29 Dec Does type 1 diabetes occur in the gut?
Type 1 diabetes is an autoimmune disease that occurs as a result of the interaction between genetic and environmental factors. Autoimmune diseases make up the spectrum of multifactorial diseases whose incidence is increasing dramatically worldwide. Genetic predisposition has long been thought to be a major factor in triggering autoimmunity. However, recent research suggests that environmental factors may be triggers for the development of autoimmune diseases in genetically predisposed individuals.
In this post, I will share with you new evidence about the interaction of factors in the gut, which according to some authors make a “perfect storm”, which is a trio of factors critical for the development of type 1 diabetes.
The trio of factors in the gut:
- Altered intestinal microbiota (dysbiosis) – the presence of specific microorganisms is associated (either quantitatively or qualitatively) with development of type 1 diabetes.
- Increased permeability and impaired intestinal barrier function – proven on animal models of type 1 diabetes and in people with autoimmune diabetes or with an increased risk of disease.
- Altered reactivity of intestinal immune cells – responsible for break of immune tolerance and development of autoimmunity in type 1 diabetes.
The complex interactions between these factors in the gut are a fruitful area for future research on the role of the intestinal immune system in the development and prevention of type 1 diabetes in order to find new therapeutic approaches.
1. Type 1 diabetes is an organ specific autoimmune disease
Type 1 diabetes is one of the organ-specific autoimmune diseases in which the autoimmune response takes place in a single tissue or organ. In type 1 diabetes, the disease occurs as a consequence of the destruction of insulin-producing β-cells in the islets of Langerhans in the pancreas by immune cells. Pancreatic β-cells are a kind of “thermostat” that responds to changes in glucose concentration and releases insulin, a hormone that maintains physiological glucose levels in a relatively narrow range. During type 1 diabetes, the β-cells of the pancreas are destroyed, insulin production is reduced or completely absent, which results in increased blood glucose levels (hyperglycemia). Patients with type 1 diabetes can develop acute conditions (ketoacidosis, severe hypoglycemia) and secondary complications in several organ systems (heart and blood vessel diseases, blindness, kidney diseases).
Characteristic clinical symptoms and signs of type 1 diabetes are:
- increased urination (polyuria)
- increased thirst (polydipsia)
- increased feeling of hunger (polyphagia)
- weight loss
Type 1 diabetes is a lifelong, progressive and incurable disease, and treatment of patients with type 1 diabetes involves lifelong administration of exogenous insulin.
2. What factors affect the development of type 1 diabetes
Type 1 diabetes occurs as a consequence of a combination of genetic predisposition, still insufficiently known environmental factors and stochastic events. Many environmental factors including infections (especially viral), diet, population hygiene, sun exposure and others have been the reason for the dramatic increase in the incidence of type 1 diabetes over the last two decades. Type 1 diabetes most often occurs in people under the age of 18, but also in older adults.
Genetic predisposition – Type 1 diabetes is a polygenic disease with more than 50 gene loci associated with the risk of developing the disease, including those encoding Human Leukocyte Antigens (HLA), especially the genes for HLA-DR and ‐DQ that make up 40% to 50% of the risk for this disease. Other genes associated with the risk of autoimmune diabetes encode molecules and transcription factors important for immune cell function, particularly regulatory T lymphocytes (Treg) including CTLA-4, IL-2, AIRE, FoxP3, STAT3.
Environmental factors – Environmental factors contribute to the development of type 1 diabetes including food ingredients (β-casein or bovine insulin from cow’s milk, gluten), exposure to infectious agents (enteroviruses), and especially altered intestinal microbiota (dysbiosis) due to antibiotics, alcohol abuse, inadequate diet, chronic diseases.
Gut microbiota – It is becoming increasingly clear that type 1 diabetes is associated with a complex interaction between the intestinal immune system and the gut microbiota. Normal intestinal barrier function plays a particularly important role in the communication between the intestinal immune system and the microbiota.
Altered function of immune system cells – In type 1 diabetes there is a breakdown of immune tolerance, activation of autoreactive T and B lymphocytes, proinflammatory response of myeloid antigen presenting cells and the presence of autoantibodies to pancreatic islet antigens.
