Function of the intestinal epithelium and its dysregulation in inflammatory bowel disease

Henderson, Paul; Limbergen, Johan Van; Schwarze, Jürgen; Wilson, David C.

doi:10.1002/ibd.21379

Cited by 108 publications

(115 citation statements)

References 203 publications

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“…Therefore, the altered expression of inflammation-associated genes may be the initial abnormality in the pathogenesis of IBD, which is supported by the finding that IBD is a disease caused by an unbalanced immune response to intestinal commensal organisms (24)(25)(26). However, it is also possible that abnormal cell structure may trigger the impairment of barrier function prior to the induction of an unbalanced immune response to the gut microbiota (27). The precise associations among inflammation, nutrition absorption and cell structure require further investigation.…”

Section: Discussionmentioning

confidence: 94%

Gene expression alterations in inflamed and unaffected colon mucosa from patients with mild inflammatory bowel disease

Lian

et al. 2016

Molecular Medicine Reports

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Abstract. An endoscopic examination is currently the most reliable method for monitoring disease activity in patients with inflammatory bowel disease (IBD). However, endoscopic evaluations are unable to detect mucosal inflammation at the earliest stages. The present study aimed to evaluate the molecular profiles of inflamed and unaffected colon mucosa from patients with mild Crohn's disease (CD) and ulcerative colitis (UC), in order to identify a more sensitive method for monitoring mucosal impairment. Patients were recruited and colon biopsies from the inflamed and the normal-appearing mucosa of patients with mild IBD were obtained by colonoscopy. Gene expression analysis was performed using microarrays, after which Gene Ontology and clustering were performed using bioinformatics. In addition, the levels of inflammatory cytokines were analyzed by reverse transcription-quantitative polymerase chain reaction. A total of 620 genes in the inflamed and 210 genes in the unaffected colon mucosa with at least a 3-fold change, as compared with healthy controls, were detected in patients with mild CD, and 339 genes in the inflamed and 483 genes in the unaffected colon mucosa were detected in patients with mild UC. Heat mapping demonstrated a similarity in the gene alteration patterns, and altered transcripts overlapped, between the inflamed and unaffected colon mucosa. Interferon-γ and interleukin-17 mRNA levels were comparably elevated in the inflamed and unaffected colon mucosa from patients with IBD. Marked gene expression alterations were detected in the inflamed and unaffected colon mucosa from patients with mild IBD, and these showed marked similarity and overlap between the two groups. The results of the present study suggested that inflammation was not limited to the endoscopic lesions and that gene expression profiling may be considered a sensitive tool for monitoring mucosal inflammation, predicting relapses and optimizing therapeutic strategies for patients with IBD.

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Section: Discussionmentioning

confidence: 94%

Gene expression alterations in inflamed and unaffected colon mucosa from patients with mild inflammatory bowel disease

Lian

et al. 2016

Molecular Medicine Reports

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“…Repeated intestinal epithelial damage and the consequent disruption of the intestinal barrier function is a key mechanism of IBD [3,6]. Namely, the alteration of intestinal barrier function may result in translocation of commensal bacteria into the intestinal wall, leading to uncontrolled T-cell activation and inflammation.…”

Section: Restoration Of Barrier Dysfunction and Stimulation Of Mucosamentioning

confidence: 99%

“…The recent consensus is that IBDs are initiated and perpetuated by an impaired immune response against the gut microbiota in genetically susceptible individuals [1,2] and the disease is caused by a combination of factors, including genetics, immune dysregulation, barrier dysfunction, change in microbial flora and environmental influences (see reviews [3][4][5][6][7]). …”

