Complex dietary-polysaccharide modulates gut immune function and microbiota, and promotes protection from autoimmune diabetes

ABSTRACTSince the dietary supplement and prebiotic value of β-glucan-rich products have been widely recognized and the dietary approaches for modulating autoimmunity have been increasingly explored, we assessed the impact of oral administration of high-pure yeast β-glucan (YBG) on gut immune function, microbiota and type 1 diabetes (T1D) using mouse models. Oral administration of this non-digestible complex polysaccharide caused a Dectin-1-dependent immune response involving increased expression of IL10, retinaldehyde dehydrogenase (Raldh) and pro-inflammatory cytokines in the gut mucosa. YBG-exposed intestinal DCs induced/expanded primarily Foxp3+, IL10+ and IL17+ T cells, ex vivo. Importantly, prolonged oral administration of low-dose YBG at pre-diabetic stage suppressed insulitis and significantly delayed the T1D incidence in non-obese diabetic (NOD) mice. Further, prolonged treatment with YBG showed increased Foxp3+ T cell frequencies, and a significant change in the gut microbiota, particularly an increase in the abundance of Bacteroidetes and a decrease in the Firmicute members. Oral administration of YBG, together with Raldh-substrate and β-cell antigen, resulted in a better protection of NOD mice from T1D. These observations suggest that YBG not only has a prebiotic property, but also has an oral tolerogenic-adjuvant-like effect, and these features could be exploited for modulating autoimmunity in T1D.

Download Full-text

Polysaccharide A-dependent opposing effects of mucosal and systemic exposures to human gut commensalBacteroides fragilisin type 1 diabetes

10.1101/492579 ◽

2018 ◽

Author(s):

M. Hanief. Sofi ◽

Benjamin M. Johnson ◽

Radhika R. Gudi ◽

Amy Jolly ◽

Marie-Claude Gaudreau ◽

...

Keyword(s):

Type 1 Diabetes ◽

Oral Administration ◽

Disease Progression ◽

Inflammatory Responses ◽

Nod Mice ◽

Gut Permeability ◽

Opposing Effects ◽

The Impact ◽

Systemic Compartment

AbstractBacteroides fragilis(BF) is an integral component of the human colonic commensal microbiota. BF is also the most commonly isolated organism from clinical cases of intra-abdominal abscesses suggesting its potential to induce pro-inflammatory responses, upon accessing the systemic compartment. Hence, we examined the impact of mucosal and systemic exposures to BF on type 1 diabetes (T1D) incidence in non-obese diabetic (NOD) mice. The impact of intestinal exposure to BF under chemically-induced enhanced gut permeability condition, which permits microbial translocation, in T1D was also examined. While oral administration of pre-diabetic mice with heat-killed (HK) BF caused enhanced immune regulation and suppression of autoimmunity resulting in delayed hyperglycemia, mice that received HK BF by i.v. injection showed rapid disease progression. Importantly, polysaccharide-A deficient (ΔPSA) BF failed to produce these opposing effects upon oral and systemic deliveries. Further, BF induced modulation of disease progression was observed in WT, but not TLR2-deficient, NOD mice. Interestingly, oral administration of BF under enhanced gut permeability condition resulted in accelerated disease progression and rapid onset of hyperglycemia in NOD mice. Overall, these observations suggest that BF-like gut commensals can cause pro-inflammatory responses upon gaining access to systemic compartment and contribute to T1D in at-risk subjects.

Download Full-text

Neutrophil elastase triggers the development of autoimmune diabetes by exacerbating innate immune responses in pancreatic islets of non-obese diabetic mice

Clinical Science ◽

10.1042/cs20200021 ◽

2020 ◽

Vol 134 (13) ◽

pp. 1679-1696 ◽

Cited By ~ 1

Author(s):

Lingling Shu ◽

Ling Zhong ◽

Yang Xiao ◽

Xiaoping Wu ◽

Yang Liu ◽

...

