Intestinal permeability in type 1 diabetes: An updated comprehensive overview

Mønsted, Mia Øgaard; Falck, Nora Dakini; Pedersen, Kristina; Buschard, Karsten; Holm, Laurits J.; Haupt‐Jorgensen, Martin

doi:10.1016/j.jaut.2021.102674

Cited by 48 publications

(35 citation statements)

References 70 publications

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“…However, in a human cohort of diabetic patients, the level of glycated hemoglobin (HbA1c) was positively correlated with intestinal length [ 18 ]. This result is in accordance with our data, but question intestinal absorptive surface in T1D patients and conclusion on increasing IP in T1D patients based on in vivo measurements ([ 19 – 22 ] and for review [ 23 ]).…”

Section: Discussionsupporting

confidence: 92%

Revisiting definition and assessment of intestinal trans-epithelial passage

Ilchmann-Diounou

Buléon

Bacquié

et al. 2021

Cell. Mol. Life Sci.

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This study aims to remind that Intestinal Passage (IP) measurement is a complex task that cannot be achieved by a unique measure of an orally given exogenous marker in blood or urine. This will be illustrated in the case of NOD mice. Indeed, various methods have been proposed to measure IP. Among them ex vivo measurement in Ussing chambers of luminal to serosal fluxes of exogenous markers and in vivo measurement of exogenous markers in blood or urine after oral gavage are the more commonly used. Even though they are commonly used indifferently, they do not give the same information and can provide contradictory results. Published data showed that diabetic status in female Non Obese Diabetic (NOD) mice increased FD4 concentration in blood after gavage but did not modify FD4 fluxes in Ussing chamber. We observed the same results in our experimental conditions and tracked FD4 concentrations in blood over a kinetic study (Area Under the Curve—AUC). In vivo measurements are a dynamic process and address not only absorption (IP and intestinal surface) but also distribution, metabolism and excretion (ADME). Diabetic status in NOD mice was associated with an increase of intestinal length (absorptive surface), itself positively correlated with AUC of FD4 in blood. We concluded that increased intestinal length induced by diabetic status will extend the absorptive surface and increase FD4 concentration in plasma (in vivo measurement) despite no modification on IP of FD4 (ex vivo measurement). In addition, this study characterized intestinal function in diabetic NOD mice. Diabetic status in NOD female mice increases intestinal length and decreases paracellular IP (FSS) without affecting transcellular IP (HRP, FD4). Histological studies of small and large intestine did not show any modification of intestinal circumference nor villi and crypt size. Finally, diabetic status was not associated with intestinal inflammation (ELISA).

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Section: Discussionsupporting

confidence: 92%

Revisiting definition and assessment of intestinal trans-epithelial passage

Ilchmann-Diounou

Buléon

Bacquié

et al. 2021

Cell. Mol. Life Sci.

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“…Loss of gut epithelial barrier function has been linked to the activation of autoreactive T cells and T1D onset ( 44 ). Moreover, vitamin D was demonstrated to maintain gut barrier integrity ( 45 ).…”

Section: Resultsmentioning

confidence: 99%

“…As mentioned before, intestinal dysbiosis, low-grade intestinal inflammation, and intestinal barrier dysfunction at an early age, allowing increased antigen (i.e., dietary or microbial) trafficking, could trigger T1D initiation via the activation of diabetogenic T cells in the intestinal mucosa ( 44 , 65 ). Alternatively, loss of intestinal barrier function could allow the release of bacterial pathogens with molecular mimicry to islet antigens in the periphery, which could directly damage insulin-producing β cells or activate islet-reactive T cells within the PLN and pancreas ( 8 ).…”

Section: Discussionmentioning

confidence: 99%

High Serum Vitamin D Concentrations, Induced via Diet, Trigger Immune and Intestinal Microbiota Alterations Leading to Type 1 Diabetes Protection in NOD Mice

Vangoitsenhoven

Centelles-Lodeiro²,

Ellis³

et al. 2022

Front. Immunol.

