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

2020 ◽  
Vol 22 (1) ◽  
pp. 125
Author(s):  
Duaa Ahmed Elhag ◽  
Manoj Kumar ◽  
Souhaila Al Khodor
Keyword(s):  
Type 1 Diabetes ◽  
Immune System ◽  
Environmental Factors ◽  
Gut Microbiome ◽  
Association Studies ◽  
Host Immune System ◽  
Genome Wide Association Studies ◽  
Immune Disorder ◽  
Microbiome Composition

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.

scholarly journals Host Genetics and Gut Microbiome: Perspectives for Multiple Sclerosis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1181
Author(s):  
Alessandro Maglione ◽  
Miriam Zuccalà ◽  
Martina Tosi ◽  
Marinella Clerico ◽  
Simona Rolla
Keyword(s):  
Multiple Sclerosis ◽  
Environmental Factors ◽  
Lupus Erythematosus ◽  
Gut Microbiome ◽  
Complex Disease ◽  
Current Knowledge ◽  
Association Studies ◽  
Future Research ◽  
Genome Wide Association Studies ◽  
Host Genetics

As a complex disease, Multiple Sclerosis (MS)’s etiology is determined by both genetic and environmental factors. In the last decade, the gut microbiome has emerged as an important environmental factor, but its interaction with host genetics is still unknown. In this review, we focus on these dual aspects of MS pathogenesis: we describe the current knowledge on genetic factors related to MS, based on genome-wide association studies, and then illustrate the interactions between the immune system, gut microbiome and central nervous system in MS, summarizing the evidence available from Experimental Autoimmune Encephalomyelitis mouse models and studies in patients. Finally, as the understanding of influence of host genetics on the gut microbiome composition in MS is in its infancy, we explore this issue based on the evidence currently available from other autoimmune diseases that share with MS the interplay of genetic with environmental factors (Inflammatory Bowel Disease, Rheumatoid Arthritis and Systemic Lupus Erythematosus), and discuss avenues for future research.

scholarly journals A comprehensive integrated post-GWAS analysis of Type 1 diabetes reveals enhancer-based immune dysregulation

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257265
Author(s):  
Seung-Soo Kim ◽  
Adam D. Hudgins ◽  
Jiping Yang ◽  
Yizhou Zhu ◽  
Zhidong Tu ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Target Genes ◽  
Association Studies ◽  
Regulatory Elements ◽  
Immune Dysregulation ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Gwas Analysis ◽  
Regulatory Variants

Type 1 diabetes (T1D) is an organ-specific autoimmune disease, whereby immune cell-mediated killing leads to loss of the insulin-producing β cells in the pancreas. Genome-wide association studies (GWAS) have identified over 200 genetic variants associated with risk for T1D. The majority of the GWAS risk variants reside in the non-coding regions of the genome, suggesting that gene regulatory changes substantially contribute to T1D. However, identification of causal regulatory variants associated with T1D risk and their affected genes is challenging due to incomplete knowledge of non-coding regulatory elements and the cellular states and processes in which they function. Here, we performed a comprehensive integrated post-GWAS analysis of T1D to identify functional regulatory variants in enhancers and their cognate target genes. Starting with 1,817 candidate T1D SNPs defined from the GWAS catalog and LDlink databases, we conducted functional annotation analysis using genomic data from various public databases. These include 1) Roadmap Epigenomics, ENCODE, and RegulomeDB for epigenome data; 2) GTEx for tissue-specific gene expression and expression quantitative trait loci data; and 3) lncRNASNP2 for long non-coding RNA data. Our results indicated a prevalent enhancer-based immune dysregulation in T1D pathogenesis. We identified 26 high-probability causal enhancer SNPs associated with T1D, and 64 predicted target genes. The majority of the target genes play major roles in antigen presentation and immune response and are regulated through complex transcriptional regulatory circuits, including those in HLA (6p21) and non-HLA (16p11.2) loci. These candidate causal enhancer SNPs are supported by strong evidence and warrant functional follow-up studies.

scholarly journals Similarities Between Bacterial GAD and Human GAD65: Implications in Gut Mediated Autoimmune Type 1 Diabetes

2021 ◽  
Author(s):  
Monica Westley ◽  
Tiffany Richardson ◽  
Suhana Bedi ◽  
Baofeng Jia ◽  
Fiona S.L. Brinkman ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cells ◽  
Gut Microbiome ◽  
Pancreatic Beta Cells ◽  
Acid Decarboxylase ◽  
Host Immune System ◽  
Gamma Aminobutyric Acid ◽  
Human Gut ◽  
Autoimmune Attack

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), a producer of gamma-aminobutyric acid (GABA) in human pancreatic beta cells. Interestingly, bacterial populations within the human gut also express GAD65 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 silico analyses, we show here that 25 GAD sequences from different human gut bacterial sources show sequence and motif similarities to human beta cell GAD65. Our motif analyses determined that a majority of gut GAD sequences contain the pyroxical dependent decarboxylase 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 humans and bacterial GAD, these deputized immune cells may then go on to target human beta cells leading to the development of T1D.

scholarly journals Integrative Pathway-Based Approach for Genome-Wide Association Studies: Identification of New Pathways for Rheumatoid Arthritis and Type 1 Diabetes

PLoS ONE ◽  
2013 ◽  
Vol 8 (10) ◽  
pp. e78577 ◽  
Author(s):  
Finja Büchel ◽  
Florian Mittag ◽  
Clemens Wrzodek ◽  
Andreas Zell ◽  
Thomas Gasser ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Type 1 Diabetes ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

scholarly journals Aging and serum MCP-1 are associated with gut microbiome composition in a murine model

