Loss of gut barrier integrity triggers activation of islet-reactive T cells and autoimmune diabetes

Abstract

Low-grade intestinal inflammation and alterations of gut barrier integrity are found in patients affected by extraintestinal autoimmune diseases such as type 1 diabetes (T1D), but a direct causal link between enteropathy and triggering of autoimmunity is yet to be established. Here, we found that onset of autoimmunity in preclinical models of T1D is associated with alterations of the mucus layer structure and loss of gut barrier integrity. Importantly, we showed that breakage of the gut barrier integrity in BDC2.5XNOD mice carrying a transgenic T cell receptor (TCR) specific for a beta cell autoantigen leads to activation of islet-reactive T cells within the gut mucosa and onset of T1D. The intestinal activation of islet-reactive T cells requires the presence of gut microbiota and is abolished when mice are depleted of endogenous commensal microbiota by antibiotic treatment. Our results indicate that loss of gut barrier continuity can lead to activation of islet-specific T cells within the intestinal mucosa and to autoimmune diabetes and provide a strong rationale to design innovative therapeutic interventions in “at-risk” individuals aimed at restoring gut barrier integrity to prevent T1D occurrence.

Connecting the dots in type 1 diabetes: The role for gut–pancreas axis

“…In a complimentary study, Sorini et al. demonstrated the relationship between gut alterations and the onset of T1D in the context of the gut–pancreas axis . In this study, NOD mice displayed an augmented gut permeability along with an impaired physical barrier, in particular, in the mucus layer.…”

Evaluating the Causal Role of Gut Microbiota in Type 1 Diabetes and Its Possible Pathogenic Mechanisms

“…The translocation of these microbial components to systemic compartment could trigger systemic inflammation and autoimmune progression by directly damaging pancreatic beta cells (96). Alternately, these microbial components could be untaken by antigen-presenting cells (APCs), which can process and present the antigen to autoreactive T cells (87,97), leading to the destruction of islet beta cells (57, 89). Another possible mechanism by which these translocated microbial antigens initiate the diabetes onset is molecular mimicry.…”

Autoimmune diabetes mellitus and the leaky gut

“…This response could be partially blocked by anti-MHCII antibodies, arguing in favor of a TCR-dependent response against a microbial mimic. This particular marker profile was also noted in islet-infiltrating T cells, leading the investigators to conclude that diabetogenic T cells were activated directly in the GALT and then migrated to the pancreas to induce diabetes (7).…”

“…In particular, expression of anti-inflammatory membrane-associated proteins Muc1 and Muc3 was lowered, while that of the proinflammatory Muc4 was increased, creating a proinflammatory milieu within the colonic wall before and during development of T1D. Indeed mucus changes coincided with elevation of proinflammatory cytokine levels, and subsequently, starting around 10 to 12 wk of age proinflammatory Th17 cells became elevated at the expense of regulatory T (Treg) cells (7).…”

“…Although TCR transgenic BDC2.5 T cells surround the pancreatic islets, invasion and destruction of islets and development of diabetes depend on additional activation stimuli, provided for example by a concomitant infection (14). To determine whether a compromised intestinal barrier can deliver these additional stimuli, Sorini et al (7) targeted the mucus layer by repeated administration of low-dose dextran sodium sulfate (DSS), a chemical irritant that opens the gut barrier, allowing bacterial translocation to the mesenteric lymph nodes. In a streptozotocin-induced diabetes model intestinal bacteria traveled farther onto pancreatic lymph nodes to facilitate stimulation of diabetogenic T cells (15).…”