scholarly journals The DNA Sensor AIM2 Protects against Streptozotocin-Induced Type 1 Diabetes by Regulating Intestinal Homeostasis via the IL-18 Pathway

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 959 ◽  
Author(s):  
Jefferson Antônio Leite ◽  
Gabriela Pessenda ◽  
Isabel C. Guerra-Gomes ◽  
Alynne Karen Mendonça de Santana ◽  
Camila André Pereira ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gut Microbiota ◽  
Bacterial Translocation ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Dna Sensor ◽  
Proinflammatory Response

Pattern recognition receptors (PRRs), such as Nod2, Nlrp3, Tlr2, Trl4, and Tlr9, are directly involved in type 1 diabetes (T1D) susceptibility. However, the role of the cytosolic DNA sensor, AIM2, in T1D pathogenesis is still unknown. Here, we demonstrate that C57BL/6 mice lacking AIM2 (AIM2−/−) are prone to streptozotocin (STZ)-induced T1D, compared to WT C57BL/6 mice. The AIM2−/− mice phenotype is associated with a greater proinflammatory response in pancreatic tissues, alterations in gut microbiota and bacterial translocation to pancreatic lymph nodes (PLNs). These alterations are related to an increased intestinal permeability mediated by tight-junction disruption. Notably, AIM2−/− mice treated with broad-spectrum antibiotics (ABX) are protected from STZ-induced T1D and display a lower pancreatic proinflammatory response. Mechanistically, the AIM2 inflammasome is activated in vivo, leading to an IL-18 release in the ileum at 15 days after an STZ injection. IL-18 favors RegIIIγ production, thus mitigating gut microbiota alterations and reinforcing the intestinal barrier function. Together, our findings show a regulatory role of AIM2, mediated by IL-18, in shaping gut microbiota and reducing bacterial translocation and proinflammatory response against insulin-producing β cells, which ultimately results in protection against T1D onset in an STZ-induced diabetes model.

scholarly journals ER stress and development of type 1 diabetes

2016 ◽  
Vol 64 (1) ◽  
pp. 2-6 ◽  
Author(s):  
Feyza Engin
Keyword(s):  
Type 1 Diabetes ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Adaptive Responses ◽  
Β Cell ◽  
Cellular Homeostasis ◽  
Unfolded Protein

Type 1 diabetes (T1D) results from an autoimmune-mediated destruction of pancreatic β cells. The incidence of T1D is on the rise globally around 3% to 5% per year and rapidly increasing incidence in younger children is of the greatest concern. currently, there is no way to cure or prevent T1D; hence, a deeper understanding of the underlying molecular mechanisms of this disease is essential to the development of new effective therapies. The endoplasmic reticulum (ER) is an organelle with multiple functions that are essential for cellular homeostasis. Excessive demand on the ER, chronic inflammation, and environmental factors lead to ER stress and to re-establish cellular homeostasis, the adaptive unfolded protein response (UPR) is triggered. However, chronic ER stress leads to a switch from a prosurvival to a proapoptotic UPR, resulting in cell death. Accumulating data have implicated ER stress and defective UPR in the pathogenesis of inflammatory and autoimmune diseases, and ER stress has been implicated in β-cell failure in type 2 diabetes. However, the role of ER stress and the UPR in β-cell pathophysiology and in the initiation and propagation of the autoimmune responses in T1D remains undefined. This review will highlight the current understanding and recent in vivo data on the role of ER stress and adaptive responses in T1D pathogenesis and the potential therapeutic aspect of enhancing β-cell ER function and restoring UPR defects as novel clinical strategies against this disease.

scholarly journals Effects of Dietary Fibres on Acute Indomethacin-Induced Intestinal Hyperpermeability in the Elderly: A Randomised Placebo Controlled Parallel Clinical Trial