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The hormonally-active form of vitamin D, 1,25-dihydroxyvitamin D3, can modulate both innate and adaptive immunity, through binding to the nuclear vitamin D receptor expressed in most immune cells. A high dose of regular vitamin D protected non-obese diabetic (NOD) mice against type 1 diabetes (T1D), when initiated at birth and given lifelong. However, considerable controversy exists on the level of circulating vitamin D (25-hydroxyvitamin D3, 25(OH)D3) needed to modulate the immune system in autoimmune-prone subjects and protect against T1D onset. Here, we evaluated the impact of two doses of dietary vitamin D supplementation (400 and 800 IU/day), given to female NOD mice from 3 until 25 weeks of age, on disease development, peripheral and gut immune system, gut epithelial barrier function, and gut bacterial taxonomy. Whereas serum 25(OH)D3 concentrations were 2.6- (400 IU/day) and 3.9-fold (800 IU/day) higher with dietary vitamin D supplementation compared to normal chow (NC), only the 800 IU/day vitamin D-supplemented diet delayed and reduced T1D incidence compared to NC. Flow cytometry analyses revealed an increased frequency of FoxP3+ Treg cells in the spleen of mice receiving the 800 IU/day vitamin D-supplemented diet. This vitamin D-induced increase in FoxP3+ Treg cells, also expressing the ecto-5’-nucleotidase CD73, only persisted in the spleen of mice at 25 weeks of age. At this time point, the frequency of IL-10-secreting CD4+ T cells was also increased in all studied immune organs. High-dose vitamin D supplementation was unable to correct gut leakiness nor did it significantly modify the increased gut microbial diversity and richness over time observed in NOD mice receiving NC. Intriguingly, the rise in alpha-diversity during maturation occurred especially in mice not progressing to hyperglycaemia. Principal coordinates analysis identified that both diet and disease status significantly influenced the inter-individual microbiota variation at the genus level. The abundance of the genera Ruminoclostridium_9 and Marvinbryantia gradually increased or decreased, respectively in faecal samples of mice on the 800 IU/day vitamin D-supplemented diet compared to mice on the 400 IU/day vitamin D-supplemented diet or NC, irrespective of disease outcome. In summary, dietary vitamin D reduced T1D incidence in female NOD mice at a dose of 800, but not of 400, IU/day, and was accompanied by an expansion of Treg cells in various lymphoid organs and an altered intestinal microbiota signature.

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“…These results support the previous hypothesis of the loss of intestinal barrier integrity in T1D resulting in low-grade chronic inflammation as well as increased diffusion of bacterial components into the blood. Previous studies showed intestinal barrier dysfunction assessed by measuring blood markers of intestinal damage or bacterial translocation other than I-FABP [ 24 , 25 , 26 ]. Elevated levels of zonulin [ 27 , 28 , 29 ], cytokeratin 18 caspase-cleaved fragment [ 30 ], lipopolysaccharides [ 28 ], and peptidoglycans [ 31 ] indicate both increased paracellular permeability and a profound damage to the intestine, allowing bacterial components to enter the bloodstream.…”

Section: Discussionmentioning

confidence: 99%

Could I-FABP Be an Early Marker of Celiac Disease in Children with Type 1 Diabetes? Retrospective Study from the Tertiary Reference Centre

et al. 2022

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Patients with type 1 diabetes (T1D) are at higher risk of celiac disease (CD). Recently, intestinal fatty acid binding protein (I-FABP) has been shown to be a serological biomarker of impaired intestinal barrier in CD. Thus, the aim of this study was to verify whether I-FABP could be an early marker of CD in pediatric T1D patients. I-FABP was measured in sera of patients with T1D (n = 156), active CD (n = 38), T1D with active CD (T1D-CD, n= 51), and age-matched healthy children (n = 55). Additionally, I-FABP was determined in T1D patients with negative CD serology at least one year before CD diagnosis (T1D-CD-1, n = 22), in CD patients on a gluten-free diet (CD-GFD, n = 36), and T1D-CD patients on GFD (T1D-CD-GFD, n = 39). Sera were tested using immunoenzymatic assay. Significantly increased levels of I-FABP were found in the T1D, active CD, and T1D-CD groups (1153 ± 665, 1104 ± 916, and 1208 ± 878, respectively) in comparison to healthy with controls (485 ± 416, p < 0.05). GFD induced a significant decrease in I-FABP levels in CD and T1D-CD groups (510 ± 492 and 548 ± 439, respectively). Interestingly, in T1D-CD-1 and T1D, I-FABP levels were comparable (833 ± 369 vs. 1153 ± 665), and significantly increased in relation to healthy controls and T1D-CD values on GFD. The results indicate that the epithelial barrier is disrupted in T1D patients independently of CD development; therefore, I-FABP cannot serve as an early marker of CD in T1D patients. Although GFD can improve epithelial recovery, the question remains as to whether GFD could exert beneficial effects on the intestinal barrier in early stages of T1D.

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Intestinal permeability in type 1 diabetes: An updated comprehensive overview

Cited by 48 publications

References 70 publications

Revisiting definition and assessment of intestinal trans-epithelial passage

Revisiting definition and assessment of intestinal trans-epithelial passage

High Serum Vitamin D Concentrations, Induced via Diet, Trigger Immune and Intestinal Microbiota Alterations Leading to Type 1 Diabetes Protection in NOD Mice

Could I-FABP Be an Early Marker of Celiac Disease in Children with Type 1 Diabetes? Retrospective Study from the Tertiary Reference Centre

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