2016 ◽  
Author(s):  
Melissa N. Conley ◽  
Carmen P. Wong ◽  
Kyle M. Duyck ◽  
Norman Hord ◽  
Emily Ho ◽  
...  
Keyword(s):  
Immune System ◽  
Murine Model ◽  
Gut Microbiome ◽  
Inflammatory Marker ◽  
Low Grade ◽  
Host Immune System ◽  
Cancer Type ◽  
Microbiome Composition ◽  
Aged Mice ◽  
Age Related

Introduction Age is the primary risk factor for major human chronic diseases, including cardiovascular disorders, cancer, type 2 diabetes, and neurodegenerative diseases. Chronic, low-grade, systemic inflammation is associated with aging and the progression of immunosenescence. Immunosenescence may play an important role in the development of age-related chronic disease and the widely observed phenomenon of increased production of inflammatory mediators that accompany this process, referred to as “inflammaging”. While it has been demonstrated that the gut microbiome and immune system interact, the relationship between the gut microbiome and age remains to be clearly defined, particularly in the context of inflammation. The aim of the study was to clarify the associations between age, the gut microbiome, and pro-inflammatory marker serum MCP-1 in a C57BL/6 murine model. Results We used 16S rRNA gene sequencing to profile the composition of fecal microbiota associated with young and aged mice. Our analysis identified an association between microbiome structure and mouse age, and revealed specific groups of taxa whose abundances stratify young and aged mice. This includes the Ruminococcaceae, Clostridiaceae, and Enterobacteriaceae. We also profiled pro-inflammatory serum MCP-1 levels of each mouse and found that aged mice exhibited elevated serum MCP-1, a phenotype consistent with inflammaging. Robust correlation tests identified several taxa whose abundance in the microbiome associates with serum MCP-1 status, indicating that they may interact with the mouse immune system. We find that taxonomically similar organisms can exhibit differing, even opposite, patterns of association with the host immune system. We also find that many of the OTUs that associate with serum MCP-1 also stratify individuals by age. Discussion Our results demonstrate that gut microbiome composition is associated with age and the pro-inflammatory marker, serum MCP-1. The correlation between age, relative abundance of specific taxa in the gut microbiome, and serum MCP-1 status in mice indicates that the gut microbiome may play a modulating role in age-related inflammatory processes. These findings warrant further investigation of taxa associated with the inflammaging phenotype and the role of gut microbiome in the health status and immune function of aged individuals.

scholarly journals Genes Expression in Type 1 Diabetes: An Update

2019 ◽  
Vol 6 (2) ◽  
pp. 4327-4331
Author(s):  
Dr. Kishore Kumar Soni ◽  
Dr. Sushil Singh
Keyword(s):  
Type 1 Diabetes ◽  
Association Studies ◽  
Disease Onset ◽  
Genome Wide Association Studies ◽  
Autoimmune Destruction ◽  
Disease Biology ◽  
Genome Wide ◽  
Genes Expression ◽  
Practical Effect

Type 1 Diabetes (T1D) is autoimmune disease with a sturdy genetic component, which, through interactions with particular environmental factors, causes disease onset. T1D usually reveals in early to mid-childhood through the autoimmune destruction of pancreatic cells resulting in a lack of insulin production. Traditionally, prior to genome-wide association studies (GWAS), six loci in the genome were fully established to be associated with T1D. The originations of genetic factors involved in T1D through GWAS present the first step in a long process leading to cure. Genes uncovered using this approach is indeed necessary to disease biology and will define the key molecular pathways leading to cure of T1D. However, such genome wide scans can lack coverage in certain regions where it is difficult to , thus, it is possible that other loci with practical effect sizes remain to be uncovered through whole genome sequencing approaches. In this review, we address recent expansions in the genetics of T1D and provide an update on the latest predisposition loci added to the list of genes involved in the of T1D

scholarly journals Risk variants disrupting enhancers of TH1 and TREG cells in type 1 diabetes

2019 ◽  
Vol 116 (15) ◽  
pp. 7581-7590 ◽  
Author(s):  
Peng Gao ◽  
Yasin Uzun ◽  
Bing He ◽  
Sarah E. Salamati ◽  
Julie K. M. Coffey ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Retinoic Acid Receptor ◽  
Association Studies ◽  
Cell Types ◽  
Treg Cells ◽  
Genome Wide Association Studies ◽  
Enhancer Activity ◽  
Functional Interpretation ◽  
Immune Genes

Genome-wide association studies (GWASs) have revealed 59 genomic loci associated with type 1 diabetes (T1D). Functional interpretation of the SNPs located in the noncoding region of these loci remains challenging. We perform epigenomic profiling of two enhancer marks, H3K4me1 and H3K27ac, using primary TH1 and TREG cells isolated from healthy and T1D subjects. We uncover a large number of deregulated enhancers and altered transcriptional circuitries in both cell types of T1D patients. We identify four SNPs (rs10772119, rs10772120, rs3176792, rs883868) in linkage disequilibrium (LD) with T1D-associated GWAS lead SNPs that alter enhancer activity and expression of immune genes. Among them, rs10772119 and rs883868 disrupt the binding of retinoic acid receptor α (RARA) and Yin and Yang 1 (YY1), respectively. Loss of binding by YY1 also results in the loss of long-range enhancer–promoter interaction. These findings provide insights into how noncoding variants affect the transcriptomes of two T-cell subtypes that play critical roles in T1D pathogenesis.

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