Keyword(s):

Type 1 Diabetes ◽

Neutrophil Elastase ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Islet Inflammation ◽

The Impact

Abstract Type 1 diabetes is an autoimmune disease resulted from self-destruction of insulin-producing pancreatic β cells. However, the pathological pathways that trigger the autoimmune destruction remain poorly understood. Clinical studies have demonstrated close associations of neutrophils and neutrophil elastase (NE) with β-cell autoimmunity in patients with Type 1 diabetes. The present study aims to investigate the impact of NE inhibition on development of autoimmune diabetes in NOD mice. NE pharmacological inhibitor (sivelestat) or biological inhibitor (elafin) was supplemented into NOD mice to evaluate their effects on islet inflammation and diabetogenesis. The impact of NE inhibition on innate and adaptive immune cells was measured with flow cytometry and immunohistochemistry. A significant but transient increase in neutrophil infiltration accompanied with elevated NE activity was observed in the neonatal period of NOD mice. Treatment of NOD mice with sivelestat or elafin at the early age led to a marked reduction in spontaneous development of insulitis and autoimmune diabetes. Mechanistically, inhibition of NE significantly attenuated infiltration of macrophages and islet inflammation, thus ameliorating cytotoxic T cell-mediated autoimmune attack of pancreatic β cells. In vitro studies showed that NE directly induced inflammatory responses in both min6 β cells and RAW264.7 macrophages, and promoted macrophage migration. These findings support an important role of NE in triggering the onset and progression of β-cell autoimmunity, and suggest that pharmacological inhibition of NE may represent a promising therapeutic strategy for treatment of autoimmune diabetes.

Download Full-text

Faculty Opinions recommendation of The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717957533.793461940 ◽

2012 ◽

Author(s):

Mark Atkinson ◽

Patrick Rowe

Keyword(s):

Type 1 Diabetes ◽

Candidate Genes ◽

Inflammatory Cytokines ◽

Pancreatic Islet ◽

Human Pancreatic Islet ◽

Transcriptome Expression ◽

The Impact ◽

Pro Inflammatory Cytokines

Download Full-text

A form of Autoimmune Diabetes in Adults Named LADA – An Update on Essential Features and Controversies

Current Diabetes Reviews ◽

10.2174/1573399814666180716152342 ◽

2019 ◽

Vol 15 (3) ◽

pp. 172-173 ◽

Cited By ~ 1

Author(s):

Valdemar Grill ◽

Bjørn O. Åsvold

Keyword(s):

Genetic Background ◽

Clinical Utility ◽

Autoimmune Diabetes ◽

Classical Type ◽

Phenotypic Characteristics ◽

Latent Autoimmune Diabetes ◽

The Impact

Latent Autoimmune Diabetes in the Adult, LADA has been investigated less than “classical” type 1 and type 2 diabetes and the criteria for and the relevance of a LADA diagnosis has been challenged. Despite the absence of a genetic background that is exclusive to LADA, this form of diabetes displays phenotypic characteristics that distinguish it from other forms of diabetes. LADA is heterogeneous in terms of the impact of autoimmunity and lifestyle factors, something that poses problems as to therapy and follow-up perhaps particularly in those with marginal positivity. Yet, there appears to be clear clinical utility in classifying individuals as LADA.

Download Full-text

Protection against Autoimmune Diabetes by Silkworm-Produced GFP-Tagged CTB-Insulin Fusion Protein

Clinical and Developmental Immunology ◽

10.1155/2011/831704 ◽

2011 ◽

Vol 2011 ◽

pp. 1-14 ◽

Cited By ~ 5

Author(s):

Qiaohong Meng ◽

Wenfeng Wang ◽

Xiaowen Shi ◽

Yongfeng Jin ◽

Yaozhou Zhang

Keyword(s):

Fusion Protein ◽

Oral Administration ◽

Fluorescent Protein ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Treg Cells ◽

