FoxO1 regulates TLR4/MyD88/MD2‐NF‐κB inflammatory signalling in mucosal barrier injury of inflammatory bowel disease

Inflammatory damage to the bowel, as occurs in inflammatory bowel disease (IBD), is debilitating to patients. In both patients and animal experimental models, histological analyses of biopsies and endoscopic examinations are used to evaluate the disease state. However, such measurements often have delays and are invasive, while endoscopy is not quantitatively objective. Therefore, a real-time quantitative method to assess compromised mucosal barrier function is advantageous. We investigated the correlation of in vivo changes in electrical transmural impedance with histological measures of inflammation. Four platinum (Pt) ball electrodes were placed in the lumen of the rat small intestine, with a return electrode under the skin. Electrodes placed within the non-inflamed intestine generated stable impedances during the 3 h testing period. Following an intraluminal injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS), an established animal model of IBD, impedances in the inflamed region significantly decreased relative to a region not exposed to TNBS ( p < 0.05). Changes in intestinal transmural impedance were correlated ( p < 0.05) with histologically assessed damage to the mucosa and increases in neutrophil, eosinophil and T-cell populations at 3 h compared with tissue from control regions. This quantitative, real-time assay may have application in the diagnosis and clinical management of IBD.

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Role of RING-Type E3 Ubiquitin Ligases in Inflammatory Signalling and Inflammatory Bowel Disease

Mediators of Inflammation ◽

10.1155/2020/5310180 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Liguo Zhu ◽

Ying Li ◽

Longyuan Zhou ◽

Guang Yang ◽

Ying Wang ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Protein Modification ◽

Ubiquitin Ligases ◽

E3 Ubiquitin Ligases ◽

Ring Type ◽

Ubiquitin Ligase E3 ◽

Inflammatory Bowel ◽

Inflammatory Signalling ◽

Functional Mechanisms

Ubiquitination is a three-step enzymatic cascade for posttranslational protein modification. It includes the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3). RING-type E3 ubiquitin ligases catalyse the posttranslational proteolytic and nonproteolytic functions in various physiological and pathological processes, such as inflammation-associated signal transduction. Resulting from the diversity of substrates and functional mechanisms, RING-type ligases regulate microbe recognition and inflammation by being involved in multiple inflammatory signalling pathways. These processes also occur in autoimmune diseases, especially inflammatory bowel disease (IBD). To understand the importance of RING-type ligases in inflammation, we have discussed their functional mechanisms in multiple inflammation-associated pathways and correlation between RING-type ligases and IBD. Owing to the limited data on the biology of RING-type ligases, there is an urgent need to analyse their potential as biomarkers and therapeutic targets in IBD in the future.

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Intestinal Permeability in Inflammatory Bowel Disease: Pathogenesis, Clinical Evaluation, and Therapy of Leaky Gut

Mediators of Inflammation ◽

10.1155/2015/628157 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 181

Author(s):

Andrea Michielan ◽

Renata D’Incà

Keyword(s):

Inflammatory Bowel Disease ◽

Intestinal Permeability ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Mucosal Barrier ◽

Mucosal Inflammation ◽

Confocal Laser Endomicroscopy ◽

Confocal Laser ◽

Sugar Absorption ◽

Inflammatory Bowel

The pathogenesis of inflammatory bowel disease (IBD) is multifactorial with data suggesting the role of a disturbed interaction between the gut and the intestinal microbiota. A defective mucosal barrier may result in increased intestinal permeability which promotes the exposition to luminal content and triggers an immunological response that promotes intestinal inflammation. IBD patients display several defects in the many specialized components of mucosal barrier, from the mucus layer composition to the adhesion molecules that regulate paracellular permeability. These alterations may represent a primary dysfunction in Crohn’s disease, but they may also perpetuate chronic mucosal inflammation in ulcerative colitis. In clinical practice, several studies have documented that changes in intestinal permeability can predict IBD course. Functional tests, such as the sugar absorption tests or the novel imaging technique using confocal laser endomicroscopy, allow anin vivoassessment of gut barrier integrity. Antitumor necrosis factor-α(TNF-α) therapy reduces mucosal inflammation and restores intestinal permeability in IBD patients. Butyrate, zinc, and some probiotics also ameliorate mucosal barrier dysfunction but their use is still limited and further studies are needed before considering permeability manipulation as a therapeutic target in IBD.

