scholarly journals Somatic evolution in non-neoplastic IBD-affected colon

2019 ◽  
Author(s):  
Sigurgeir Olafsson ◽  
Rebecca E. McIntyre ◽  
Tim Coorens ◽  
Timothy Butler ◽  
Hyunchul Jung ◽  
...  
Keyword(s):  
Chronic Inflammatory Disease ◽  
Interleukin 17 ◽  
Normal Colon ◽  
Synonymous Mutations ◽  
Somatic Evolution ◽  
Colonic Crypts ◽  
Increased Risk ◽  
Inflammatory Bowel ◽  
Selection Mechanisms ◽  
Mutational Processes

Summary paragraphInflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers. Here, we whole-genome sequenced 447 colonic crypts from 46 IBD patients, and compared these to 412 crypts from 41 non-IBD controls. The average mutation rate of affected colonic epithelial cells is 2.4-fold that of healthy colon and this increase is mostly driven by acceleration of mutational processes ubiquitously observed in normal colon. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeter-scale clonal expansions. We discovered non-synonymous mutations in ARID1A, FBXW7, PIGR and ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, under positive selection in IBD. These results suggest distinct selection mechanisms in the colitis-affected colon and that somatic mutations potentially play a causal role in IBD pathogenesis.

scholarly journals DOP50 The landscape of somatic mutations in non-neoplastic IBD-affected colon

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S088-S089
Author(s):  
S Olafsson ◽  
R E McIntyre ◽  
T Coorens ◽  
T Butler ◽  
P Robinson ◽  
...  
Keyword(s):  
Positive Selection ◽  
Somatic Mutations ◽  
Intestinal Inflammation ◽  
Base Substitution ◽  
Interleukin 17 ◽  
Clonal Structure ◽  
Normal Colon ◽  
Colonic Crypts ◽  
Mutation Burden ◽  
Chronic Intestinal Inflammation

Abstract Background Under normal physiological conditions, colonic crypts accrue ~40 somatic mutations for every year of life. That somatic mutations contribute to the development of cancer is well established, but their patterns, burden and functional consequences in diseases other than cancer have not been extensively studied and our understanding of the effects of chronic inflammation on the mutational profile and clonal structure of the colon is limited. Here, we investigated how the recurrent cycles of inflammation, ulceration and regeneration seen in IBD impact the mutational and clonal structure of intestinal epithelia. Methods We isolated and whole-genome sequenced ~400 individual colonic crypts from 46 IBD patients and compared these to ~400 crypts from 41 non-IBD controls. We compared the mutation burden, mutational signature exposure, clonal structure and cancer driver mutation landscape in crypts from actively and previously inflamed regions with crypts dissected from controls. Results We estimated the base substitution rate of affected colonic epithelial cells to be doubled after IBD onset. This change was primarily driven by acceleration of mutational processes ubiquitously observed in normal colon (Figure 1), and we did not detect an IBD-specific mutational process. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimetre-scale clonal expansions, even in the absence of mutations in KRAS, TP53 and APC (Figure 2). We discovered that mutations in ARID1A, PIGR and ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, were under positive selection in colonic crypts from IBD patients (Figure 3). With the exception of ARID1A, these genes and pathways have not been previously associated with cancer risk. A previously published mouse model of ZC3H12A suggests that LoF mutations in this gene may facilitate healing of affected mucosa without promoting tumorigenesis. This could make the encoded protein an attractive drug target. The observed enrichment of mutations in PIGR and IL17 and TLR pathways suggests that somatic mutations may initiate, maintain or perpetuate IBD pathogenesis through disruption of microbe-epithelial homeostasis. Conclusion Our results provide new insights into the consequences of chronic intestinal inflammation on the mutational profile and clonal structure of colonic epithelia. We identify the mutagens driving the increase in mutation burden and mutations which are under positive selection in the context of inflammation. Our results suggest that studying somatic mutations in the colon can reveal putative drug targets and pathogenic mechanisms for IBD.

scholarly journals Risk of Inflammatory Bowel Disease in Psoriasis Patients Treated with Anti-Interleukin-17 Agents: A Bayesian Metaanalysis

