Gut mucosa alterations and loss of segmented filamentous bacteria in type 1 diabetes are associated with inflammation rather than hyperglycaemia

ObjectiveType 1 diabetes (T1D) is an autoimmune disease caused by the destruction of pancreatic β-cells producing insulin. Both T1D patients and animal models exhibit gut microbiota and mucosa alterations, although the exact cause for these remains poorly understood. We investigated the production of key cytokines controlling gut integrity, the abundance of segmented filamentous bacteria (SFB) involved in the production of these cytokines, and the respective role of autoimmune inflammation and hyperglycaemia.DesignWe used several mouse models of autoimmune T1D as well as mice rendered hyperglycaemic without inflammation to study gut mucosa and microbiota dysbiosis. We analysed cytokine expression in immune cells, epithelial cell function, SFB abundance and microbiota composition by 16S sequencing. We assessed the role of anti-tumour necrosis factor α on gut mucosa inflammation and T1D onset.ResultsWe show in models of autoimmune T1D a conserved loss of interleukin (IL)-17A, IL-22 and IL-23A in gut mucosa. Intestinal epithelial cell function was altered and gut integrity was impaired. These defects were associated with dysbiosis including progressive loss of SFB. Transfer of diabetogenic T-cells recapitulated these gut alterations, whereas induction of hyperglycaemia with no inflammation failed to do so. Moreover, anti-inflammatory treatment restored gut mucosa and immune cell function and dampened diabetes incidence.ConclusionOur results demonstrate that gut mucosa alterations and dysbiosis in T1D are primarily linked to inflammation rather than hyperglycaemia. Anti-inflammatory treatment preserves gut homeostasis and protective commensal flora reducing T1D incidence.

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Fasting and meal-stimulated residual beta cell function is positively associated with serum concentrations of proinflammatory cytokines and negatively associated with anti-inflammatory and regulatory cytokines in patients with longer term type 1 diabetes

Diabetologia ◽

10.1007/s00125-013-2883-3 ◽

2013 ◽

Vol 56 (6) ◽

pp. 1356-1363 ◽

Cited By ~ 5

Author(s):

M. N. Pham ◽

◽

H. Kolb ◽

T. Battelino ◽

J. Ludvigsson ◽

...

Keyword(s):

Type 1 Diabetes ◽

Beta Cell ◽

Proinflammatory Cytokines ◽

Beta Cell Function ◽

Cell Function ◽

Serum Concentrations ◽

Negatively Associated ◽

Anti Inflammatory ◽

Term Type

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Abstract 590: Loss of Myeloid Cell Prostaglandin E Receptor 4 Does Not Alter Diabetes-Accelerated Atherosclerosis in a Murine Model of Type 1 Diabetes

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.590 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Sara N Vallerie ◽

Farah Kramer ◽

Jenny E Kanter ◽

Shelley Barnhart ◽

Richard M Breyer ◽

...

Keyword(s):

Type 1 Diabetes ◽

Mouse Model ◽

Myeloid Cells ◽

Myeloid Cell ◽

Prostaglandin E ◽

Lesion Area ◽

Accelerated Atherosclerosis ◽

Anti Inflammatory

Diabetes is associated with an increased risk of cardiovascular disease, largely due to increased atherosclerosis. Our studies have suggested myeloid cell prostaglandin E 2 (PGE 2 ) production as a possible mediator of diabetes-accelerated atherosclerosis in a virally-induced mouse model of type 1 diabetes. Prostaglandin E Receptor 4 (EP4; Ptger4 ) is a major PGE 2 receptor in myeloid cells. We hypothesized that generation of a mouse model of myeloid cell-targeted EP4-deficiency would allow us to test the role of myeloid EP4 in diabetes-accelerated atherosclerosis. Thus, we generated a Ptger4 flox/flox LysM-Cre tg/tg mouse model. Peritoneal macrophages isolated from these myeloid cell EP4-deficient (EP4 M-/- ) mice expressed <90% Ptger4 mRNA compared to LysM-Cre tg/tg controls (n=10; p<0.0001). To analyze the role of myeloid cell EP4 in diabetes-accelerated atherosclerosis, we transplanted bone marrow from EP4 M-/- mice and littermate controls into lethally irradiated Ldlr -/- RIP-LCMV mice (the model of type 1 diabetes) and, after 7 weeks of recovery, induced diabetes by viral infection and fed the mice a low-fat semi-purified diet for an additional 12 weeks. Diabetic EP4 M-/- mice had similar blood glucose (568 ± 15 vs. 569 ± 15 mg/dl), blood cholesterol (531 ± 29 vs. 510 ± 37 mg/dl), and plasma triglycerides (249 ± 49 vs. 247 ± 44 mg/dl) as diabetic controls (n=15 all groups; mean ± SEM). At the endpoint, aortas were harvested for lesion area quantification. Diabetic EP4 M-/- and diabetic wild type mice had similar lesion area (1.9% ± 0.2 vs. 1.7% ± 0.2), which were both increased (p < 0.01; n=9-15) as compared to their non-diabetic controls. Additionally, we analyzed the role of EP4 in inflammatory activation of myeloid cells ex vivo. EP4-deficiency had no significant effect on basal or lipopolysaccharide (LPS)-induced inflammatory gene expression in the absence of PGE 2 . Pretreatment of the cells with PGE 2 (10 nM) followed by LPS stimulation resulted in a significant reduction of Tnfa and Il6 mRNA compared to LPS alone, and this anti-inflammatory effect of PGE 2 was completely blocked in EP4-deficient cells. These results suggest that myeloid cell EP4 mediates anti-inflammatory actions of PGE 2 but that it is not involved in diabetes-accelerated atherosclerosis.