3. What is the role of the immune system in type 1 diabetes
In type 1 diabetes, the autoimmune process takes place in the pancreatic islets and can last for years before the clinical signs of the disease appear. In type 1 diabetes, autoreactive T lymphocytes infiltrate the pancreatic islets and destroy β-cells resulting in reduced production or complete lack of insulin. In the pancreatic islets, an inflammatory response develops with high levels of proinflammatory cytokines IL-1 (interleukin-1), TNF-α (tumor necrosis factor-α) and INF-γ (interferon-γ) triggered by autoreactive helper CD4 + and cytotoxic CD8 + lymphocytes. This is accompanied by a decreased number of regulatory T lymphocytes (Treg) that have an immunosuppressive role and maintain immune tolerance by producing the cytokines IL-10 and TGF-β. Decreased presence and/or defective function of Treg are associated with the development and progression of type 1 diabetes.
Proinflammatory cytokines trigger the destruction of β-cells in the pancreatic islets by apoptosis (a mechanism also known as programmed cell death) that involves the cascade of caspase enzyme activation, but also the mechanisms of β-cell necrosis and necroptosis. In addition to the action of proinflammatory cytokines, β-cell apoptosis can be induced directly through the contact of autoreactive cytotoxic CD8+ T lymphocytes with β-cells through the action of perforin or Fas / Fas ligand interaction.
In clinical practice, autoantibodies to pancreatic islet antigens, including autoantibodies to insulin (IAA), glutamic acid decarboxylase (GAD65), anti-protein tyrosine phosphatase (IA ‐ 2A), and zinc transporter antibody 8 (ZnT8A) are used to diagnose diabetes type 1 and to identify high-risk individuals.
DiMeglio LA, Evans-Molina C, Oram RA. Type 1 diabetes. Lancet. 2018 Jun 16;391(10138):2449-2462. doi: 10.1016/S0140-6736(18)31320-5. PMID: 29916386; PMCID: PMC6661119.
4. Does type 1 diabetes occur in the gut?
The interrelationship between the intestinal immune system and type 1 diabetes is undoubtedly intriguing and is the subject of modern research. The intestinal mucosa is in constant contact with antigens of microorganisms and food ingredients in the intestinal lumen and has the ability to maintain immune tolerance to antigens of its self tissues and commensal, nonpathogenic microbes, but at the same time provides an immune response to pathogenic microorganisms and harmful substances. The mucus layer as part of the intestinal barrier, together with local IgA secretion and antimicrobial peptides, has a protective role against the intestinal microbiota. However, commensal microbes in the microbiota maintain an intensive interaction with the cells of the immune system of the intestinal mucosa and contribute to intestinal homeostasis.
How do intestinal immune cells perform this dual function?
Dendritic cells (DC), which express the CD103 integrin molecule (tolerogenic DC), present antigens from the intestinal lumen to T lymphocytes in the draining lymph nodes of the intestinal lymphoid tissue (GALT) and initiate oral tolerance mediated by regulatory T lymphocytes. In the case of pathogenic microbes, an immune response mediated by effector Th1, Th2 and Th17 cells is triggered, which has a protective function.
The balance between effector and regulatory immune cells in the lymphoid tissue of the intestine ensures homeostasis in the intestines.
The balance between effector and regulatory immune cells of the intestine is disturbed in type 1 diabetes according to the results of research on animal models of autoimmune diabetes, but also in people suffering from this disease.
What is the evidence of impaired intestinal homeostasis in type 1 diabetes?
The permeability and function of the intestinal barrier is altered – changes in the intestinal barrier precede the development of type 1 diabetes in NOD (nonobese diabetic) mice that spontaneously develop autoimmune diabetes. The permeability of the intestinal barrier is increased, the production of mucus protein (mucins) of the intestinal barrier is reduced, the secretion of IgA in the intestines is reduced and the number of intraepithelial lymphocytes is reduced.
The gut microbiota is altered – there is dysbiosis, which implies an altered composition of microbes, primarily bacteria in the intestines of NOD mice that precede the development of type 1 diabetes.