2019 ◽  
Author(s):  
N. Gill ◽  
M. Pietrosanu ◽  
R. Gniadecki
Keyword(s):  
Risk Factors ◽  
Inflammatory Bowel Disease ◽  
Family History ◽  
Bowel Disease ◽  
Hidradenitis Suppurativa ◽  
Absolute Risk ◽  
Interleukin 17 ◽  
Increased Risk ◽  
History Of ◽  
Inflammatory Bowel

AbstractBackgroundUse of interleukin-17 inhibitors (IL-17i) in psoriasis has been associated with an increased risk of inflammatory bowel disease (IBD). However, the clinical significance of this association is not understood.ObjectivesTo quantify the absolute risk of IBD in patients with psoriasis treated with IL-17i, stratified by known IBD risk factors.MethodsLiterature searches were performed to identify known IBD risk factors and the prevalences were quantified by a meta-analysis of proportions. The Bayesian model was used to estimate the probability of a new-onset or a flare of IBD in patients with psoriasis.ResultsThe prevalence of Crohn’s disease (CD) or ulcerative colitis (UC) in the general psoriasis population was 0.0010. Use of IL-17i increased the risk of CD to 0.0037 and UC to 0.0028, translating to a number needed to harm (NNH) of 373 for CD and 564 for UC. In patients who had concomitant hidradenitis suppurativa, the use of IL-17i was associated with a decrease in NNH for CD and UC to 18 and 76, respectively, whereas for patients with a family history of IBD, the NNH values were 6 (for CD) and 10 (for UC).ConclusionsIn patients with no risk factors, the probability of IBD flare or onset during IL-17i treatment is negligible and additional IBD screening procedures are not indicated. In contrast, the patients with psoriasis who have hidradenitis suppurativa or first-degree family history of IBD as risk factors should be monitored for signs and symptoms of CD and UC during IL-17i therapy.

Thrombosis in IBD in the Era of JAK Inhibition

2020 ◽  
Vol 22 (1) ◽  
pp. 126-136
Author(s):  
Virginia Solitano ◽  
Gionata Fiorino ◽  
Ferdinando D’Amico ◽  
Laurent Peyrin-Biroulet ◽  
Silvio Danese
Keyword(s):  
Small Molecules ◽  
Arterial Thrombosis ◽  
Protective Role ◽  
Jak Inhibitors ◽  
Thrombotic Risk ◽  
Increased Risk ◽  
Bowel Diseases ◽  
Thrombotic Complications ◽  
Inflammatory Bowel ◽  
Inflammatory Effect

: Patients with inflammatory bowel diseases (IBD) have an increased risk of thrombosis. The interaction between inflammation and coagulation has been extensively studied. It is well-known that some drugs can influence the haemostatic system, but several concerns on the association between therapies and increased risk of thrombosis remain open. While biologics seem to have a protective role against thrombosis via their anti-inflammatory effect, some concerns about an increased risk of thrombosis with JAK inhibitors have been raised. We conducted a literature review to assess the association between biologics/small molecules and venous/arterial thrombotic complications. An increased risk of venous and arterial thrombosis was found in patients treated with corticosteroids, whereas anti-TNF were considered protective agents. No thromboembolic adverse event was reported with vedolizumab and ustekinumab. In addition, thromboembolic events rarely occurred in patients with ulcerative colitis (UC) after therapy with tofacitinib. The overall risk of both venous and arterial thrombosis was not increased based on the available evidence. Finally, in the era of JAK inhibitors, treatment should be individualized by evaluating the pre-existing potential thrombotic risk balanced with the intrinsic risk of the medication used.

