From genetics of inflammatory bowel disease towards mechanistic insights

Graham, Daniel B.; Xavier, Ramnik J.

doi:10.1016/j.it.2013.04.001

Cited by 85 publications

(79 citation statements)

References 95 publications

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“…Numerous genetic studies have tried to identify genes implicated in IBD onset, and more than 160 susceptibility loci have been implicated in IBD, yet these loci only account for a small fraction of disease heritability (10). Accumulating evidence has also pointed to epigenetics as an important factor (3).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic control of intestinal barrier function and inflammation in zebrafish

Marjoram¹,

Alvers²,

Deerhake

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

166

168

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The intestinal epithelium forms a barrier protecting the organism from microbes and other proinflammatory stimuli. The integrity of this barrier and the proper response to infection requires precise regulation of powerful immune homing signals such as tumor necrosis factor (TNF). Dysregulation of TNF leads to inflammatory bowel diseases (IBD), but the mechanism controlling the expression of this potent cytokine and the events that trigger the onset of chronic inflammation are unknown. Here, we show that loss of function of the epigenetic regulator ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1) in zebrafish leads to a reduction in tnfa promoter methylation and the induction of tnfa expression in intestinal epithelial cells (IECs). The increase in IEC tnfa levels is microbe-dependent and results in IEC shedding and apoptosis, immune cell recruitment, and barrier dysfunction, consistent with chronic inflammation. Importantly, tnfa knockdown in uhrf1 mutants restores IEC morphology, reduces cell shedding, and improves barrier function. We propose that loss of epigenetic repression and TNF induction in the intestinal epithelium can lead to IBD onset.inflammation | Uhrf1 | DNA methylation | tumor necrosis factor | zebrafish I ntestinal epithelial cells (IECs) function as a barrier to prevent luminal contents from accessing underlying tissues, and loss of barrier function is a crucial factor leading to the development of inflammatory bowel diseases (IBD) (1). IBD, including Crohn's disease and ulcerative colitis, are intestinal disorders of poorly understood origin thought to arise from genetic susceptibility, luminal microbiota, immune responses, and environmental factors (2-4). A key element in IBD onset is the up-regulation of the proinflammatory cytokine tumor necrosis factor (TNF) by various cell types including immune cells and IECs. TNF overexpression has been detected in the Paneth cells within the epithelium of human IBD patients (5), and anti-TNF treatments are used successfully to treat patients with Crohn's disease (6). Previous research in mice has demonstrated that intestinal TNF exposure leads to loss of barrier function (7), and overexpression of TNF in mouse IECs is sufficient to elicit an IBD phenotype (8). Despite its pathogenic relevance, the genetic mechanisms regulating TNF expression and IBD onset remain largely unknown.Genome-wide association studies have identified numerous susceptibility loci associated with IBD including ubiquitin-like protein containing PHD and RING finger domains 1 (UHRF1) and the DNA methyltransferases DNMT1 and DNMT3a (9, 10), which are genes involved in DNA methylation controlling epigenetic transcriptional repression. Moreover, low concordance rates have been observed in monozygotic twin studies (3), leading to the hypothesis that epigenetic regulation also contributes to IBD pathogenesis. Changes in DNA and histone modifications associated with epigenetic regulation have been detected in IBD patients (3, 4, 9, 11, 12), but direct links to the I...

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Section: Discussionmentioning

confidence: 99%

Epigenetic control of intestinal barrier function and inflammation in zebrafish

Marjoram¹,

Alvers²,

Deerhake

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

166

168

View full text Add to dashboard Cite

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“…Even though many advances in investigating IBD were achieved, the disease pathogenesis remains in part unclear. Genetics, microbiota and especially the "Western style diet" might have a major influence on disease onset and progress [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Dietary Habits and Nutrient Intake in Patients with Inflammatory Bowel Disease