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SUMOylation pathway alteration coupled with downregulation of SUMO E2 enzyme at mucosal epithelium modulates inflammation in inflammatory bowel disease

Open Biology ◽

10.1098/rsob.170024 ◽

2017 ◽

Vol 7 (6) ◽

pp. 170024 ◽

Cited By ~ 7

Author(s):

Salman Ahmad Mustfa ◽

Mukesh Singh ◽

Aamir Suhail ◽

Gayatree Mohapatra ◽

Smriti Verma ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Endoscopic Biopsy ◽

Spectrometric Analysis ◽

Post Translational Modification ◽

Inflammatory Gene Expression ◽

Cellular Processes ◽

Mucosal Tissues ◽

Inflammatory Bowel ◽

Inflammatory Signalling

Post-translational modification pathways such as SUMOylation are integral to all cellular processes and tissue homeostasis. We investigated the possible involvement of SUMOylation in the epithelial signalling in Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD). Initially in a murine model of IBD, induced by dextran–sulfate–sodium (DSS mice), we observed inflammation accompanied by a lowering of global SUMOylation of colonic epithelium. The observed SUMOylation alteration was due to a decrease in the sole SUMO E2 enzyme (Ubc9). Mass-spectrometric analysis revealed the existence of a distinct SUMOylome (SUMO-conjugated proteome) in DSS mice with alteration of key cellular regulators, including master kinase Akt1. Knocking-down of Ubc9 in epithelial cells resulted in dramatic activation of inflammatory gene expression, a phenomenon that acted via reduction in Akt1 and its SUMOylated form. Importantly, a strong decrease in Ubc9 and Akt1 was also seen in endoscopic biopsy samples ( N = 66) of human CD and UC patients. Furthermore, patients with maximum disease indices were always accompanied by severely lowered Ubc9 or SUMOylated-Akt1. Mucosal tissues with severely compromised Ubc9 function displayed higher levels of pro-inflammatory cytokines and compromised wound-healing markers. Thus, our results reveal an important and previously undescribed role for the SUMOylation pathway involving Ubc9 and Akt1 in modulation of epithelial inflammatory signalling in IBD.

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P059 Cytokine responsive transcriptional networks in inflammatory bowel disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.188 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S164-S164

Author(s):

A Treveil ◽

P Pavlidis ◽

A Tsakmaki ◽

G Bewick ◽

T Korcsmaros ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Inflammatory Diseases ◽

Mucosal Healing ◽

Mucosal Barrier ◽

Transcriptional Networks ◽

Intestinal Epithelial ◽

Transcriptomics Data ◽

Inflammatory Bowel ◽

Regulatory Effects

Abstract Background Interactions between the immune system and the intestinal epithelium play an important role in the pathogenesis of chronic immune mediated inflammatory diseases, including inflammatory bowel disease (IBD). In IBD, debilitating symptoms and complications including abscesses and cancer are associated with aberrant cytokine production and resulting intestinal epithelial damage. Despite the advent of biological therapies targeting key pathogenic cytokines, like tumour necrosis α (TNF), only 18% of IBD patients will achieve complete disease control and mucosal healing. Here, we provide new insights into the epithelial response to cytokines using network analysis of transcriptomics data from colonic organoids (colonoids). Methods We generated an atlas of the transcriptomic effects of cytokines by treating human-derived colonoids with IFNg, IL13, IL9, IL17A and TNF (independently). By integrating the observed transcriptional changes with previously published signalling and regulatory interactions, we generated causal networks to elucidate the effect of cytokine cues on epithelial cells. These networks comprised experimentally verified protein–protein and transcription factor (TF)–target gene interactions, forming signalling pathways linking cytokines to TFs and from TFs to differentially expressed genes. Results With this analysis, we identified previously unrecognised levels of shared and distinct transcriptional regulation of colonic epithelial function by different cytokines. While IL9 had a negligible impact on the transcriptome, the transcripts with differential expression induced by IFNg, IL13, IL17A or TNF were consistent with their recognised function in other tissues. IFNg and TNF exhibited similar magnitude and directional effects on key immune pathways while IL13 had the opposite effect. Using a network approach, we found that regulatory effects of cytokines are primarily transduced through unique signalling routes, some of which converge on the same key transcription factors; CEBPA, E2F1, E2F2, ETS1, FOS, IRF1 and MAZ. We observed independent regulatory mechanisms of the different cytokines as well as complementarity in the epithelial responses regulated by different canonical cytokines. Conclusion The generated cytokine transcriptional atlas provides a unique insight into the immune-epithelial interactome by allowing the identification of shared and distinct transcriptional pathways across different types of immunity at the mucosal barrier. In addition, it provides the unique opportunity to study cytokine responses in the context of human disease and generate novel hypotheses.