37 Monitoring the evolution of inflammatory bowel disease (IBD) in pediatric and adult cohorts of patients to identify biomarkers to predict cancer risk

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A38-A38
Author(s):  
Shilpa Ravindran ◽  
Heba Sidahmed ◽  
Harshitha Manjunath ◽  
Rebecca Mathew ◽  
Tanwir Habib ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Mesenchymal Transition ◽  
Increased Risk ◽  
Hamad Medical Corporation ◽  
Inflammatory Bowel ◽  
Left And Right

BackgroundPatients with inflammatory bowel disease (IBD) have increased risk of developing colorectal cancer (CRC), depending on the duration and severity of the disease. The evolutionary process in IBD is driven by chronic inflammation leading to epithelial-to-mesenchymal transition (EMT) events in colonic fibrotic areas. EMT plays a determinant role in tumor formation and progression, through the acquisition of ‘stemness’ properties and the generation of neoplastic cells. The aim of this study is to monitor EMT/cancer initiating tracts in IBD in association with the deep characterization of inflammation in order to assess the mechanisms of IBD severity and progression towards malignancy.Methods10 pediatric and 20 adult IBD patients, admitted at Sidra Medicine (SM) and Hamad Medical Corporation (HMC) respectively, have been enrolled in this study, from whom gut tissue biopsies (from both left and right side) were collected. Retrospectively collected tissues (N=10) from patients with malignancy and history of IBD were included in the study. DNA and RNA were extracted from fresh small size (2–4 mm in diameter) gut tissues using the BioMasher II (Kimble) and All Prep DNA/RNA kits (Qiagen). MicroRNA (miRNA; N=700) and gene expression (N=800) profiling have been performed (cCounter platform; Nanostring) as well as the methylation profiling microarray (Infinium Methylation Epic Bead Chip kit, Illumina) to interrogate up to 850,000 methylation sites across the genome.ResultsDifferential miRNA profile (N=27 miRNA; p<0.05) was found by the comparison of tissues from pediatric and adult patients. These miRNAs regulate: i. oxidative stress damage (e.g., miR 99b), ii. hypoxia induced autophagy; iii. genes associated with the susceptibility to IBD (ATG16L1, NOD2, IRGM), iv. immune responses, such as TH17 T cell subset (miR 29). N=6 miRNAs (miR135b, 10a196b, 125b, let7c, 375) linked with the regulation of Wnt/b-catenin, EM-transaction, autophagy, oxidative stress and play role also in cell proliferation and mobilization and colorectal cancer development were differentially expressed (p<0.05) in tissues from left and right sides of gut. Gene expression signature, including genes associated with inflammation, stemness and fibrosis, has also been performed for the IBD tissues mentioned above. Methylation sites at single nucleotide resolution have been analyzed.ConclusionsAlthough the results warrant further investigation, differential genomic profiling suggestive of altered pathways involved in oxidative stress, EMT, and of the possible stemness signature was found. The integration of data from multiple platforms will provide insights of the overall molecular determinants in IBD patients along with the evolution of the disease.Ethics ApprovalThis study was approved by Sidra Medicine and Hamad Medical Corporation Ethics Boards; approval number 180402817 and MRC-02-18-096, respectively.

scholarly journals The interplay of Clostridioides difficile infection and inflammatory bowel disease

2021 ◽  
Vol 14 ◽  
pp. 175628482110202
Author(s):  
Kanika Sehgal ◽  
Devvrat Yadav ◽  
Sahil Khanna
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Adverse Outcomes ◽  
Molecular Tests ◽  
Clostridioides Difficile ◽  
Increased Risk ◽  
Clostridioides Difficile Infection ◽  
Pros And Cons ◽  
Inflammatory Bowel ◽  
High Index Of Suspicion

Inflammatory bowel disease (IBD) is a chronic disease of the intestinal tract that commonly presents with diarrhea. Clostridioides difficile infection (CDI) is one of the most common complications associated with IBD that lead to flare-ups of underlying IBD. The pathophysiology of CDI includes perturbations of the gut microbiota, which makes IBD a risk factor due to the gut microbial alterations that occur in IBD, predisposing patients CDI even in the absence of antibiotics. Superimposed CDI not only worsens IBD symptoms but also leads to adverse outcomes, including treatment failure and an increased risk of hospitalization, surgery, and mortality. Due to the overlapping symptoms and concerns with false-positive molecular tests for CDI, diagnosing CDI in patients with IBD remains a clinical challenge. It is crucial to have a high index of suspicion for CDI in patients who seem to be experiencing an exacerbation of IBD symptoms. Vancomycin and fidaxomicin are the first-line treatments for the management of CDI in IBD. Microbiota restoration therapies effectively prevent recurrent CDI in IBD patients. Immunosuppression for IBD in IBD patients with CDI should be managed individually, based on a thorough clinical assessment and after weighing the pros and cons of escalation of therapy. This review summarizes the epidemiology, pathophysiology, the diagnosis of CDI in IBD, and outlines the principles of management of both CDI and IBD in IBD patients with CDI.

