Transcriptomic analysis of ileal tissue from Crohn’s disease patients identifies extracellular matrix genes that distinguish individuals by age at diagnosis

Crohn’s disease (CD) is a debilitating gastrointestinal (GI) disorder that can impact the entirety of the GI tract. While substantial progress has been made in the medical management of CD, it remains incurable, frequently relapses, and is a significant financial and medical burden. The pathophysiology of CD is not well understood, but it is thought to arise in genetically susceptible individuals upon an environmental insult. Further elucidation of the disease etiology promises to expose additional therapeutic avenues, with the hope of reducing the burden of CD. One approach to understanding disease pathophysiology is to identify clinically relevant molecular disease subsets by using transcriptomics. In this report, we use hierarchical clustering of the ileal transcriptomes of 34 patients and identify two CD subsets. Clinically, these clusters differed in the age of the patients at CD diagnosis, suggesting that age of onset affects disease pathophysiology. The clusters were segregated by three major gene ontology categories: developmental processes, ion homeostasis, and the immune response. Of the genes constituting the immune system category, expression of extracellular matrix-associated genes, COL4A1, S100A9, ADAMTS2, SERPINE1, and FCN1, exhibits the strongest correlation with an individual’s age at CD diagnosis. Together these findings demonstrate that transcriptional profiling is a powerful approach to subclassify CD patients.

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ACTIVATED INTESTINAL MUSCLE CELLS PROMOTE PREADIPOCYTE MIGRATION: A NOVEL MECHANISM OF CREEPING FAT FORMATION IN CROHN’S DISEASE

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa347.082 ◽

2021 ◽

Vol 27 (Supplement_1) ◽

pp. S34-S34

Author(s):

Ren Mao ◽

Genevieve Doyon ◽

Ilyssa Gordon ◽

Jiannan Li ◽

Sinan Lin ◽

...

Keyword(s):

Extracellular Matrix ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Ex Vivo ◽

Muscularis Propria ◽

Dominant Factor ◽

Stricture Formation ◽

Intestinal Tissue ◽

Mesenteric Fat

Abstract Background and Aims Creeping fat, the wrapping of mesenteric fat around the bowel wall, is a typical feature of Crohn’s disease, and is associated with stricture formation and bowel obstruction. How creeping fat forms is unknown, and we interrogated potential mechanisms using novel intestinal tissue and cell interaction systems. Methods Tissues from normal, ulcerative colitis, non-strictured and strictured Crohn’s disease intestinal specimens were obtained. Fresh and decellularized tissue, mesenteric fat explants, primary human adipocytes, pre-adipocytes, muscularis propria cells, and native extracellular matrix were used in multiple ex vivo and in vitro systems involving cell growth, differentiation and migration, proteomics, and integrin expression. Results Crohn’s disease muscularis propria cells produced an extracellular matrix scaffold which is in direct spatial and functional contact with the immediately overlaid creeping fat. The scaffold contained multiple proteins, but only fibronectin production was singularly upregulated by TGF-b1. The muscle cell-derived matrix triggered migration of pre-adipocytes out of mesenteric fat, fibronectin being the dominant factor responsible for their migration. Blockade of α5β1 on the pre-adipocyte surface inhibited their migration out of mesenteric fat and on 3D decellularized intestinal tissue extracellular matrix. Conclusion Crohn’s disease creeping fat appears to result from the migration of pre-adipocytes out of mesenteric fat and differentiation into adipocytes in response to an increased production of fibronectin by activated muscularis propria cells. These new mechanistic insights may lead to novel approaches for prevention of creeping fat-associated stricture formation.

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Classifying Crohn’s disease into colon-involving versus non-colon-involving groups is a better predictor of clinical outcomes than the Montreal classification

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284820968732 ◽

2020 ◽

Vol 13 ◽

pp. 175628482096873

Author(s):