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Residual beta-cell function and spontaneous clinical remission in type 1 diabetes mellitus: the role of puberty

Acta Diabetologica ◽

10.1007/s005920050110 ◽

1998 ◽

Vol 35 (2) ◽

pp. 91-95 ◽

Cited By ~ 28

Author(s):

R. Bonfanti ◽

E. Bognetti ◽

F. Meschi ◽

A. Brunelli ◽

M. C. Riva ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Beta Cell ◽

Type 1 Diabetes Mellitus ◽

Clinical Remission ◽

Beta Cell Function ◽

Cell Function

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Methanolic extract of Origanum vulgare ameliorates type 1 diabetes through antioxidant, anti-inflammatory and anti-apoptotic activity

British Journal Of Nutrition ◽

10.1017/s0007114514004048 ◽

2015 ◽

Vol 113 (5) ◽

pp. 770-782 ◽

Cited By ~ 25

Author(s):

Milica Vujicic ◽

Ivana Nikolic ◽

Vassiliki G. Kontogianni ◽

Tamara Saksida ◽

Pantelis Charisiadis ◽

...

Keyword(s):

Type 1 Diabetes ◽

Diabetes Incidence ◽

Inflammatory Disorder ◽

T Helper ◽

Origanum Vulgare ◽

Anti Inflammatory ◽

The Impact ◽

Diabetes Induction

Type 1 diabetes (T1D), an autoimmune inflammatory disorder, develops as a consequence of pancreatic β-cell destruction and results in hyperglycaemia. Since current T1D therapy mainly involves insulin replacement, the aim of the present study was to evaluate the therapeutic potential of Origanum vulgare L. ssp. hirtum (Greek oregano) leaf extract rich in biophenols for the treatment of T1D. The phytochemical profile of methanolic oregano extract (MOE) and aqueous oregano extract (AOE) was determined by liquid chromatography/electrospray ion-trap tandem MS (LC/DAD/ESI-MSn), while their main compounds were quantified by HPLC with diode array detection. After establishing their potent in vitro antioxidant activity, the extracts were administered to C57BL/6 mice treated with multiple low doses of streptozotocin for diabetes induction. While prophylactic AOE therapy had no impact on diabetes induction, MOE reduced diabetes incidence and preserved normal insulin secretion. In addition, MOE scavenged reactive oxygen and nitrogen species and, therefore, alleviated the need for the up-regulation of antioxidant enzymes. MOE treatment specifically attenuated the pro-inflammatory response mediated by T helper 17 cells and enhanced anti-inflammatory T helper 2 and T regulatory cells through the impact on specific signalling pathways and transcription factors. Importantly, MOE preserved β-cells from in vitro apoptosis via blockade of caspase 3. Finally, rosmarinic acid, a predominant compound in MOE, exhibited only partial protection from diabetes induction. In conclusion, acting as an antioxidant, immunomodulator and in an anti-apoptotic manner, MOE protected mice from diabetes development. Seemingly, there is more than one compound responsible for the beneficial effect of MOE.

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Celiac Disease in Children, Particularly with Accompanying Type 1 Diabetes, Is Characterized by Substantial Changes in the Blood Cytokine Balance, Which May Reflect Inflammatory Processes in the Small Intestinal Mucosa

Journal of Immunology Research ◽

10.1155/2019/6179243 ◽

2019 ◽

Vol 2019 ◽

pp. 1-17 ◽

Cited By ~ 4

Author(s):

Tamara Vorobjova ◽

Aili Tagoma ◽

Astrid Oras ◽

Kristi Alnek ◽

Kalle Kisand ◽

...