Section: Introductionmentioning

confidence: 99%

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Gyires¹,

Tóth²,

Zádori

2014

CPD

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Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory condition of the gastrointestinal tract. The two main forms of IBD are Crohn's disease and ulcerative colitis. According to the recent concept the disease is caused by a combination of factors, including genetics, immune dysregulation, barrier dysfunction and the change in microbial flora. Environmental factors, such as changes in diet, antibiotic use, smoking or improved domestic hygiene (e.g. eradication of intestinal helminths) probably contribute to the development and increased prevalence of IBD. Dysregulation of mucosal immunity in IBD causes an overproduction of inflammatory cytokines which resulted in uncontrolled intestinal inflammation. Based on extensive research over the last decade, besides the conventional therapy, there are several novel pathways and specific targets, on which focus new therapeutics. New therapeutics aim 1./ to correct genetic susceptibility by stimulating NOD2 expression, TLR3 signaling or inhibition of TLR4 pathway, 2./ to restore the immune dysregulation by inhibition of pro-inflammatory cytokines (TNF-, IL-6, IL-13, IL-17, IL-18, IL-21), Th1 polarisation (IL-2, IL-12, IL-23, IFN-), T-cell activation, leukocyte adhesion, as well as by immunostimulation (GM-CSF, G-CSF) and anti-inflammatory cytokines (IL-10, IL-11, IFN--1a), 3./ to restore mucosal barrier function and stimulate mucosal healing by different growth factors, such as GH, EGF, KGF, TGF-, VEGF, 4./ to restore the normal bacterial flora by antibiotics, probiotics. However, in spite of these numerous potential targets, the true value and clinical significance of most of the new biologics and molecules are not clear yet.

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“…In contrast, Sirt6 is a nuclear and chromatin-bound protein that emerges as an important epigenetic regulator regions of the world (2,3). Crypt epithelial cell damage associated with colonic inflammation is a distinctive pathological hallmark of IBD (4). However, prevention and treatment of IBD remain a challenge, as the pathogenesis of the iNTRODuCTiON Inflammatory bowel disease (IBD) is an idiopathic disorder affecting approximately 1.5 million Americans and others worldwide (1,2).…”

mentioning

confidence: 99%

Sirtuin-6 Preserves R-spondin-1 Expression and increases Resistance of intestinal Epithelium to injury in Mice

Liu¹,

Bu²,

Geng³

et al. 2017

Mol Med

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Sirtuin-6 (Sirt6) is a critical epigenetic regulator, but its function in the gut is unknown. Here, we studied the role of intestinal epithelial Sirt6 in colitis-associated intestinal epithelial injury. We found that Sirt6, which is predominantly expressed in epithelial cells in intestinal crypts, is decreased in colitis in both mice and humans. Colitis-derived inflammatory mediators including interferon-γ and reactive oxygen species strongly inhibited Sirt6 protein expression in young adult mouse colonocyte (YAMC) cells. The susceptibility of the cells to injurious insults was increased after knockdown of Sirt6 expression. In contrast, YAMC cells with Sirt6 overexpression exhibited more resistance to injurious insult. Furthermore, intestinal epithelial-specific Sirt6 (Sirt6 IEC-KO) knockout mice exhibited greater susceptibility to dextran sulfate sodium (DSS)-induced colitis. RNA sequencing transcriptome analysis revealed that inflammatory mediators such as tumor necrosis factor (TNF)-α suppressed expression of R-spondin-1 (Rspo1, a critical growth factor for intestinal epithelial cells) in Sirt6-silenced YAMC cells in vitro. In addition, lipopolysaccharide was found to inhibit colonic Rspo1 expression in Sirt6 IEC-KO mice but not their control littermates. Furthermore, Sirt6 IEC-KO mice with DSS-induced colitis also exhibited in a significant decrease in Rspo1 expression in colons. In vitro, knockdown of Rspo1 attenuated the effect of ectopic expression of Sirt6 on protection of YAMC cells against cell death challenges. In conclusion, Sirt6 plays an important role in protecting intestinal epithelial cells against inflammatory injury in a mechanism associated with preserving Rspo1 levels in the cells.

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Function of the intestinal epithelium and its dysregulation in inflammatory bowel disease

Cited by 108 publications

References 203 publications

Gene expression alterations in inflamed and unaffected colon mucosa from patients with mild inflammatory bowel disease

Gene expression alterations in inflamed and unaffected colon mucosa from patients with mild inflammatory bowel disease

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Sirtuin-6 Preserves R-spondin-1 Expression and increases Resistance of intestinal Epithelium to injury in Mice

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