scholarly journals OP36 Investigating the role of bioactives produced by gut bacteria to modulate immune response in inflammatory bowel disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S037-S038
Author(s):  
R Giri ◽  
K Shamsunnahar ◽  
A Salim ◽  
R Capon ◽  
M Morrison ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Ex Vivo ◽  
Gut Bacteria ◽  
Healthy Controls ◽  
Healthy Human ◽  
Chronic Inflammatory Condition ◽  
Inflammatory Bowel ◽  
Colitis Model

Abstract Background inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract. Although the pathogenesis of IBD is not fully understood, it is believed to result from the interaction between various genetic and environmental factors, including the microbiome, resulting in inappropriate gut inflammation. Under homeostatic conditions, the gut immune system exists in a tolerogenic state with the microbiota. However, microbial dysbiosis and an imbalance of pro- and anti-inflammatory cytokines in the gut characterise IBD and recently faecal microbiota transplantation studies have demonstrated that manipulation of the microbiome can induce remission. In this study, the ability of bioactives produced from single species of anaerobic gut bacteria cultured from healthy human faecal samples to modulate NF-kB activity was investigated, their biochemical properties were assessed and their ability to alleviate colitis was also investigated. Methods The NF-κB suppressive effects of culture supernatants (CSs) from 23 different isolates were tested on colonic epithelial cell lines. Suppressive CSs were also tested on human-derived colonic organoids from IBD patients and healthy controls and IL-8 expression was measured. Furthermore, CS from AHG0001 strain was also tested in spontaneous colitis model Winnie in vivo. The supernatant was further characterised by extraction in multiple solvents and fractionated through reversed-phase analytic HPLC column to test for suppressive fractions and further investigate their chemical characteristics. Results LS174T and Caco-2 reporter cells stimulated with TNFα and IL-1β respectively, resulted in NF-κB activation. Of the 23 isolates screened, CS from five isolates significantly suppressed NF-κB activation. The selected CSs also suppressed IL-8 secretion in PBMCs and gut organoids from both UC and CD patients, as well as healthy controls, with notable individual variation. Rectal gavage of CS from AHG0001 also reduced disease activity, improved histologic inflammation and reduced the pro-inflammatory gene expression in Winnie mice. Furthermore, a potent small molecule (IC50 = 3 nM) produced by AHG0001 was also identified through bioassay-guided solvent extractions and filtrations, followed by UPLC-QTOF and comparative metabolomics. Conclusion Our anaerobic culturing and NF-κB reporter assay system allows for the rapid identification of bacteria producing immunomodulatory bioactives, which could lead to the future development of novel therapeutics. Our in vivo and ex vivo testing utilising spontaneous colitis model and patient-derived organoids demonstrates the potential of precision medicine-based approaches for bacterial based therapeutics.

scholarly journals Inflammatory Bowel Disease–associated GP2 Autoantibodies Inhibit Mucosal Immune Response to Adherent-invasive Bacteria

2020 ◽  
Vol 26 (12) ◽  
pp. 1856-1868
Author(s):  
Stefanie Derer ◽  
Ann-Kathrin Brethack ◽  
Carlotta Pietsch ◽  
Sebastian T Jendrek ◽  
Thomas Nitzsche ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Ex Vivo ◽  
Expression Patterns ◽  
Mucosal Immune Response ◽  
Disease Manifestation ◽  
Inflammatory Bowel

Abstract Adherent-invasive Escherichia coli have been suggested to play a pivotal role within the pathophysiology of inflammatory bowel disease (IBD). Autoantibodies against distinct splicing variants of glycoprotein 2 (GP2), an intestinal receptor of the bacterial adhesin FimH, frequently occur in IBD patients. Hence, we aimed to functionally characterize GP2-directed autoantibodies as a putative part of IBD’s pathophysiology. Ex vivo, GP2-splicing variant 4 (GP2#4) but not variant 2 was expressed on intestinal M or L cells with elevated expression patterns in IBD patients. The GP2#4 expression was induced in vitro by tumor necrosis factor (TNF)-α. The IBD-associated GP2 autoantibodies inhibited FimH binding to GP2#4 and were decreased in anti-TNFα-treated Crohn’s disease patients with ileocolonic disease manifestation. In vivo, mice immunized against GP2 before infection with adherent-invasive bacteria displayed exacerbated intestinal inflammation. In summary, autoimmunity against intestinal expressed GP2#4 results in enhanced attachment of flagellated bacteria to the intestinal epithelium and thereby may drive IBD’s pathophysiology.