Keyword(s):

Type 1 Diabetes ◽

Celiac Disease ◽

Small Bowel ◽

Inflammatory Response ◽

Lamina Propria ◽

Small Bowel Mucosa ◽

Anti Inflammatory ◽

Bowel Mucosa

Cytokines play a pivotal role in the maintenance of intestinal homeostasis inducing pro- or anti-inflammatory response and mucosal barrier function in celiac disease (CD) and type 1 diabetes (T1D). We aimed to compare the levels of pro- and anti-inflammatory cytokines in CD patients without and with coexisting T1D, as well as to evaluate its association with the presence of enteroviruses (EV), regulatory T cells (Tregs), and dendritic cells (DCs) in small bowel mucosa. Altogether, 72 patients (median age 10.1 years) who had undergone small bowel biopsy were studied. The study group consisted of 24 patients with CD (median age 6.5 years), 9 patients with CD and concomitant T1D (median age 7.0 years), two patients with T1D (median age 8.5 years), and 37 patients (median age 14.0 years) with functional gastrointestinal disorders (FGD) and a normal small bowel mucosa as controls. The levels of 33 cytokines in serum were measured by multiple analysis using the Milliplex® MAP Magnetic Bead assay. The densities of FOXP3+ Tregs, CD11c+ DC, indoleamine 2,3-dioxygenase+ (IDO+) DC, langerin+ (CD207+) DCs, and EV were evaluated by immunohistochemistry as described in our previous studies. Circulating anti-EV IgA and IgG were evaluated using ELISA. The most important finding of the study is the significant increase of the serum levels of IL-5, IL-8, IL-13, IL-15, IL-17F, IL-22, IL-27, IP-10, MIP-1β, sIL-2Rα, sTNFRII, and TNFαin CD patients compared to controls and its correlation with the degree of small bowel mucosa damage graded according to the Marsh classification. The leptin level was higher in females in all study groups. The levels of IL-2, IL-6, IL-12 (P70), IL-15, IP-10, and IFNγcorrelated significantly with the density of FOXP3+ Tregs inlamina propriaof the small bowel mucosa, which supports the evidence about the signaling role of these cytokines in the peripheral maintenance of FOXP3+ Tregs. At the same time, a significant negative correlation occurred between the level of IL-4 and density of FOXP3+ Tregs in controls. Another important finding of our study was the correlation of IL-17F, IP-10, sTNFRII, MCP-1, and GM-CSF with the density of EV-positive cells in thelamina propriaof the small bowel mucosa. Correlation of MIP-1 (CCL-4) with CD103+ DC and langerin+ DC densities may point to their significance in the recruitment of immune cells into thelamina propriaand in driving the inflammatory response in CD patients. Our results suggest the predominance of Th1 and Th17 immune responses over EV VP1 protein in CD and T1D patients. The significant elevation of Th2 cytokines, like IL-5 and IL-13, but not IL-4, in CD patients and its correlation with the degree of small bowel mucosa damage could reflect the role of these cytokines in gut defense and inflammation.

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The Role of Age and Excess Body Mass Index in Progression to Type 1 Diabetes in At-Risk Adults

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-01490 ◽

2017 ◽

Vol 102 (12) ◽

pp. 4596-4603

Author(s):

Christine T Ferrara ◽

Susan M Geyer ◽

Carmella Evans-Molina ◽

Ingrid M Libman ◽

Dorothy J Becker ◽

...

Keyword(s):

Body Mass Index ◽

Type 1 Diabetes ◽

Body Mass ◽

Protective Factor ◽

Diabetes Incidence ◽

Increased Risk ◽

Diabetes Progression ◽

The Impact

Abstract Background Given the global rise in both type 1 diabetes incidence and obesity, the role of body mass index (BMI) on type 1 diabetes pathophysiology has gained great interest. Sustained excess BMI in pediatric participants of the TrialNet Pathway to Prevention (PTP) cohort increased risk for progression to type 1 diabetes, but the effects of age and obesity in adults remain largely unknown. Objective To determine the effect of age and sustained obesity on the risk for type 1 diabetes in adult participants in the TrialNet PTP cohort (i.e., nondiabetic autoantibody-positive relatives of patients with type 1 diabetes). Research Design and Methods Longitudinally accumulated BMI >25 kg/m2 was calculated to generate a cumulative excess BMI (ceBMI) for each participant, with ceBMI values ≥0 kg/m2 and ≥5 kg/m2 representing sustained overweight or obese status, respectively. Recursive partitioning analysis yielded sex- and age-specific thresholds for ceBMI that confer the greatest risk for type 1 diabetes progression. Results In this cohort of 665 adults (age 20 to 50 years; median follow-up, 3.9 years), 49 participants developed type 1 diabetes. Age was an independent protective factor for type 1 diabetes progression (hazard ratio, 0.95; P = 0.008), with a threshold of >35 years that reduced risk for type 1 diabetes. In men age >35 years and women age <35 years, sustained obesity (ceBMI ≥5 kg/m2) increased the risk for type 1 diabetes. Conclusions Age is an important factor for type 1 diabetes progression in adults and influences the impact of elevated BMI, indicating an interplay of excess weight, age, and sex in adult type 1 diabetes pathophysiology.

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