Nutrients ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1954
Author(s):  
John-Peter Ganda Mall ◽  
Frida Fart ◽  
Julia A. Sabet ◽  
Carl Mårten Lindqvist ◽  
Ragnhild Nestestog ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
The Elderly ◽  
Intestinal Barrier Function ◽  
Elderly Subjects ◽  
Microbiota Composition ◽  
Dietary Fibres ◽  
Gut Microbiota Composition

The effect of dietary fibres on intestinal barrier function has not been well studied, especially in the elderly. We aimed to investigate the potential of the dietary fibres oat β-glucan and wheat arabinoxylan to strengthen the intestinal barrier function and counteract acute non-steroid anti-inflammatory drug (indomethacin)-induced hyperpermeability in the elderly. A general population of elderly subjects (≥65 years, n = 49) was randomised to a daily supplementation (12g/day) of oat β-glucan, arabinoxylan or placebo (maltodextrin) for six weeks. The primary outcome was change in acute indomethacin-induced intestinal permeability from baseline, assessed by an in vivo multi-sugar permeability test. Secondary outcomes were changes from baseline in: gut microbiota composition, systemic inflammatory status and self-reported health. Despite a majority of the study population (85%) showing a habitual fibre intake below the recommendation, no significant effects on acute indomethacin-induced intestinal hyperpermeability in vivo or gut microbiota composition were observed after six weeks intervention with either dietary fibre, compared to placebo.

Exposure to environmental chemicals and type 1 diabetes: an update

2019 ◽  
Vol 73 (6) ◽  
pp. 483-488 ◽  
Author(s):  
Sarah G Howard
Keyword(s):  
Type 1 Diabetes ◽  
Experimental Studies ◽  
Epidemiological Studies ◽  
Environmental Chemicals ◽  
Exposure Level ◽  
Environmental Chemical ◽  
Timing Of Exposure

This narrative review summarises recently published epidemiological and in vivo experimental studies on exposure to environmental chemicals and their potential role in the development of type 1 diabetes mellitus (T1DM). These studies focus on a variety of environmental chemical exposures, including to air pollution, arsenic, some persistent organic pollutants, pesticides, bisphenol A and phthalates. Of the 15 epidemiological studies identified, 14 include measurements of exposures during childhood, 2 include prenatal exposures and 1 includes adults over age 21. Together, they illustrate that the role of chemicals in T1DM may be complex and may depend on a variety of factors, such as exposure level, timing of exposure, nutritional status and chemical metabolism. While the evidence that these exposures may increase the risk of T1DM is still preliminary, it is critical to investigate this possibility further as a means of preventing T1DM.

scholarly journals The Role of Gut Microbiota in Intestinal Inflammation with Respect to Diet and Extrinsic Stressors

2019 ◽  
Vol 7 (8) ◽  
pp. 271 ◽  
Author(s):  
Stefani Lobionda ◽  
Panida Sittipo ◽  
Hyog Young Kwon ◽  
Yun Kyung Lee
Keyword(s):  
Gut Microbiota ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Environmental Stressors ◽  
Intestinal Barrier Function ◽  
Symbiotic Relationship ◽  
Inflammatory Bowel ◽  
Host Metabolism ◽  
The Relationship

The gut microbiota maintains a symbiotic relationship with the host and regulates several important functions including host metabolism, immunity, and intestinal barrier function. Intestinal inflammation and inflammatory bowel disease (IBD) are commonly associated with dysbiosis of the gut microbiota. Alterations in the gut microbiota and associated changes in metabolites as well as disruptions in the intestinal barrier are evidence of the relationship between the gut microbiota and intestinal inflammation. Recent studies have found that many factors may alter the gut microbiota, with the effects of diet being commonly-studied. Extrinsic stressors, including environmental stressors, antibiotic exposure, sleep disturbance, physical activity, and psychological stress, may also play important roles in altering the composition of the gut microbiota. Herein, we discuss the roles of the gut microbiota in intestinal inflammation in relation to diet and other extrinsic stressors.