Alpha-MSH Targeted Liposomal Nanoparticle for Imaging in Inflammatory Bowel Disease (IBD)

2020 ◽  
Vol 26 (31) ◽  
pp. 3840-3846 ◽  
Author(s):  
Tuula Peñate-Medina ◽  
Christabel Damoah ◽  
Miriam Benezra ◽  
Olga Will ◽  
Kalevi Kairemo ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Ex Vivo ◽  
Activity Index ◽  
Disease Activity Index ◽  
Delivery Vehicle ◽  
Disease Treatment ◽  
Melanocortin 1 Receptor ◽  
Inflammatory Bowel

Background: The purpose of our study was to find a novel targeted imaging and drug delivery vehicle for inflammatory bowel disease (IBD). IBD is a common and troublesome disease that still lacks effective therapy and imaging options. As an attempt to improve the disease treatment, we tested αMSH for the targeting of nanoliposomes to IBD sites. αMSH, an endogenous tridecapeptide, binds to the melanocortin-1 receptor (MC1-R) and has anti-inflammatory and immunomodulating effects. MC1-R is found on macrophages, neutrophils and the renal tubule system. We formulated and tested a liposomal nanoparticle involving αMSH in order to achieve a specific targeting to the inflamed intestines. Methods: NDP-αMSH peptide conjugated to Alexa Fluor™ 680 was linked to the liposomal membrane via NSuccinyl PE and additionally loaded into the lumen of the liposomes. Liposomes without the αMSH-conjugate and free NDP-αMSH were used as a control. The liposomes were also loaded with ICG to track them. The liposomes were tested in DSS treated mice, which had received DSS via drinking water order to develop a model IBD. Inflammation severity was assessed by the Disease Activity Index (DAI) score and ex vivo histological CD68 staining of samples taken from different parts of the intestine. The liposome targeting was analyzed by analyzing the ICG and ALEXA 680 fluorescence in the intestine compared to the biodistribution. Results: NPD-αMSH was successfully labeled with Alexa and retained its biological activity. Liposomes were identified in expected regions in the inflamed bowel regions and in the kidneys, where MC1-R is abundant. In vivo liposome targeting correlated with the macrophage concentration at the site of the inflammation supporting the active targeting of the liposomes through αMSH. The liposomal αMSH was well tolerated by animals. Conclusions: This study opens up the possibility to further develop an αMSH targeted theranostic delivery to different clinically relevant applications in IBD inflammation but also opens possibilities for use in other inflammations like lung inflammation in Covid 19.

scholarly journals A Gut-Ex-Vivo System to Study Gut Inflammation Associated to Inflammatory Bowel Disease (IBD)

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 605
Author(s):  
Mara Gagliardi ◽  
Romina Monzani ◽  
Nausicaa Clemente ◽  
Luca Fusaro ◽  
Valentina Saverio ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Dynamic Condition ◽  
Transglutaminase 2 ◽  
Effective Manner ◽  
Junction Protein ◽  
Inflammatory Bowel

Inflammatory bowel disease (IBD) is a complex, chronic, and dysregulated inflammatory condition which etiology is still largely unknown. Its prognosis and disease progression are highly variable and unpredictable. IBD comprises several heterogeneous inflammatory conditions ranging from Ulcerative Colitis (UC) to Crohn’s Disease (CD). Importantly, a definite, well-established, and effective clinical treatment for these pathologies is still lacking. The urgent need for treatment is further supported by the notion that patients affected by UC or CD are also at risk of developing cancer. Therefore, a deeper understanding of the molecular mechanisms at the basis of IBD development and progression is strictly required to design new and efficient therapeutic regimens. Although the development of animal models has undoubtedly facilitated the study of IBD, such in vivo approaches are often expensive and time-consuming. Here we propose an organ ex vivo culture (Gut-Ex-Vivo system, GEVS) based on colon from Balb/c mice cultivated in a dynamic condition, able to model the biochemical and morphological features of the mouse models exposed to DNBS (5–12 days), in 5 h. Indeed, upon DNBS exposure, we observed a dose-dependent: (i) up-regulation of the stress-related protein transglutaminase 2 (TG2); (ii) increased intestinal permeability associated with deregulated tight junction protein expression; (iii) increased expression of pro-inflammatory cytokines, such as TNFα, IFNγ, IL1β, IL6, IL17A, and IL15; (iv) down-regulation of the anti-inflammatory IL10; and (v) induction of Endoplasmic Reticulum stress (ER stress), all markers of IBD. Altogether, these data indicate that the proposed model can be efficiently used to study the pathogenesis of IBD, in a time- and cost-effective manner.

