Exploring the Triple Interaction between the Host Genome, the Epigenome, and the Gut Microbiome in Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) is an auto-immune disorder characterized by a complex interaction between the host immune system and various environmental factors in genetically susceptible individuals. Genome-wide association studies (GWAS) identified different T1D risk and protection alleles, however, little is known about the environmental factors that can be linked to these alleles. Recent evidence indicated that, among those environmental factors, dysbiosis (imbalance) in the gut microbiota may play a role in the pathogenesis of T1D, affecting the integrity of the gut and leading to systemic inflammation and auto-destruction of the pancreatic β cells. Several studies have identified changes in the gut microbiome composition in humans and animal models comparing T1D subjects with controls. Those changes were characterized by a higher abundance of Bacteroides and a lower abundance of the butyrate-producing bacteria such as Clostridium clusters IV and XIVa. The mechanisms by which the dysbiotic bacteria and/or their metabolites interact with the genome and/or the epigenome of the host leading to destructive autoimmunity is still not clear. As T1D is a multifactorial disease, understanding the interaction between different environmental factors such as the gut microbiome, the genetic and the epigenetic determinants that are linked with the early appearance of autoantibodies can expand our knowledge about the disease pathogenesis. This review aims to provide insights into the interaction between the gut microbiome, susceptibility genes, epigenetic factors, and the immune system in the pathogenesis of T1D.

Keywords: HLA; NOD mice; immuno-regulation; intestinal permeability; microbial dysbiosis; short-chain fatty acid; single nucleotide polymorphism; virome.

Figure 1

Interaction between host genetic, the gut microbiome in individuals with T1D. T1D is well known to be associated with microbial dysbiosis, a leaky gut, and intestinal inflammation. Changes in the gut microbial composition can enhance different pathological mechanisms in which each microbiome shows a different role, affecting the expression of the pancreatic exocrine enzymes such as α-amylase2 (AMY2A and AMY2B) genes as well as the thiamine metabolism genes known to be involved in T1D. The figure was created using BioRender.com and Science slides software.

Figure 2

Comparison between the opposite effects of probiotics and early-life use of antibiotics in NOD mice. (A) T1D protective effects of probiotic bacteria in NOD mice: Lactobacillus johnsonii N6 enhances the expression of INFγ and indolesamine 2,3-dioxygenase enzyme (IDO) which in turn increase the production of claudin-1 tight junction protein that maintains the integrity of the gut epithelium. Lactobacillus casei has probiotic properties, lowering the number of the splenic CD8⁺ cytotoxic T cells and promoting the expression of the anti-inflammatory cytokines (IL2, IL10) leading to increased immune tolerance in the gut. VSL3# probiotic has immune-modulatory functions, enhancing the expression of IL-33 cytokine that is necessary to maintain immune-tolerance in the gut and mesenchymal lymph nodes (MLN). (B) Role of antibiotic mediated dysbiosis in enhancing autoimmunity and pancreatic β-cells destruction in NOD mice: dysbiosis mediated by the use of antibiotics enhances the growth of pathogenic bacteria which promotes the inflammatory response via the TLR pathway which influences the gut permeability leading to metabolic endotoxemia. Endotoxemia stimulates the autoreactive T cells in the pancreatic lymph nodes leading to insulitis and β cell destruction. The figure was created using BioRender.com and Science slides software.

Figure 3

Role of microbial metabolites in the epigenetic regulation in T1D. Gut microbiota synthesize most of the B vitamins (Niacin, Biotin, Riboflavin, Pantothenate) that show different epigenetic roles and can modulate the expression of T1D associated genes. The therapeutic effects of SCFAs (mainly pentanoate) on autoimmune disorders are mediated by Th 17, macrophages, and dendritic cells (DC) via lowering the expression of inflammatory genes including IL-6, IL-12, IL-17A, IL-21, Rorc (RAR-related orphan receptor C gene), Stat3 (Signal transducer and activator of transcription 3), nitric oxide (NO), lowering the immune response towards intestinal microbiota and enhancing the immune tolerance in the gut by T cell-independent IgA response. The figure was created using BioRender.com and Science slides software.