scholarly journals IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Juan Huang ◽  
Qiyuan Tan ◽  
Ningwen Tai ◽  
James Alexander Pearson ◽  
Yangyang Li ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Gut Microbiota ◽  
Spontaneous Diabetes ◽  
Nod Mice ◽  
Treg Cells ◽  
Diabetes Development

Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of insulin-producing β cells. BDC2.5 T cells in BDC2.5 CD4+ T cell receptor transgenic Non-Obese Diabetic (NOD) mice (BDC2.5+ NOD mice) can abruptly invade the pancreatic islets resulting in severe insulitis that progresses rapidly but rarely leads to spontaneous diabetes. This prevention of diabetes is mediated by T regulatory (Treg) cells in these mice. In this study, we investigated the role of interleukin 10 (IL-10) in the inhibition of diabetes in BDC2.5+ NOD mice by generating Il-10-deficient BDC2.5+ NOD mice (BDC2.5+Il-10-/- NOD mice). Our results showed that BDC2.5+Il-10-/- NOD mice displayed robust and accelerated diabetes development. Il-10 deficiency in BDC2.5+ NOD mice promoted the generation of neutrophils in the bone marrow and increased the proportions of neutrophils in the periphery (blood, spleen, and islets), accompanied by altered intestinal immunity and gut microbiota composition. In vitro studies showed that the gut microbiota from BDC2.5+Il-10-/- NOD mice can expand neutrophil populations. Moreover, in vivo studies demonstrated that the depletion of endogenous gut microbiota by antibiotic treatment decreased the proportion of neutrophils. Although Il-10 deficiency in BDC2.5+ NOD mice had no obvious effects on the proportion and function of Treg cells, it affected the immune response and activation of CD4+ T cells. Moreover, the pathogenicity of CD4+ T cells was much increased, and this significantly accelerated the development of diabetes when these CD4+ T cells were transferred into immune-deficient NOD mice. Our study provides novel insights into the role of IL-10 in the modulation of neutrophils and CD4+ T cells in BDC2.5+ NOD mice, and suggests important crosstalk between gut microbiota and neutrophils in type 1 diabetes development.

The crucial role of early-life gut microbiota in the development of type 1 diabetes

2020 ◽  
Author(s):  
He Zhou ◽  
Lin Sun ◽  
Siwen Zhang ◽  
Xue Zhao ◽  
Xiaokun Gang ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gut Microbiota ◽  
Crucial Role ◽  
Early Life

scholarly journals A Novel Role of A2AR in the Maintenance of Intestinal Barrier Function of Eteric Glia from Hypoxia-Induced Injury by Combining with mGluR5

2021 ◽  
Vol 12 ◽  
Author(s):  
Lihua Sun ◽  
Xiang Li ◽  
Haidi Guan ◽  
Shuaishuai Chen ◽  
Xin Fan ◽  
...  
Keyword(s):  
Metabotropic Glutamate Receptor ◽  
Ischemia Reperfusion ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Metabotropic Glutamate ◽  
Enteric Glial Cells ◽  
Intestinal Ischemia Reperfusion

During acute intestinal ischemia reperfusion (IR) injury, the intestinal epithelial barrier (IEB) function is often disrupted. Enteric glial cells (EGCs) play an important role in maintaining the integrity of IEB functions. However, how EGCs regulate IEB function under IR stimulation is unknown. The present study reveals that the adenosine A2A receptor (A2AR) is important for mediating the barrier-modulating roles of EGCs. A2AR knockout (KO) experiments revealed more serious intestinal injury in A2AR KO mice than in WT mice after IR stimulation. Moreover, A2AR expression was significantly increased in WT mice when challenged by IR. To further investigate the role of A2AR in IEB, we established an in vitro EGC-Caco-2 co-culture system. Hypoxia stimulation was used to mimic the process of in vivo IR. Treating EGCs with the CGS21680 A2AR agonist attenuated hypoxia-induced intestinal epithelium damage through up-regulating ZO-1 and occludin expression in cocultured Caco-2 monolayers. Furthermore, we showed that A2AR and metabotropic glutamate receptor 5 (mGluR5) combine to activate the PKCα-dependent pathway in conditions of hypoxia. This study shows, for the first time, that hypoxia induces A2AR-mGluR5 interaction in EGCs to protect IEB function via the PKCα pathway.