scholarly journals WISP1 Is Increased in Intestinal Mucosa and Contributes to Inflammatory Cascades in Inflammatory Bowel Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Qi Zhang ◽  
Cuiping Zhang ◽  
Xiaoyu Li ◽  
Yanan Yu ◽  
Kun Liang ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Mononuclear Cells ◽  
Regulatory Mechanisms ◽  
Matricellular Protein ◽  
Healthy Controls ◽  
Trinitrobenzenesulfonic Acid ◽  
Inflammatory Bowel ◽  
Colonic Biopsies

Inflammatory bowel disease (IBD) is mainly characterized by intestinal tissue damage, which is caused by excessive autoimmune responses poorly controlled by corresponding regulatory mechanisms. WISP1, which belongs to the CCN protein family, is a secreted matricellular protein regulating several inflammatory pathways, such as Wnt/β-catenin pathway, and has been reported in several diseases including cancer. Here we examined the expression, regulatory mechanisms, and functions of WISP1 in IBD. WISP1 mRNA and protein expression was upregulated in colonic biopsies and lamina propria mononuclear cells (LPMC) of IBD patients compared with those of healthy controls. Tumor necrosis factor- (TNF-)αinduced WISP1 expression in LPMC from healthy controls. Consistently, WISP1 mRNA expression was downregulated in colonic biopsies from IBD patients who had achieved clinical remission with infliximab (IFX). Furthermore, WISP1 expression was also found to be increased in colons from 2,4,6-trinitrobenzenesulfonic acid- (TNBS-) induced mice compared with those from control mice. Further studies confirmed that administration of rWISP1 could aggravate TNBS-induced colitis in vivo. Therefore, we concluded that WISP1 is increased in IBD and contributes to the proinflammatory cascades in the gut.

scholarly journals Anti-Inflammatory Effects of Urocanic Acid Derivatives in Models Ex Vivo and In Vivo of Inflammatory Bowel Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Arthur Kammeyer ◽  
Charlotte P. Peters ◽  
Sybren L. Meijer ◽  
Anje A. te Velde
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Ex Vivo ◽  
Urocanic Acid ◽  
Ethyl Esters ◽  
Fine Tuning ◽  
Additional Indication ◽  
Inflammatory Bowel ◽  
Anti Inflammatory

Urocanic acid (UCA) derivatives were tested for their anti-inflammatory activity in inflammatory bowel disease (IBD) in two models: ex vivo and an experimental mouse model. Ex vivo: inflamed colonic tissue was incubated in culture medium with or without the UCA derivatives. Biopsies, incubated with UCA derivatives, produced lower levels of proinflammatory cytokines IL-6 and IL-8 as compared to control biopsies. The same compounds also showed increased levels of IL-10, providing an additional indication for anti-inflammatory properties. In vivo: a combination of two imidazoles and a combination of two of their ethyl esters were administered to mice while colitis was induced by oral administration of dextran sodium sulfate (DSS). Some parameters did not show conclusive effects, but the imidazoles and their ethyl esters reduced the area of inflammation and the number of infiltrating neutrophils. Fibrosis and the sum of all histological aspects were reduced by the imidazoles, whereas the ethyl esters reduced the colon weight to length ratio. These results suggest that the UCA derivatives have anti-inflammatory effect on IBD. In addition, fine tuning of the ex vivo model may provide an elegant way to predict anti-inflammatory effects of potential drugs in humans, which may decrease the need for animal experiments.

scholarly journals Five genetic markers in the interleukin 1 family in relation to inflammatory bowel disease

Gut ◽  
1998 ◽  
Vol 43 (1) ◽  
pp. 33-39 ◽  
Author(s):  
P C F Stokkers ◽  
B E van Aken ◽  
N Basoski ◽  
P H Reitsma ◽  
G N J Tytgat ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Genetic Markers ◽  
Bowel Disease ◽  
Cytokine Production ◽  
Ex Vivo ◽  
Interleukin 1 ◽  
Healthy Controls ◽  
Allelic Frequencies ◽  
Length Polymorphisms ◽  
Inflammatory Bowel