Inflammatory and autoreactive T cells are present in the lamina propria of the intestine – inflammatory cells, such as Th17 and ILC3, are present in greater numbers, while tolerogenic DC and Treg are significantly reduced in the lamina propria of the intestine and in draining intestinal lymph nodes in NOD mice with impaired oral tolerance before the onset of type 1 diabetes. It has recently been shown that insulin-directed autoreactive T lymphocytes exist in the lymphoid tissue of the intestine and have the ability to migrate to pancreatic lymph nodes and pancreatic islets where they destroy insulin-producing β-cells.
There is translocation of the microbiota to the pancreatic lymph nodes – increased permeability and altered intestinal barrier function is associated with translocation of the microbiota to the pancreatic lymph nodes which can trigger an autoimmune reaction as shown in animal models of type 1 diabetes.
Initiation of autoimmunity in pancreatic lymph nodes (intestinal-pancreatic axis) – it has recently been shown that in addition to mesenteric, the pancreatic lymph nodes drain antigens from the duodenum and that oral tolerance and induction of Treg by tolerogenic DCs can be maintained in pancreatic lymph nodes. The onset of type 1 diabetes is accompanied by a decrease in the number and prevalence of tolerogenic DC and Treg. Gut-derived antigens and pancreatic antigens share the same spatial localization in pancreatic lymph nodes. Maintaining a balance between effector and regulatory immune cells in the pancreatic lymph nodes is essential to prevent discontinuation of tolerance to pancreatic islet antigens and the development of autoreactive T lymphocytes that travel to the pancreas and initiate β-cell destruction causing type 1 diabetes.
Menezes-Silva L, Fonseca DMD. Connecting the dots in type 1 diabetes: The role for gut-pancreas axis. J Leukoc Biol. 2019 Sep;106(3):501-503. doi: 10.1002/JLB.3CE0719-242R. Epub 2019 Aug 1. PMID: 31369695.
Understanding both the genetic components and the role of the intestinal barrier, the intestinal microbiota and the intestinal immune system and their communication with the pancreas will provide a new perspective in understanding the pathogenesis of type 1 diabetes.
I would highlight the importance of research in animal models of type 1 diabetes that convincingly shows that there is the possibility of modulating and strengthening a healthy intestinal barrier through changes in the microbiota or diet that can reduce the possibility of activating autoreactive T cells in the gut and prevent disease in people at increased risk of diabetes type 1 which will be discussed in the following posts.
I invite you to share the blog post with colleagues, to send comments or questions that I will be happy to answer.
- DiMeglio LA, Evans-Molina C, Oram RA. Type 1 diabetes. Lancet. 2018 Jun 16;391(10138):2449-2462. doi: 10.1016/S0140-6736(18)31320-5. PMID: 29916386; PMCID: PMC6661119.
- Vaarala O, Atkinson MA, Neu J. The “perfect storm” for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity. Diabetes. 2008 Oct;57(10):2555-62. doi: 10.2337/db08-0331. PMID: 18820210; PMCID: PMC2551660.
- Menezes-Silva L, Fonseca DMD. Connecting the dots in type 1 diabetes: The role for gut-pancreas axis. J Leukoc Biol. 2019 Sep;106(3):501-503. doi: 10.1002/JLB.3CE0719-242R. Epub 2019 Aug 1. PMID: 31369695.
- Sorini C, Cosorich I, Lo Conte M, De Giorgi L, Facciotti F, Lucianò R, Rocchi M, Ferrarese R, Sanvito F, Canducci F, Falcone M. Loss of gut barrier integrity triggers activation of islet-reactive T cells and autoimmune diabetes. Proc Natl Acad Sci USA 2019;116(30):15140-15149. doi: 10.1073/pnas.1814558116.
- Miranda MCG, Oliveira RP, Torres L, Aguiar SLF, Pinheiro-Rosa N, Lemos L, Guimarães MA, Reis D, Silveira T, Ferreira Ê, Moreira TG, Cara DC, Maioli TU, Kelsall BL, Carlos D, Faria AMC. Frontline Science: Abnormalities in the gut mucosa of non-obese diabetic mice precede the onset of type 1 diabetes. J Leukoc Biol. 2019 Sep;106(3):513-529. doi: 10.1002/JLB.3HI0119-024RR. Epub 2019 Jul 16. PMID: 31313381.