Similarities between bacterial GAD and human GAD65: Implications in gut mediated autoimmune type 1 diabetes

Abstract

A variety of islet autoantibodies (AAbs) can predict and possibly dictate eventual type 1 diabetes (T1D) diagnosis. Upwards of 75% of those with T1D are positive for AAbs against glutamic acid decarboxylase (GAD65 or GAD), a producer of gamma-aminobutyric acid (GABA) in human pancreatic beta cells. Interestingly, bacterial populations within the human gut also express GAD and produce GABA. Evidence suggests that dysbiosis of the microbiome may correlate with T1D pathogenesis and physiology. Therefore, autoimmune linkages between the gut microbiome and islets susceptible to autoimmune attack need to be further elucidated. Utilizing in silico analyses, we show that 25 GAD sequences from human gut bacterial sources show sequence and motif similarities to human beta cell GAD65. Our motif analyses determined that most gut GAD sequences contain the pyroxical dependent decarboxylase (PDD) domain of human GAD65, which is important for its enzymatic activity. Additionally, we showed overlap with known human GAD65 T cell receptor epitopes, which may implicate the immune destruction of beta cells. Thus, we propose a physiological hypothesis in which changes in the gut microbiome in those with T1D result in a release of bacterial GAD, thus causing miseducation of the host immune system. Due to the notable similarities we found between human and bacterial GAD, these deputized immune cells may then target human beta cells leading to the development of T1D.

Type 1 diabetes mellitus prevention

“…Some bacteria show sequence similarities in the GAD of human gut bacteria and the GAD65 of the β-cell. Changes in the gut microbiome result in the release of bacterial GAD and the miseducation of antigen-presenting cells (APCs), which then recognise GAD65 pancreatic β cells [9][10][11].…”

Pathophysiology of Type 1 Diabetes and Gut Microbiota Role

“…A hypothesis is based on the evidence that some gut bacteria express GAD and produce gamma-aminobutyric acid. The GAD released from bacteria as a consequence of gut bacterial destruction (e.g., through viral- or antibiotic-mediated mechanisms) may act as an antigen to activate submucosal T-cells, causing miseducation of the host immune system and leading to the development of T1D [ 69 , 70 ].…”

Environmental Triggering of Type 1 Diabetes Autoimmunity

“…Based on a higher incidence of infections with Mycobacterium avium paratuberculosis in Type 1 diabetic patients in Sardinia, a study has shown a cross-reactivity with ZnT8 which could explain a high T1D incidence (179). Another study showed cross-reactivities between hGAD-65 and the gut bacterial GAD with an identified bacterial GAD peptide overlapping with a hGAD-65 specific TCR epitope (180). But more studies will be required to demonstrate the role of molecular mimicry.…”