Background—An imbalance between the proinflammatory cytokine interleukin 1β (IL-1β) and the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1ra) has been postulated as a pathogenic factor in inflammatory bowel disease (IBD).Aims—To study allelic frequencies of novel polymorphisms in the genes for IL-1β and IL-1ra in patients with IBD and to assess the relation between ex vivo cytokine production and allelic variants of the IL-1β and IL-1ra genes.Subjects—Two hundred and seventy healthy controls, 74 patients with ulcerative colitis (UC), 72 with Crohn’s disease (CD), 40 with primary sclerosing cholangitis for the allelic frequencies, and 60 healthy individuals for the ex vivo stimulation test.Methods—Genotyping was performed by polymerase chain reaction and subsequent cleavage with specific endonucleases (Mwo1, MspAI1, Alu1, Taq1, BsoF1) for five novel restriction fragment length polymorphisms (RFLPs) in the genes for IL-1ra and IL-1β.Results—No significant differences were found in the allelic frequencies or allele carriage rates of the markers in the IL-1β and IL-1ra genes between CD, UC, and healthy controls. No association between the genetic markers and cytokine production levels was observed. Patients with UC carried the combination of both the infrequent allele of the Taq1 RFLP and the Mwo1 RFLP significantly more frequently (35.2% in UC versus 71.1% in controls).Conclusions—UC is associated with carriage of both infrequent alleles of the Taq1 and Mwo1 RFLPs. However, it could not be confirmed whether the association reflects a pathogenic mechanism underlying UC.

Experimental and Clinical Evidence of Endothelial Dysfunction in Inflammatory Bowel Disease

2020 ◽  
Vol 26 (30) ◽  
pp. 3733-3747 ◽  
Author(s):  
Mariana Ferreira-Duarte ◽  
Joana Beatriz Sousa ◽  
Carmen Diniz ◽  
Teresa Sousa ◽  
Margarida Duarte-Araújo ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Endothelial Dysfunction ◽  
Bowel Disease ◽  
Clinical Evidence ◽  
High Cardiovascular Risk ◽  
Considerable Evidence ◽  
Chronic Inflammatory Condition ◽  
Inflammatory Bowel ◽  
Repurposed Drugs ◽  
Main Effects

The endothelium has a crucial role in proper hemodynamics. Inflammatory bowel disease (IBD) is mainly a chronic inflammatory condition of the gastrointestinal tract. However, considerable evidence points to high cardiovascular risk in patients with IBD. This review positions the basic mechanisms of endothelial dysfunction in the IBD setting (both clinical and experimental). Furthermore, we review the main effects of drugs used to treat IBD in endothelial (dys)function. Moreover, we leave challenging points for enlarging the therapeutic arsenal for IBD with new or repurposed drugs that target endothelial dysfunction besides inflammation.

Preparation, characterization, and in vivo evaluation of anti-inflammatory activities of selenium nanoparticles synthesized by Kluyveromyces lactis GG799

2021 ◽  
Author(s):  
Xiao fan Song ◽  
Lei Qiao ◽  
Shuqi Yan ◽  
Yue Chen ◽  
Xina Dou ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Kluyveromyces Lactis ◽  
Selenium Nanoparticles ◽  
Human Diseases ◽  
In Vivo Evaluation ◽  
Inflammatory Bowel ◽  
Anti Inflammatory

Selenium (Se) as an essential micronutrient that has implications in human diseases, including inflammatory bowel disease (IBD), especially with respect to Se deficiencies. Recently, selenium nanoparticles (SeNPs) have attracted significant...

scholarly journals The food additive EDTA aggravates colitis and colon carcinogenesis in mouse models

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rayko Evstatiev ◽  
Adam Cervenka ◽  
Tina Austerlitz ◽  
Gunther Deim ◽  
Maximilian Baumgartner ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Mouse Models ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Food Additives ◽  
Colorectal Carcinogenesis ◽  
Testing Procedures ◽  
Inflammatory Models ◽  
Inflammatory Bowel

AbstractInflammatory bowel disease is a group of conditions with rising incidence caused by genetic and environmental factors including diet. The chelator ethylenediaminetetraacetate (EDTA) is widely used by the food and pharmaceutical industry among numerous other applications, leading to a considerable environmental exposure. Numerous safety studies in healthy animals have revealed no relevant toxicity by EDTA. Here we show that, in the presence of intestinal inflammation, EDTA is surprisingly capable of massively exacerbating inflammation and even inducing colorectal carcinogenesis at doses that are presumed to be safe. This toxicity is evident in two biologically different mouse models of inflammatory bowel disease, the AOM/DSS and the IL10−/− model. The mechanism of this effect may be attributed to disruption of intercellular contacts as demonstrated by in vivo confocal endomicroscopy, electron microscopy and cell culture studies. Our findings add EDTA to the list of food additives that might be detrimental in the presence of intestinal inflammation, but the toxicity of which may have been missed by regulatory safety testing procedures that utilize only healthy models. We conclude that the current use of EDTA especially in food and pharmaceuticals should be reconsidered. Moreover, we suggest that intestinal inflammatory models should be implemented in the testing of food additives to account for the exposure of this primary organ to environmental and dietary stress.

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