Schink¹,

Mirsch²,

Dieterich³

et al. 2017

J Nutr Food Sci

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Patients with inflammatory bowel diseases (IBD) are often affected by nutrient deficiencies. Besides a limited nutrient intake by disease-related side effects and malabsorption, the influence of diets and dietary changes is much discussed. However, data about food patterns are mostly based on subjective declarations. Therefore, this study aimed to achieve a detailed and objective analysis of nutrient intake and individual food habits in IBD, a prerequisite for an appropriate nutritional intervention in risk patients. One hundred IBD patients (n=70 Crohn's disease (CD), n=30 ulcerative colitis (UC)) and 30 healthy controls (HC) were included in the study. All participants filled in a disease-related and food frequency questionnaire. Fifteen healthy controls and 71 IBD patients additionally completed a questionnaire for self-imposed food restrictions. Most IBD patients and healthy controls showed a normal body mass index. However, within the IBD group, UC patients were more often overweight than CD patients (p=0.007). Food restrictions were common in all participants, but significantly more IBD patients restricted their consumption of fast food (p=0.037), fruits and vegetables (p=0.019). Especially CD patients with acute relapse consumed less fruits and vegetables (p=0.035). Contrary to subjective assessment, an objective survey of dietary intake revealed a significantly higher sugar intake of IBD patients compared to healthy controls (p<0.001) with an increased ingestion of sugar/confectionery (p=0.041), soft/isotonic drinks (p<0.001) and fruit/vegetable juices (p=0.022). Additionally, IBD patients ingested higher amounts of salt than healthy controls (p=0.005). Both groups showed an insufficient ingestion of folate, vitamin D and pantothenic acid.In conclusion, self-managed food restrictions appear to be common in IBD patients. The huge discrepancy between the subjective view of dietary habits and objective evaluation of nutrient intake indicates that nutrient assessment should be based on objective tools. A repetitive professional nutritional counseling is recommended to prevent and treat nutritional deficiencies.

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“…If clinical therapy fails to produce responsiveness, surgical intervention becomes compulsory. The downside of IBD is that it could well develop into colorectal carcinoma or other cancers in the gut [1][2][3][4][5][6][7][8].…”

Section: Inflammatory Bowel Disease (Ibd)mentioning

confidence: 99%

CCR6-CCL20 Axis in IBD: What have we learnt in the past 20 years?

Ranasinghe¹,

Eri²

2018

Preprint

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Inflammatory bowel disease (IBD) is a CC chemokine receptor 6 (CCR6) -associated immune mediated disorder which has attracted an extensive superfluity of experimental analyses. IBD has come to the fore of varied scrutinizing owing to its complexity by nature for comprising of two synergistic sub phenotypes; Crohn's disease (CD) and Ulcerative colitis (UC). Both these disease entities cause potent immune dysregulation followed by intense tissue damage within the gut mucosal system, initiating symptoms which are severely debilitating. Multiple causative factors are said to be responsible for IBD but direct immune dysfunction is kindled by overplay of innate and adaptive immune responses produced against a pathogenic microbial attack through the weakened or leaky gut epithelial barrier. Once immune homeostasis is not achieved by tolerating agents, the self-assertive adaptive immunity mobilize its various T and B cell cohorts initializing their allied immune mechanisms by vigorously deploying them towards the site of infection. CCR6 and its unique solitary ligand CC-chemokine ligand 20 (CCL20) are small protein molecules which are abundantly expressed by T and B lymphocytes and act as chemotactic immune-modulatory envoys that help in the deployment of the effector lymphocyte arm of the immune system, producing two directly opposing outcomes in IBD. This dichotomous immunity consists of either immune tolerance or inflammation which then develops into a chronic state, remaining catatonic to inherent immunity or targeted clinical therapy. In this review, we have chronologically identified a plethora of experimental studies radiating into 14 different compartments highlighted in the visual depiction which have employed both mouse models and clinical subjects spanning a period of nearly two decades. In doing so, we expect the research community would further benefit by tracing through the history, thereby understanding the CCR6 -CCL20 axis in IBD and identifying the gaps in literature which can be fortuitously filled in the future.Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted:

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From genetics of inflammatory bowel disease towards mechanistic insights

Cited by 85 publications

References 95 publications

Epigenetic control of intestinal barrier function and inflammation in zebrafish

Epigenetic control of intestinal barrier function and inflammation in zebrafish

Dietary Habits and Nutrient Intake in Patients with Inflammatory Bowel Disease

CCR6-CCL20 Axis in IBD: What have we learnt in the past 20 years?

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