Ethnic Differences in the Smoking-Related Risk of Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

2021 ◽  
Author(s):  
Daniele Piovani ◽  
Claudia Pansieri ◽  
Soumya R R Kotha ◽  
Amanda C Piazza ◽  
Celia-Louise Comberg ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Latin American ◽  
Bowel Disease ◽  
Meta Analysis ◽  
Study Data ◽  
Future Research ◽  
Related Risk ◽  
Increased Risk ◽  
Inflammatory Bowel

Abstract Background and aims The association between smoking and inflammatory bowel disease (IBD) relies on old meta-analyses including exclusively non-Jewish White populations. Uncertainty persists regarding the role of smoking in other ethnicities. Methods We systematically searched Medline/PubMed, Embase and Scopus for studies examining tobacco smoking and the risk of developing IBD, i.e., Crohn’s disease (CD) or ulcerative colitis (UC). Two authors independently extracted study data and assessed each study’s risk-of-bias. We examined heterogeneity and small-study effect, and calculated summary estimates using random-effects models. Stratified analyses and meta-regression were employed to study the association between study-level characteristics and effect estimates. The strength of epidemiological evidence was assessed through prespecified criteria. Results We synthesized 57 studies examining the smoking-related risk of developing CD and UC. Non-Jewish White smokers were at increased risk of CD (29 studies; RR: 1.95, 95% CI: 1.69‒2.24; moderate evidence). No association was observed in Asian, Jewish and Latin-American populations (11 studies; RR: 0.97; 95% CI: 0.83–1.13), with no evidence of heterogeneity across these ethnicities. Smokers were at reduced risk of UC (51 studies; RR: 0.55, 95% CI: 0.48–0.64; weak evidence) irrespectively of ethnicity; however, cohort studies, large studies and those recently published showed attenuated associations. Conclusions This meta-analysis did not identify any increased risk of CD in smokers in ethnicities other than non-Jewish Whites, and confirmed the protective effect of smoking on UC occurrence. Future research should characterize the genetic background of CD patients across different ethnicities to improve our understanding on the role of smoking in CD pathogenesis.

scholarly journals Overview of Inositol and Inositol Phosphates on Chemoprevention of Colitis-Induced Carcinogenesis

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 31
Author(s):  
Samuel E. Weinberg ◽  
Le Yu Sun ◽  
Allison L. Yang ◽  
Jie Liao ◽  
Guang Yu Yang
Keyword(s):  
Inositol Phosphates ◽  
Human Cancer ◽  
Energy Transduction ◽  
Nutritional Deficiencies ◽  
Increased Risk ◽  
Rna Export ◽  
Inflammatory Bowel ◽  
And Function ◽  
Biologic Function ◽  
Atp Regeneration

Chronic inflammation is one of the most common and well-recognized risk factors for human cancer, including colon cancer. Inflammatory bowel disease (IBD) is defined as a longstanding idiopathic chronic active inflammatory process in the colon, including ulcerative colitis and Crohn’s disease. Importantly, patients with IBD have a significantly increased risk for the development of colorectal carcinoma. Dietary inositol and its phosphates, as well as phospholipid derivatives, are well known to benefit human health in diverse pathologies including cancer prevention. Inositol phosphates including InsP3, InsP6, and other pyrophosphates, play important roles in cellular metabolic and signal transduction pathways involved in the control of cell proliferation, differentiation, RNA export, DNA repair, energy transduction, ATP regeneration, and numerous others. In the review, we highlight the biologic function and health effects of inositol and its phosphates including the nature and sources of these molecules, potential nutritional deficiencies, their biologic metabolism and function, and finally, their role in the prevention of colitis-induced carcinogenesis.

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