Immunological Tolerance ◽

Protein Vaccine ◽

Green Fluorescent

In animals, oral administration of the cholera toxin B (CTB) subunit conjugated to the autoantigen insulin enhances the specific immune-unresponsive state. This is called oral tolerance and is capable of suppressing autoimmune type 1 diabetes (T1D). However, the process by which the CTB-insulin (CTB-INS) protein works as a therapy for T1Din vivoremains unclear. Here, we successfully expressed a green fluorescent protein- (GFP-) tagged CTB-Ins (CTB-Ins-GFP) fusion protein in silkworms in a pentameric form that retained the native ability to activate the mechanism. Oral administration of the CTB-Ins-GFP protein induced special tolerance, delayed the development of diabetic symptoms, and suppressed T1D onset in nonobese diabetic (NOD) mice. Moreover, it increased the numbers of CD4+CD25+Foxp3+T regulatory (Treg) cells in peripheral lymph tissues and affected the biological activity of spleen cells. This study demonstrated that the CTB-Ins-GFP protein produced in silkworms acted as an oral protein vaccine, inducing immunological tolerance involving CD4+CD25+Foxp3+Treg cells in treating T1D.

Download Full-text

Replacing murine insulin 1 with human insulin protects NOD mice from diabetes

10.1101/823393 ◽

2019 ◽

Author(s):

Colleen M. Elso ◽

Nicholas A. Scott ◽

Lina Mariana ◽

Emma I. Masterman ◽

Andrew P.R. Sutherland ◽

...

Keyword(s):

Type 1 Diabetes ◽

Beta Cells ◽

Mouse Models ◽

Human Insulin ◽

Murine Model ◽

Pancreatic Beta Cells ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Human Type 1 Diabetes

AbstractType 1, or autoimmune, diabetes is caused by the T-cell mediated destruction of the insulin-producing pancreatic beta cells. Non-obese diabetic (NOD) mice spontaneously develop autoimmune diabetes akin to human type 1 diabetes. For this reason, the NOD mouse has been the preeminent murine model for human type 1 diabetes research for several decades. However, humanized mouse models are highly sought after because they offer both the experimental tractability of a mouse model and the clinical relevance of human-based research. Autoimmune T-cell responses against insulin, and its precursor proinsulin, play central roles in the autoimmune responses against pancreatic beta cells in both humans and NOD mice. As a first step towards developing a murine model of the human autoimmune response against pancreatic beta cells we set out to replace the murine insulin 1 gene (Ins1) with the human insulin gene (INS) using CRISPR/Cas9. Here we describe a NOD mouse strain that expresses human insulin in place of murine insulin 1, referred to as HuPI. HuPI mice express human insulin, and C-peptide, in their serum and pancreata and have normal glucose tolerance. Compared with wild type NOD mice, the incidence of diabetes is much lower in HuPI mice. Only 15-20% of HuPI mice developed diabetes after 300 days, compared to more than 60% of unmodified NOD mice. Immune-cell infiltration into the pancreatic islets of HuPI mice was not detectable at 100 days but was clearly evident by 300 days. This work highlights the feasibility of using CRISPR/Cas9 to create mouse models of human diseases that express proteins pivotal to the human disease. Furthermore, it reveals that even subtle changes in proinsulin protect NOD mice from diabetes.

Download Full-text

Long-Term Provision of Acidified Drinking Water Fails to Influence Autoimmune Diabetes and Encephalomyelitis

Journal of Diabetes Research ◽

10.1155/2018/3424691 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Sundararajan Jayaraman ◽

Arathi Jayaraman

Keyword(s):

Drinking Water ◽

Autoimmune Diseases ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Autoimmune Encephalomyelitis ◽

Gastrointestinal Pathogen ◽

Onset Of Diabetes ◽

Partial Blocking

Induction of autoimmune diseases is predisposed by background genetics and influenced by environmental factors including diet and infections. Since consumption of acidified drinking water leads to eradication of gastrointestinal pathogens in animals, we tested whether it may also influence the development of autoimmune diseases. The frequency of spontaneously occurring type 1 diabetes in female NOD mice that were maintained on acidified drinking water by the vendor did not alter after switching to neutral water in our facility. In addition, experimentally induced autoimmune encephalomyelitis was also unaffected by the pH of the drinking water. Interestingly, administration of complete Freund’s adjuvant alone or emulsified with a neuronal peptide to induce neurodegenerative disease during the prediabetic stage completely prevented the onset of diabetes regardless of the pH of the drinking water. However, exposure to microbial products later in life had only a partial blocking effect on diabetes induction, which was also not influenced by the ionic content of the drinking water. Taken together, these data indicate that the onset of autoimmune diseases is not influenced by the gastrointestinal pathogen-depleting treatment, acidified drinking water. Thus, administration of acidic drinking water does not appear to be an option for treating autoimmune diseases.