Si-Nan Lin ◽

Dan-Ping Zheng ◽

Yun Qiu ◽

Sheng-Hong Zhang ◽

Yao He ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Abdominal Surgery ◽

Clinical Outcomes ◽

Protective Factor ◽

Age Of Onset ◽

Disease Classification ◽

Major Abdominal Surgery ◽

Montreal Classification

Background: A suitable disease classification is essential for individualized therapy in patients with Crohn’s disease (CD). Although a potential mechanistic classification of colon-involving and non-colon-involving disease was suggested by recent genetic and microbiota studies, the clinical implication has seldom been investigated. We aimed to explore the association of this colonic-based classification with clinical outcomes in patients with CD compared with the Montreal classification. Methods: This was a retrospective study of CD patients from a tertiary referral center. Patients were categorized into colon-involving and non-colon-involving disease, and according to the Montreal classification. Clinico-demographic data, medications, and surgeries were compared between the two classifications. The primary outcome was the need for major abdominal surgery. Results: Of 934 patients, those with colonic involvement had an earlier median (interquartile range) age of onset [23.0 (17.0–30.0) versus 26.0 (19.0–35.0) years, p = 0.001], higher frequency of perianal lesions (31.2% versus 14.5%, p < 0.001) and extraintestinal manifestations (21.8% versus 14.5%, p = 0.010), but lower frequency of stricture (B2) (16.3% versus 24.0%, p = 0.005), than those with non-colon-involving disease. Colon-involving disease was a protective factor against major abdominal surgery [hazard ratio, 0.689; 95% confidence interval (CI), 0.481–0.985; p = 0.041]. However, patients with colon-involving CD were more prone to steroids [odds ratio (OR), 1.793; 95% CI, 1.206–2.666; p = 0.004] and azathioprine/6-mercaptopurine (AZA/6-MP) treatment (OR, 1.732; 95% CI, 1.103–2.719; p = 0.017) than were patients with non-colon-involving disease. The Montreal classification was not predictive of surgery or steroids and AZA/6-MP treatment. Conclusion: This study supports the rationale for disease classification based on the involvement of colon. This new classification of CD is a better predictor of clinical outcomes than the Montreal classification.

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Perianal Abscesses in Infants Are Not Associated With Crohn’s Disease in a Surgical Cohort

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz105 ◽

2019 ◽

Vol 14 (6) ◽

pp. 773-777

Author(s):

Mariëlle Roskam ◽

Tim de Meij ◽

Reinoud Gemke ◽

Roel Bakx

Keyword(s):

Inflammatory Bowel Disease ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Bowel Disease ◽

Disease Risk ◽

Age Of Onset ◽

Faecal Calprotectin ◽

Young Infants ◽

Inflammatory Bowel

Abstract Aims The aim of this study is to search for an association between infantile perianal abscesses and [development of] Crohn’s disease in a surgical population of children. Methods Patients who were surgically treated in the Amsterdam UMC between January 2000 and December 2014 were included in this retrospective cohort study. Data collected include: sex, date of birth, underlying conditions, age of onset, additional symptoms, pus cultures, endoscopic examination, histological examination, magnetic resonance imaging, faecal calprotectin levels, antibiotic treatment, surgical treatment strategy, and number of recurrences. Follow-up data were gathered from medical records and by contacting the patients and/or parents or the general practitioner. Results The study consisted of 62 patients of whom 60 were boys. Median age was 5 months [range 0–17 months]; 92% were under 1 year of age at diagnosis. A minority of patients had accompanying symptoms. In total, 72 abscesses were treated, 19 fistulas and 23 abscesses with fistula-in-ano. Follow-up data of 46 patients [74%] were available; none of the patients developed Crohn’s disease. Conclusions We found no association between isolated perianal abscesses as presenting symptom in early childhood and [development of] Crohn's disease. In young infants with isolated perianal disease, risk for inflammatory bowel disease seems low. In this specific population there seems no place for routine performance of endoscopic investigations. One should always take the risk of very-early-onset inflammatory bowel disease into account. Further research with a larger cohort of children and a longer follow-up time is required.

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Correlation between age of onset and gastrointestinal stenosis in hospitalized patients with Crohn's disease

World Journal of Clinical Cases ◽

10.12998/wjcc.v8.i13.2769 ◽

2020 ◽

Vol 8 (13) ◽

pp. 2769-2777

Author(s):

Shan-Bing Yang ◽

Shu-Wen Du ◽

Ji-Heng Wang

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Age Of Onset ◽

Hospitalized Patients

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Pathophysiology of Crohn’s disease inflammation and recurrence

Biology Direct ◽

10.1186/s13062-020-00280-5 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

L. Petagna ◽

A. Antonelli ◽

C. Ganini ◽

V. Bellato ◽

M. Campanelli ◽

...

