Host-microbiota interactions shaping T-cell response and tolerance in type 1 diabetes

Abstract

Type-1 Diabetes (T1D) is a complex polygenic autoimmune disorder involving T-cell driven beta-cell destruction leading to hyperglycemia. There is no cure for T1D and patients rely on exogenous insulin administration for disease management. T1D is associated with specific disease susceptible alleles. However, the predisposition to disease development is not solely predicted by them. This is best exemplified by the observation that a monozygotic twin has just a 35% chance of developing T1D after their twin’s diagnosis. This makes a strong case for environmental triggers playing an important role in T1D incidence. Multiple studies indicate that commensal gut microbiota and environmental factors that alter their composition might exacerbate or protect against T1D onset. In this review, we discuss recent literature highlighting microbial species associated with T1D. We explore mechanistic studies which propose how some of these microbial species can modulate adaptive immune responses in T1D, with an emphasis on T-cell responses. We cover topics ranging from gut-thymus and gut-pancreas communication, microbial regulation of peripheral tolerance, to molecular mimicry of islet antigens by microbial peptides. In light of the accumulating evidence on commensal influences in neonatal thymocyte development, we also speculate on the link between molecular mimicry and thymic selection in the context of T1D pathogenesis. Finally, we explore how these observations could inform future therapeutic approaches in this disease.

A short history from Karelia study to biodiversity and public health interventions

“…The asthma preventive effect of farming environment has been convincingly shown ( 82 ). Altered microbiome precedes or associates with types 1 and 2 diabetes ( 83 , 84 ), cardiovascular disease ( 85 ) or autoimmune diseases ( 86 ). The risk of type 1 diabetes is decreased in children with disease associated HL-DQ alleles, who are exposed to an agricultural environment early in life ( 87 ).…”

Two putative glutamate decarboxylases of Streptococcus pneumoniae as possible antigens for the production of anti-GAD65 antibodies leading to type 1 diabetes mellitus

“…In general, dysbiosis is characterized by low microbial diversity and prevalence of pathogenic bacteria. Most studies showing the involvement of dysbiosis in a variety of human diseases have been performed mainly with the gut and/or oral microbiomes (see Suárez et Particularly, gut dysbiosis is thought to be linked to various human diseases, such as type 1 diabetes mellitus (T1DM), cardiovascular diseases, obesity, in ammatory bowel disease or cancer, although the mechanisms over gut microbiota exerts its positive or harmful impacts remains largely unclear (Afzaal et al 2022;Majumdar et al 2022).…”

Two putative glutamate decarboxylases of Streptococcus pneumoniae as possible antigens for the production of anti-GAD65 antibodies leading to type 1 diabetes mellitus

“…Most studies showing the involvement of dysbiosis in a variety of human diseases have been performed mainly with the gut and/or oral microbiomes (see Suárez et al 2020 ; Abdelbary et al 2022 ; Afzaal et al 2022 for recent reviews). Particularly, gut dysbiosis is thought to be linked to various human diseases, such as type 1 diabetes mellitus (T1DM), cardiovascular diseases, obesity, inflammatory bowel disease, or cancer, although the mechanisms over gut microbiota exerting its positive or harmful impacts remain largely unclear (Afzaal et al 2022 ; Majumdar et al 2022 ).…”

“…The causes of the destructive process of β cells in the pancreas are not fully understood, but a likely explanation is that the combination of genetic susceptibility (conferred by a large number of genes) (Redondo et al 1999 ) and an environmental trigger—such as gut dysbiosis including changes to the gut microbiota, intestinal permeability, and intestinal inflammation—can initiate the autoimmune reaction (Vatanen et al 2018 ; Dedrick et al 2020 ; Geravandi et al 2020 ; Garabatos and Santamaria 2022 ; Houeiss et al 2022 ; Majumdar et al 2022 ; Zajec et al 2022 ; Zorena et al 2022 ). A possible infectious origin (in this particular case, the mumps virus) for T1DM was already proposed nearly a century ago (Gundersen 1927 ).…”