Download Full-text

Neuroinflammation in Aged Brain: Impact of the Oral Administration of Ellagic Acid Microdispersion

International Journal of Molecular Sciences ◽

10.3390/ijms21103631 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3631 ◽

Cited By ~ 2

Author(s):

Raffaella Boggia ◽

Federica Turrini ◽

Alessandra Roggeri ◽

Guendalina Olivero ◽

Francesca Cisani ◽

...

Keyword(s):

Oral Administration ◽

Ellagic Acid ◽

Ex Vivo ◽

Behavioral Skills ◽

Aged Mice ◽

Age Related ◽

The Central Nervous System ◽

The Impact ◽

Old Mice

The immune system and the central nervous system message each other to preserving central homeostasis. Both systems undergo changes during aging that determine central age-related defects. Ellagic acid (EA) is a natural product which is beneficial in both peripheral and central diseases, including aging. We analyzed the impact of the oral administration of a new oral ellagic acid micro-dispersion (EAm), that largely increased the EA solubility, in young and old mice. Oral EAm did not modify animal weight and behavioral skills in young and old mice, but significantly recovered changes in “ex-vivo, in vitro” parameters in old animals. Cortical noradrenaline exocytosis decreased in aged mice. EAm administration did not modify noradrenaline overflow in young animals, but recovered it in old mice. Furthermore, GFAP staining was increased in the cortex of aged mice, while IBA-1 and CD45 immunopositivities were unchanged when compared to young ones. EAm treatment significantly reduced CD45 signal in both young and old cortical lysates; it diminished GFAP immunopositivity in young mice, but failed to affect IBA-1 expression in both young and old animals. Finally, EAm treatment significantly reduced IL1beta expression in old mice. These results suggest that EAm is beneficial to aging and represents a nutraceutical ingredient for elders.

Download Full-text

Histidine Decarboxylase Deficiency Prevents Autoimmune Diabetes in NOD Mice

Journal of Diabetes Research ◽

10.1155/2015/965056 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Manal Alkan ◽

François Machavoine ◽

Rachel Rignault ◽

Julie Dam ◽

Michel Dy ◽

...

Keyword(s):

Histidine Decarboxylase ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Wild Type ◽

Gene Encoding ◽

Nonobese Diabetic ◽

Endogenous Histamine ◽

Wild Type Counterpart

Recent evidence has highlighted the role of histamine in inflammation. Since this monoamine has also been strongly implicated in the pathogenesis of type-1 diabetes, we assessed its effect in the nonobese diabetic (NOD) mouse model. To this end, we used mice (inactivated) knocked out for the gene encoding histidine decarboxylase, the unique histamine-forming enzyme, backcrossed on a NOD genetic background. We found that the lack of endogenous histamine in NOD HDC−/−mice decreased the incidence of diabetes in relation to their wild-type counterpart. Whereas the proportion of regulatory T and myeloid-derived suppressive cells was similar in both strains, histamine deficiency was associated with increased levels of immature macrophages, as compared with wild-type NOD mice. Concerning the cytokine pattern, we found a decrease in circulating IL-12 and IFN-γin HDC−/−mice, while IL-6 or leptin remained unchanged, suggesting that histamine primarily modulates the inflammatory environment. Paradoxically, exogenous histamine given to NOD HDC−/−mice provided also protection against T1D. Our study supports the notion that histamine is involved in the pathogenesis of diabetes, thus providing additional evidence for its role in the regulation of the immune response.

Download Full-text