Keyword(s):

Extracellular Matrix ◽

Innate Immunity ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Surgical Approaches ◽

Disease Evolution ◽

Limited Success ◽

Tnf Α ◽

Chron's Disease

Abstract Chron’s Disease is a chronic inflammatory intestinal disease, first described at the beginning of the last century. The disease is characterized by the alternation of periods of flares and remissions influenced by a complex pathogenesis in which inflammation plays a key role. Crohn’s disease evolution is mediated by a complex alteration of the inflammatory response which is characterized by alterations of the innate immunity of the intestinal mucosa barrier together with a remodeling of the extracellular matrix through the expression of metalloproteins and increased adhesion molecules expression, such as MAcCAM-1. This reshaped microenvironment enhances leucocytes migration in the sites of inflammation, promoting a TH1 response, through the production of cytokines such as IL-12 and TNF-α. IL-12 itself and IL-23 have been targeted for the medical treatment of CD. Giving the limited success of medical therapies, the treatment of the disease is invariably surgical. This review will highlight the role of inflammation in CD and describe the surgical approaches for the prevention of the almost inevitable recurrence.

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Relationship between the IL23R SNPs and Crohn’s Disease Susceptibility and Phenotype in the Polish and Bosnian Populations: A Case-Control Study

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16091551 ◽

2019 ◽

Vol 16 (9) ◽

pp. 1551

Author(s):

Krzysztof Borecki ◽

Iwona Zawada ◽

Nermin Nusret Salkić ◽

Beata Karakiewicz ◽

Grażyna Adler

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Case Control Study ◽

Age Of Onset ◽

Severe Disease ◽

Polish Population ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Increased Risk ◽

Control Study

It is suggested that IL-23/IL-17 axis and single nucleotide polymorphisms (SNPs) of IL23R may have crucial role in pathogenesis of Crohn’s disease (CD). Thus, we sought to assess the IL23R SNPs contribution to susceptibility and phenotype of CD. We recruited 117 CD subjects and 117 controls from Poland and 30 CD subjects and 30 controls from Bosnia and Herzegovina (B&H). Two common IL23R SNPs: rs1004819, rs7517847 were genotyped using TaqMan SNP assays. In the Polish population it was found that allele rs1004819: A increases the risk of CD, while allele rs7517847: A is protective against disease development. In Poles the co-carriage of two IL23R risk genotypes was associated with increased risk of CD. A significantly increased risk of CD early onset was observed in Poles carrying at least one rs7517847: G allele. It was also found that IL23R SNPs may be associated with structuring/penetrating CD behavior, as alleles rs1004819: A and rs7517847: G were significantly less frequent in patients without complications, from Poland and B&H, respectively. Allele rs1004819: A was also significantly more frequent in Poles with penetrating CD. These results confirm IL23R SNPs contribution to CD susceptibility in the Polish population and suggest their impact on early age of onset and more severe disease course.

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Anticipation in familial Crohn’s disease

Gut ◽

10.1136/gut.42.2.170 ◽

1998 ◽

Vol 42 (2) ◽

pp. 170-174 ◽

Cited By ~ 44

Author(s):

B Grandbastien ◽

M Peeters ◽

D Franchimont ◽

C Gower-Rousseau ◽

D Speckel ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Age Of Onset ◽

Severe Disease ◽

Age At Diagnosis ◽

Disease Extent ◽

Genetic Anticipation ◽

Parents And Children ◽

The Difference ◽

Parent Child

Background—Offspring with a family history of Crohn’s disease have an earlier age of onset than their parents. This might be due to genetic anticipation, characterised by earlier and/or more severe disease in subsequent generations.Aims—To investigate the possibility of genetic anticipation in affected parent-child pairs with Crohn’s disease from France and Belgium.Patients and methods—In a cohort of 160 multiply affected families with Crohn’s disease, 57 parent-first affected child pairs were detected. Clinical characteristics (age at diagnosis, disease extent, and type) of both parents and children were registered and compared.Results—Children were younger than their parents at diagnosis in 48/57 (84%) pairs. The median age at diagnosis was 16 years younger in children than in parents (p<0.0001). However, the difference was related to the age at diagnosis in the parents and was not present in 12 parent-child pairs with an early age at diagnosis for the parents. In most cases, disease extent and type were not considered more severe in children than in parents. Parental sex affected neither age at diagnosis nor extent and type of disease in children.Conclusion—Patients in the second affected generation acquire their disease at an earlier time in life in some but not all familial cases of Crohn’s disease. Several explanations including genetic anticipation and environmental factors might explain this phenomenon.

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