scholarly journals Dysregulation of metabolic pathways in circulating natural killer cells isolated from inflammatory bowel disease patients

2021 ◽  
Author(s):  
Vanessa Zaiatz Bittencourt ◽  
Fiona Jones ◽  
Miriam Tosetto ◽  
Glen A Doherty ◽  
Elizabeth J Ryan
Keyword(s):  
Inflammatory Bowel Disease ◽  
Nk Cells ◽  
Natural Killer ◽  
Bowel Disease ◽  
Metabolic Profile ◽  
Nk Cell ◽  
Intracellular Cytokines ◽  
Increased Risk ◽  
Inflammatory Bowel ◽  
Risk Of Cancer

Abstract Background and aims Inflammatory Bowel Disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC) are chronic conditions characterized by severe dysregulation of innate and adaptive immunity resulting in the destruction of the intestinal mucosa. Natural Killer (NK) cells play a pivotal role in the dynamic interaction between the innate and adaptive immune response. There is an increasing appreciation for the key role immunometabolism plays in the regulation of NK cell function, yet little remains known about the metabolic profile, cytokine secretion and killing capacity of human NK cells during active IBD. Methods PBMC were isolated from peripheral blood of patients with moderate to severely active IBD and healthy controls. NK cells were stained with a combination of cell surface receptors, intracellular cytokines, proteins and analyzed by flow cytometry. For measurements of NK cell cytotoxicity, the calcein-AM release assay was performed. Metabolic profile was analyzed by extracellular flux analyzer. Results NK cells from IBD patients produce large quantities of pro-inflammatory cytokines, IL-17A and TNF-α ex vivo but have limited killing capability. Furthermore, patient NK cells have reduced mitochondrial mass and oxidative phosphorylation. mTORC1, an important cell and metabolic regulator, demonstrated limited activity in both freshly isolated cells and cytokine stimulated cells. Conclusions Our results demonstrate that circulating NK cells of IBD patients have an unbalanced metabolic profile, with faulty mitochondria and reduced capacity to kill. These aberrations in NK cell metabolism may contribute to defective killing and thus the secondary infections and increased risk of cancer observed in IBD patients.

scholarly journals Potential Role of NK Cells in the Pathogenesis of Inflammatory Bowel Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Praveen K. Yadav ◽  
Chi Chen ◽  
Zhanju Liu
Keyword(s):  
Inflammatory Bowel Disease ◽  
Nk Cells ◽  
Proinflammatory Cytokines ◽  
Bowel Disease ◽  
Cell Activation ◽  
Potential Role ◽  
Nk Cell ◽  
Target Cells ◽  
Intestinal Epithelial ◽  
Inflammatory Bowel

NK cells are a major component of the innate immune system and play an important role in the tissue inflammation associated with autoimmune diseases such as inflammatory bowel disease (IBD). NK cells are unique in bearing both stimulatory and inhibitory receptors specific for MHC class I molecules, and their function is regulated by a series of inhibiting or activating signals. The delicate balance between activation and inhibition that decides NK cell final action provides an opportunity for their possible modulatory effect on specific therapeutic settings. Intestinal NK cells are phenotypically distinct from their counterparts in the blood and resemble “helper” NK cells, which have potentially important functions both in promoting antipathogen responses and in the maintenance of intestinal epithelial homeostasis. NK cell activities have been found to be significantly below normal levels in both remissive and active stages of IBD patients. However, some proinflammatory cytokines (e.g., IL-15, IL-21, and IL-23) could potently induce NK cell activation to secret high levels of proinflammatory cytokines (e.g., IFN-γ and TNF) and promote the cytolytic activities against the target cells. This paper provides the characteristics of intestinal NK cells and their potential role in the pathogenesis of IBD.

scholarly journals Cancer Risk in Inflammatory Bowel Disease

1995 ◽  
Vol 9 (1) ◽  
pp. 23-26 ◽  
Author(s):  
Anders M Ekbom
Keyword(s):  
Colorectal Cancer ◽  
Ulcerative Colitis ◽  
Inflammatory Bowel Disease ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Bowel Disease ◽  
Colonic Involvement ◽  
Increased Risk ◽  
Inflammatory Bowel ◽  
Risk Of Cancer

There is an increased risk of cancer in both ulcerative colitis and Crohn's disease. In 3121 patients with ulcerative colitis, 225 cases of cancer were diagnosed compared with 142.1 expected (standardized incidence ratio [SIR] 1.6, 95% CI 1.4 to 1.8), and in 1655 patients with Crohn's disease, 58 cases of cancer were detected compared with 47.1 expected (SIR 1.2, 95% CI 0.9 to 1.6). After excluding colorectal cancer the observed number of malignancies was very close to that expected for ulcerative colitis (SIR 1.0, 95% CI 0.9 to 1.2) and for Crohn's disease (SIR 1.1, 95% CI 0.8 to 1.5). Thus, the increased risk of cancer in inflammatory bowel disease is confined to colorectal cancer. In Crohn's disease 12 cases of colorectal cancer were observed (SIR 2.5, 95% CI 1.3 to 4.3). The increased risk was confined to those with colonic involvement and young age at diagnosis. In patients with colonic involvement and younger than age 30 years at diagnosis, the SIR was 20.9 (95% CI 6.8 to 48.7) versus 2.2 for those older than 30 years at diagnosis (95% CI 0.6 to 5.7). In ulcerative colitis 91 cases of colorectal cancer were observed with an SIR of 5.7 (95% CI 4.6 to 7.0). Extensive disease and young age at diagnosis were independent risk factors. Pancolitis at diagnosis resulted in an SIR of 14.8 (95% CI 11.4 to 18.9), 2.8 in left-sided colitis (95% CI 1.6 to 4.4) and 1.7 in proctitis (95% CI 0.8 to 3.2). There is great variation in the risk estimates in different studies worldwide. Different treatment strategies could be an explanation, a hypothesis that was substantiated in a study of 102 cases of colorectal cancer among patients with ulcerative colitis compared with 196 controls. Pharmacological therapy with sulfasalazine entailed a strong protective effect against colorectal cancer (relative risk of 0.34, 95% CI 0.190 to 0.62).

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.

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