The Role of Gut Microbiota and Environmental Factors in Type 1 Diabetes Pathogenesis

Abstract

Type 1 Diabetes (T1D) is regarded as an autoimmune disease characterized by insulin deficiency resulting from destruction of pancreatic β-cells. The incidence rates of T1D have increased worldwide. Over the past decades, progress has been made in understanding the complexity of the immune response and its role in T1D pathogenesis, however, the trigger of T1D autoimmunity remains unclear. The increasing incidence rates, immigrant studies, and twin studies suggest that environmental factors play an important role and the trigger cannot simply be explained by genetic predisposition. Several research initiatives have identified environmental factors that potentially contribute to the onset of T1D autoimmunity and the progression of disease in children/young adults. More recently, the interplay between gut microbiota and the immune system has been implicated as an important factor in T1D pathogenesis. Although results often vary between studies, broad compositional and diversity patterns have emerged from both longitudinal and cross-sectional human studies. T1D patients have a less diverse gut microbiota, an increased prevalence of Bacteriodetes taxa and an aberrant metabolomic profile compared to healthy controls. In this comprehensive review, we present the data obtained from both animal and human studies focusing on the large longitudinal human studies. These studies are particularly valuable in elucidating the environmental factors that lead to aberrant gut microbiota composition and potentially contribute to T1D. We also discuss how environmental factors, such as birth mode, diet, and antibiotic use modulate gut microbiota and how this potentially contributes to T1D. In the final section, we focus on existing recent literature on microbiota-produced metabolites, proteins, and gut virome function as potential protectants or triggers of T1D onset. Overall, current results indicate that higher levels of diversity along with the presence of beneficial microbes and the resulting microbial-produced metabolites can act as protectors against T1D onset. However, the specifics of the interplay between host and microbes are yet to be discovered.

Keywords: autoimmunity; environmental factors; longitudinal studies children; microbiome; type 1 diabetes.

Figure 1

Environmental factors modulate gut microbiota and potentially contribute to T1D onset. Environmental factors, such as birth mode, diet early in life, and use of antibiotics can influence gut microbiota composition and can to lead to lower bacterial diversity, decreased SCFA production and increased gut permeability. Bacterial phyla/genus/species that are affected by environmental factors and differ between T1D patients and healthy controls are depicted in the colors black/green/purple, respectively. Bacterial genus/species that have been identified in proteomic analyses and are increased in either T1D patients or healthy controls are shown in red. Bacterial genus/species that have been identified in metabolomics analyses and are increased in either T1D patients or healthy controls are shown in blue.