Previously, Altindis and his team made a surprising discovery and showed that viruses have insulin-like proteins. In the latest project, they focused on an insulin region, specifically a peptide, or a chain of amino acids—known as the B chain of insulin, or B:9-23—that is targeted by the immune cells in type 1 diabetes patients and identified mimics of this region in different microbes.The team hypothesized that because human insulin B:9-23 and microbialinsulin B:9-23 will be very similar, immune cells cannot distinguish the difference and an immune response to this bacterial B:9-23-like peptide will cross-react with the insulin and consequently will target and destroy the cells that produce insulin.
Based on the molecular mimicry hypothesis, the team identified 17 microbialpeptides very similar to insulin B:9-23. Testing them in immune cells obtained from type 1 diabetes patients, they identified one bacterial insulin B:9-23 mimic peptide in Parabacteriodes distasonis that can stimulate the immune cells specific to insulin. Using cellular and animal models of type 1 diabetes, Altindis and his colleagues showed that molecular mimicry might be triggering type 1 diabetes.
Colonization of the gut microbiome with Parabacteriodes distasonis increased type 1 diabetes rates by increasing the inflammation in different tissues, specifically in the pancreas, in mice used in type 1 diabetes T1D research, the team reported in the article "A Gut Microbial Peptide and Molecular Mimicry in the Pathogenesis of Type 1 Diabetes."
This bacterium is most likely present in the human gut, however, the study indicates that the timing of exposure is important for the development of type 1 diabetes. The team then re-analyzed published human gutmicrobiome data, obtained from the Broad Foundation’s DIABIMMUNE project, to show that children up to age three tend to develop type 1 diabetes if they are exposed to this peptide/bacterium in early life.
“Our findings analyzing published human type 1 diabetes microbiome dataobtained from 269 infants gut microbiome, sampled from ages 0 to threeyears, supports our hypothesis that being exposed to this bacterium, and more specifically to this insulin B:9-23-like bacterial peptide, in the first three years of life is a potential risk factor,” said Altindis.
Identifying the presence of the peptide is a significant step, said Altindis, who collaborated on the project with C. Ronald Kahn, MD, of the Joslin Diabetes Center, researchers at the University of Florida and the Benaroya Research Institute, and a BC team including post-doctoral researcher Khyati Girdhar, BC’s Flow Cytometry Lab Director Patrick Autissier, and undergraduate student researchers Claudia Brady and Amol Raisingani.
But there is much more work to be done, he added.
“While in this study we showed that the human immune cells that were specific to human insulin B:9-23 were reacting to the P. distasonis peptide and that P. distasonis can enhance type 1 diabetes development in the the mouse model, we have to prove that this enhancement is directly related to the peptide,” Altindis said.
To prove that, Girdhar is making a mutation in the bacterial genome by deleting the mimic peptide and will test its effects on the animal model, Altindis said. The team will also analyze another, more comprehensive type1 diabetes study, known as TEDDY.
“If these studies support our findings, this will support our initial molecular mimicry mechanism,” Altindis said. “There is more work to do, however this study and similar studies have the potential to guide us to develop new tools, including vaccines, antibiotics, or probiotics, for the prevention and treatment of type 1 diabetes.”
Ed Hayward | University Communications | September 2022
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