gut bacterial peptide, and that presence of the bacterium can accelerate the onset of diabetes in a mouse model of T1D. Further investigation also revealed a link between the presence of P. distasonis and the development of T1D in children at genetic risk of the disorder.
“Although genetics and family history contribute to the risk of developing type 1 diabetes, the incidence rate of type 1 diabetes in children is rising at rates exceeding what can be explained on a genetic basis alone,” said C. Ronald Kahn, MD, chief academic officer, Joslin Diabetes Center. “Our findings suggest that exposure to a peptide made by gut bacteria that resembles an insulin peptide could stimulate or enhance the autoimmune response that initiates type 1 diabetes.”
Kahn and colleagues reported their findings in PNAS, in a paper titled, “A gut microbial peptide and molecular mimicry in the pathogenesis of type 1 diabetes,” in which they concluded: “Taken together, our results suggest this mimic has the potential to trigger/modify T1D onset.”
In T1D, the body develops immune cells that target pancreatic beta cells, which play a critical role in the production and secretion of insulin. One of the earliest targets of this immune response is a specific sequence of amino acids, or peptides, within the insulin molecule. “One of the earliest markers of T1D is the development of islet autoantibodies (AABs),” the authors explained. These AABs target several autoantigens, including insulin, and insulin autoantibodies (IAAs) are usually the first to be detected. “One of the earliest aspects of this process is the development of autoantibodies and T cells directed at an epitope in the B-chain of insulin (insB:9–23).
What triggers this autoimmune response remains unknown. “… we hypothesized that exposure to a microbial peptide that resembles the insulin epitope, insB:9–23, could stimulate or modify the autoimmune response initiating T1D,” the authors suggested. However, they further noted, “… while molecular mimicry has long been postulated as a potential factor in autoimmune diseases, including T1D, progress in this area has been limited due to a lack of identification of microbial sequences that might trigger this response.” To investigate this further, Kahn and colleagues analyzed microbial databases and identified 47 microbial peptides matching the insB:9–23 insulin peptide target by 50% or more. The team then synthesized 17 of the most similar candidate peptides and tested them for their ability to activate insB:9–23-specific immune cells that occur in T1D.
Their experiments demonstrated that only one of the selected peptides—a peptide from the gut bacterium called P. distasonis—could activate both human and mouse immune cells specific to insB:9–23. “We identified a sequence in the human gut bacterium P. distasonis that mimics an important insulin epitope (insB:9–23),” the investigators stated. “Human and mouse immune cells specific to insB:9–23 cross-react with this bacterial mimic.”
The researchers went on to show that giving this bacterium to mice with a genetic risk for T1D (Nonobese diabetic, or NOD, mice) resulted in more severe inflammation in the insulin-producing islet cells of the pancreas, and was associated with earlier onset of diabetes. “P. distasonis can accelerate diabetes onset in a mouse model of T1D, inducing destructive immune cells and decreasing protective immune cells,” they stated. “…administration of P. distasonis bacteria by oral gavage accelerated T1D progression in NOD mice in vivo by stimulating innate immune cells and CD8+ T cells and decreasing regulatory T cells.”
A separate analysis of human gut microbiome data from a study of 269 infants, aged 0 to three years, who were genetically predisposed to T1D, also indicated that children who have this bacterium in their gut microbiome early in life have a much higher risk of developing T1D than those without it. “We found a significant association between the presence of this bacterial mimic and development of T1D in children,” the team noted. Their results, they suggested, “suggest that the presence of this peptide in the microbiome may trigger or potentiate the autoimmune response that leads to the development of T1D in genetically susceptible individuals.”
The authors concluded, “In summary, our data define a molecular mimicry mechanism in which a specific sequence in a normal commensal gut microbe can mimic a sequence in the insulin B-chain and trigger or modify the immune response involved in the development of T1D … These findings may provide a target for treatment and a window of opportunity to prevent or delay T1D development.”
Kahn added, “A plethora of human gut microbiome studies have demonstrated that the composition of gut microbiota in patients with autoimmune diseases, including multiple sclerosis, inflammatory bowel disease, and others, are significantly different from those in healthy controls. Our findings demonstrate a new link in which there is molecular mimicry between a peptide made by normal gut microbes and the autoimmune response in T1D. This suggests the potential to develop new tools, including vaccines, antibiotics, or probiotics, for the prevention and treatment of T1D and perhaps other autoimmune diseases.”
The authors further stated, “These data also have implications for other diseases with an autoimmune component … Our findings demonstrate a molecular mimicry link to gut antigens and autoimmune diseases with the potential to ultimately provide tools, including vaccines, antibiotics, or probiotics, for the prevention and treatment of autoimmune diseases.”
