The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and to electrolytes and water homeostasis. A more at...

Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer

Type 2 diabetes mellitus (T2D) is a highly prevalent metabolic disorder characterized by an imbalance in blood glucose level, altered lipid profile and high blood pressure. Genetic constituents, high-fat and high-energy dietary habits, and a sedentary lifestyle are three major factors that contribute to high risk of T2D. Several studies have reported gut microbiome dysbiosis as a factor in rapid progression of insulin resistance in T2D that accounts for about 90% of all diabetes cases worldwide. The gut microbiome dysbiosis may reshape intestinal barrier functions and host metabolic and signaling pathways, which are directly or indirectly related to the insulin resistance in T2D. Thousands of the metabolites derived from microbes interact with the epithelial, hepatic and cardiac cell receptors that modulate host physiology. Xenobiotics including dietary components, antibiotics and nonsteroidal anti-inflammatory drugs strongly affect the gut microbial composition and can promote dysbiosis. Any change in the gut microbiota can shift the host metabolism towards increased energy harvest during diabetes and obesity. However, the exact mechanisms behind the dynamics of gut microbes and their impact on host metabolism at the molecular level are yet to be deciphered. We reviewed the published literature for better understanding of the dynamics of gut microbiota, factors that potentially induce gut microbiome dysbiosis and their relation to the progression of T2D. Special emphasis was also given to understand the gut microbiome induced breaching of intestinal barriers and/or tight junctions and their relation to insulin resistance.

Gut microbiome and type 2 diabetes: where we are and where to go?

Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on the role of impaired intestinal barrier function on autoimmune pathogenesis. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiologic modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the zonulin pathway is deregulated in genetically susceptible individuals, autoimmune disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing the zonulin-dependent intestinal barrier function. Both animal models and recent clinical evidence support this new paradigm and provide the rationale for innovative approaches to prevent and treat autoimmune diseases.

Leaky Gut and Autoimmune Diseases

Associated autoimmune diseases in children and adolescents with type 1 diabetes mellitus (T1DM)

In type 1 diabetes, insulin-producing beta-cells in the pancreas are destroyed by immune-mediated mechanisms. The manifestation of the disease is preceded by the so-called pre-diabetic period that may last several years and is characterized by the appearance of circulating autoantibodies against beta-cell antigens. The role of the gut as a regulator of type 1 diabetes was suggested in animal studies, in which changes affecting the gut immune system modulated the incidence of diabetes. Dietary interventions, alterations in the intestinal microbiota and exposure to enteric pathogens, regulate the development of autoimmune diabetes in animal models. It has been demonstrated that these modulations affect the gut barrier mechanisms and intestinal immunity. Because the pancreas and the gut belong to the same intestinal immune system, the link between autoimmune diabetes and the gut is not unexpected. The gut hypothesis in the development of type 1 diabetes is also supported by the observations made in human type 1 diabetes. Early diet could modulate the development of beta-cell autoimmunity; weaning to hydrolysed casein formula decreased the risk of beta-cell autoimmunity by age 10 in the infants at genetic risk. Increased gut permeability, intestinal inflammation with impaired regulatory mechanisms and dysregulated oral tolerance have been observed in children with type 1 diabetes. The factors that contribute to these intestinal alterations are not known, but interest is focused on the microbial stimuli and function of innate immunity. It is likely that our microbial environment does not support the healthy maturation of the gut and tolerance in the gut, and this leads to the increasing type 1 diabetes as well as other immune-mediated diseases regulated by intestinal immune system. Thus, the interventions, aiming to prevent or treat type 1 diabetes in humans, should be targeting the gut immune system.

https://onlinelibrary.wiley.com/doi/pdf/10.1038/icb.2011.115

Is the origin of type 1 diabetes in the gut

OBJECTIVE There is evidence of gut barrier and immune system dysfunction in some patients with type 1 diabetes, possibly linked with exposure to dietary wheat polypeptides (WP). However, questions arise regarding the frequency of abnormal immune responses to wheat and their nature, and it remains unclear whether such responses are diabetes specific.

RESEARCH DESIGN AND METHODS In type 1 diabetic patients and healthy control subjects, the immune response of peripheral CD3+ T-cells to WPs, ovalbumin, gliadin, α-gliadin 33-mer peptide, tetanus toxoid, and phytohemagglutinin was measured using a carboxyfluorescein diacetate succinimidyl ester (CFSE) proliferation assay. T–helper cell type 1 (Th1), Th2, and Th17 cytokines were analyzed in WP-stimulated peripheral blood mononuclear cell (PBMNC) supernatants, and HLA was analyzed by PCR.

RESULTS Of 42 patients, 20 displayed increased CD3+ T-cell proliferation to WPs and were classified as responders; proliferative responses to other dietary antigens were less pronounced. WP-stimulated PBMNCs from patients showed a mixed proinflammatory cytokine response with large amounts of IFN-γ, IL-17A, and increased TNF. HLA-DQ2, the major celiac disease risk gene, was not significantly different. Nearly all responders carried the diabetes risk gene HLA-DR4. Anti-DR antibodies blocked the WP response and inhibited secretion of Th1 and Th17 cytokines. High amounts of WP-stimulated IL-6 were not blocked.

CONCLUSIONS T-cell reactivity to WPs was frequently present in type 1 diabetic patients and associated with HLA-DR4 but not HLA-DQ2. The presence of an HLA-DR–restricted Th1 and Th17 response to WPs in a subset of patients indicates a diabetes-related inflammatory state in the gut immune tissues associated with defective oral tolerance and possibly gut barrier dysfunction.

https://diabetes.diabetesjournals.org/content/diabetes/58/8/1789.full.pdf

Diabetes-Specific HLA-DR–Restricted Proinflammatory T-Cell Response to Wheat Polypeptides in Tissue Transglutaminase Antibody–Negative Patients With Type 1 Diabetes

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Diabetes-Specific HLA-DR–Restricted Proinflammatory T-Cell Response to Wheat Polypeptides in Tissue Transglutaminase Antibody–Negative Patients With Type 1 Diabetes