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Bacteria in the pathogenesis of inflammatory bowel disease

Biochemical Society Transactions ◽

10.1042/bst0391067 ◽

2011 ◽

Vol 39 (4) ◽

pp. 1067-1072 ◽

Cited By ~ 25

Author(s):

Paul Flanagan ◽

Barry J. Campbell ◽

Jonathan M. Rhodes

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Twin Studies ◽

Mucosal Barrier ◽

Pathogenic Role ◽

Genetic Studies ◽

Bacterial Interactions ◽

Risk Alleles ◽

Inflammatory Bowel

Twin studies have demonstrated the importance of environmental factors in the pathogenesis of inflammatory bowel disease, but progress has been relatively slow in identifying these, with the exception of smoking, which is positively associated with Crohn's disease and negatively associated with ulcerative colitis. Genetic studies have identified risk alleles which are involved in host–bacterial interactions and the mucosal barrier, and evidence is building for a likely pathogenic role for changes in the gut microbiome, with respect to both faecal and mucosa-associated microbiota. Some of these changes may be secondary to inflammation, nevertheless promising new therapeutic targets are beginning to emerge.

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Inflammatory bowel disease is associated with changes of enterocytic junctions

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2001.281.1.g216 ◽

2001 ◽

Vol 281 (1) ◽

pp. G216-G228 ◽

Cited By ~ 231

Author(s):

Nikolaus Gassler ◽

Claudia Rohr ◽

Armin Schneider ◽

Jürgen Kartenbeck ◽

Alfred Bach ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Inflammatory Process ◽

Mucosal Barrier ◽

Altered Expression ◽

Control Subjects ◽

Mucosal Tissues ◽

Associated Proteins ◽

Junctional Protein ◽

Inflammatory Bowel

Changes of the intestinal mucosal barrier are considered to play a role in the pathogenesis of inflammatory bowel disease (IBD). Our experiments were designed to identify dysregulation of epithelial junctional molecules in the IBD intestinum and to address whether altered expression of these molecules is a primary event in IBD or a phenomenon secondary to the inflammatory process. Noninflamed and inactively and actively inflamed mucosal tissues from patients with ulcerative colitis or Crohn's disease as well as tissues from control subjects were analyzed for the expression of junctional molecules by different methods. Marked downregulation of junctional proteins and their respective mRNAs was observed in actively inflamed IBD tissues. In IBD tissues with inactive inflammation, only a few junctional molecules such as E-cadherin and α-catenin were affected, whereas expression of desmosomal or tight junction-associated proteins appeared almost unchanged. In noninflamed IBD tissues, junctional protein expression was not different from that seen in normal control subjects. In IBD, downregulation of junctional molecule expression is apparently associated with the inflammatory process and does not likely represent a primary phenomenon.

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Streptococcus thermophilus NCIMB 41856 ameliorates signs of colitis in an animal model of inflammatory bowel disease

Beneficial Microbes ◽

10.3920/bm2016.0110 ◽

2017 ◽

Vol 8 (4) ◽

pp. 605-614 ◽

Cited By ~ 9

Author(s):

J.R. Bailey ◽

V. Vince ◽

N.A. Williams ◽

T.A. Cogan

Keyword(s):

Inflammatory Bowel Disease ◽

Gastrointestinal Bleeding ◽

Bacterial Translocation ◽

Bowel Disease ◽

Clinical Signs ◽

Streptococcus Thermophilus ◽

Mucosal Barrier ◽

Bodyweight Loss ◽

Mucosal Barrier Function ◽

Inflammatory Bowel

Treatment of inflammatory bowel disease (IBD) is mainly based on suppression of symptoms, often with numerous side effects. Trials of probiotics in IBD have frequently produced disappointing results. The majority of probiotics are unusual, since they do not require iron for growth, unlike many bacteria resident in the intestine. The IBD intestine is iron-rich due to bleeding and use of oral iron supplements; conventional probiotics would be rapidly outcompeted. We have evaluated an iron-responsive Streptococcus thermophilus strain for its potential to reduce signs of colitis. Efficacy of S. thermophilus was evaluated in the dextran sodium sulphate mouse model of colitis. Treated animals were given 1×108 cfu S. thermophilus per day and clinical observations were taken daily. At termination, gross and histopathological signs of disease, cellular infiltration, location of bacteria, and cytokine expression in the intestine were determined. S. thermophilus delayed onset of colitis and reduced clinical signs of disease, including bodyweight loss and gastrointestinal bleeding. It reduced bacterial translocation into the colonic tissue. Increased numbers of CD8+ intraepithelial lymphocytes were seen in control animals treated with S. thermophilus. S. thermophilus had no effect on gross pathology, histopathology or cytokine production in either colitic or control animals. We propose that S. thermophilus promotes maintenance of mucosal barrier function which reduces bacterial translocation, thereby reducing immune stimulation and associated inflammation. This allows mucosal healing, reducing gastrointestinal bleeding and weight loss. This could be studied as a locally-acting adjunct or alternative to current IBD treatments.

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