scholarly journals Parabacteroides distasonis enhances Type 1 Diabetes autoimmunity via molecular mimicry

2020 ◽  
Author(s):  
Qian Huang ◽  
I-Ting Chow ◽  
Claudia Brady ◽  
Amol Raisingani ◽  
Danmeng Li ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gut Microbiota ◽  
Molecular Mimicry ◽  
Nod Mice ◽  
Cross Reactivity ◽  
Nod Mouse ◽  
Human Gut ◽  
Human T Cell

ABSTRACTType 1 Diabetes (T1D) is an autoimmune disease characterized by destruction of pancreatic β-cells. Focusing on the main insulin epitope, insulin B-chain 9-23 (insB:9-23), we explored whether a microbial insB:9-23 mimic could modulate T1D. We now demonstrate that a microbial insB:9-23 mimic of Parabacteroides distasonis, a human gut commensal, exclusively stimulates non-obese diabetic (NOD) mouse T cells specific to insB:9-23. Indeed, immunization of NOD mice with either the bacterial mimic peptide or insB:9-23 further verified the cross-reactivity in vivo. Modeling P. distasonis peptide revealed a potential pathogenic register 3 binding. P. distasonis colonization of the female NOD mice gut accelerated T1D onset. In addition, adoptive transfer of splenocytes from NOD mice colonized with P. distasonis to NOD.SCID recipients conferred the enhanced disease phenotype. Integration analysis of published infant T1D gut microbiome data revealed that P. distasonis peptide is not present in the gut microbiota in the first year of life of infants that eventually develop T1D. Furthermore, P. distasonis peptide can stimulate human T cell clones specific to insB:9-23 and T1D patients demonstrated a strong humoral immune response to P. distasonis than controls. Taken together, our studies define a potential molecular mimicry link between T1D pathogenesis and the gut microbiota.One Sentence SummaryThe human gut commensal bacterium, Parabacteroides distasonis, accelerates type 1 diabetes in the NOD mouse model of the disease and involves expression of an insulin B:9-23 epitope mimic, supporting a potential disease mechanism involving molecular mimicry.

scholarly journals NKG2D signaling within the pancreatic islets reduces NOD diabetes and increases protective central memory CD8+ T cell numbers

2020 ◽  
Author(s):  
Ada Admin ◽  
Andrew P. Trembath ◽  
Kelsey L. Krausz ◽  
Neekun Sharma ◽  
Ivan C. Gerling ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Autoimmune Diabetes ◽  
Central Memory ◽  
Anatomical Location

NKG2D is implicated in autoimmune diabetes. However, the role of this receptor in diabetes pathogenesis is unclear owing to conflicting results with studies involving global inhibition of NKG2D signaling. We found that NKG2D and its ligands are present in human pancreata, with expression of NKG2D and its ligands increased in the islets of patients with type 1 diabetes. To directly assess the role of NKG2D in the pancreas, we generated NOD mice that express an NKG2D ligand in b-islet cells. Diabetes was reduced in these mice. The reduction corresponded with a decrease in the effector to central memory CD8<sup>+</sup> T cell ratio. Further, NKG2D signaling during in vitro activation of both mouse and human CD8+ T cells resulted in an increased number of central memory CD8<sup>+</sup> T cells and diabetes protection by central memory CD8<sup>+</sup> T cells in vivo. Taken together, these studies demonstrate that there is a protective role for central memory CD8<sup>+</sup> T cells in autoimmune diabetes and that this protection is enhanced with NKG2D signaling. These findings stress the importance of anatomical location when determining the role NKG2D signaling plays, as well as when developing therapeutic strategies targeting this pathway, in type 1 diabetes development.

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