P-056: Buccal epithelial cell chemokine release as a biomarker for clinical response to therapy in inflammatory bowel disease

Abstract Background Anatomical location and extent of disease are main factors that affect inflammatory bowel disease (IBD) course and prognosis. No explanation is available for segmental intestinal involvement in either Crohn’s disease (CD) or ulcerative colitis (UC), or for selective segmental response to therapy or disease complications. Therefore, studying the cellular composition of different intestinal segments may provide pathophysiological insights into these phenomena. Methods We compared location-specific cell composition and function by Cytometry Time-of-Flight (CyTOF), gene expression and single-cell (sc) RNAseq data obtained from 3 independent cohorts of healthy donors and IBD patients during remission and flare-ups. Using CyTOF data (n = 38 biopsies), we built a high-resolution screening of immune cell behaviour along the intestine. We validated the findings with gene expression data of 370 samples, and expanded screening resolution by computational methodologies. We then tested a specific pathway in scRNAseq data (n = 10 paired biopsies from 5 patients) and validated its significance by cell-specific Significance Analysis of Microarrays (csSAM). Results We found a location along the intestine to be a dominant feature determining immune and non-immune cell composition. We observed that inflammation reduced anatomic segregation beyond cell infiltration, and decreased the ability to cope with oxidative stress. An upregulated IL-6 pathway in T regulatory cells in UC patients was recognised as sigmoid-specific compared with known inflammatory IL-6 roles in macrophages, as seen in the right colon. This observation may be linked to colonic perforations associated with anti-IL-6R treatment. Suppressor of cytokine signalling 3 (SOCS3) may control IL-6 location-specific action. Conclusion Our study displays a unique and comprehensive cell map of IBD in a location-specific context, providing potential explanations to unexplained clinical phenomena. These observations may allow to tailor therapies to affected areas with improved therapeutic index and efficacy.

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Deficiency in the anti-apoptotic protein DJ-1 promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via p53

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.010143 ◽

2020 ◽

Vol 295 (13) ◽

pp. 4237-4251 ◽

Cited By ~ 1

Author(s):

Jie Zhang ◽

Min Xu ◽

Weihua Zhou ◽

Dejian Li ◽

Hong Zhang ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Epithelial Cell ◽

Bowel Disease ◽

Intestinal Epithelial Cell ◽

Intestinal Inflammation ◽

Intestinal Epithelial ◽

P53 Expression ◽

Inflammatory Bowel

Parkinson disease autosomal recessive, early onset 7 (PARK7 or DJ-1) is involved in multiple physiological processes and exerts anti-apoptotic effects on multiple cell types. Increased intestinal epithelial cell (IEC) apoptosis and excessive activation of the p53 signaling pathway is a hallmark of inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD). However, whether DJ-1 plays a role in colitis is unclear. To determine whether DJ-1 deficiency is involved in the p53 activation that results in IEC apoptosis in colitis, here we performed immunostaining, real-time PCR, and immunoblotting analyses to assess DJ-1 expression in human UC and CD samples. In the inflamed intestines of individuals with IBD, DJ-1 expression was decreased and negatively correlated with p53 expression. DJ-1 deficiency significantly aggravated colitis, evidenced by increased intestinal inflammation and exacerbated IEC apoptosis. Moreover, DJ-1 directly interacted with p53, and reduced DJ-1 levels increased p53 levels both in vivo and in vitro and were associated with decreased p53 degradation via the lysosomal pathway. We also induced experimental colitis with dextran sulfate sodium in mice and found that compared with DJ-1−/− mice, DJ-1−/−p53−/− mice have reduced apoptosis and inflammation and increased epithelial barrier integrity. Furthermore, pharmacological inhibition of p53 relieved inflammation in the DJ-1−/− mice. In conclusion, reduced DJ-1 expression promotes inflammation and IEC apoptosis via p53 in colitis, suggesting that the modulation of DJ-1 expression may be a potential therapeutic strategy for managing colitis.

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W1265 Fecal Calprotectin Values in Inflammatory Bowel Disease Patients After Induction Course of Anti-TNF Agents: Correlation With the Clinical Response

Gastroenterology ◽

10.1016/s0016-5085(10)63156-3 ◽

2010 ◽

Vol 138 (5) ◽

pp. S-686

Author(s):

Luisa Guidi ◽

Manuela Marzo ◽

Carla Felice ◽

Gianluca Andrisani ◽

Lucia Sparano ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Clinical Response ◽

Bowel Disease ◽

Fecal Calprotectin ◽

Inflammatory Bowel

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Alteration in intestinal epithelial cell expression of toll-like receptors in inflammatory bowel disease

Gastroenterology ◽

10.1016/s0016-5085(00)84829-5 ◽

2000 ◽

Vol 118 (4) ◽

pp. A673 ◽

Cited By ~ 1

Author(s):

Elke Cario ◽

Daniel K. Podolsky

Keyword(s):

Inflammatory Bowel Disease ◽

Epithelial Cell ◽

Bowel Disease ◽

Intestinal Epithelial Cell ◽

Intestinal Epithelial ◽

Toll Like Receptors ◽

Inflammatory Bowel ◽

Cell Expression

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Addition of an Immunomodulator to Infliximab Therapy Eliminates Antidrug Antibodies in Serum and Restores Clinical Response of Patients With Inflammatory Bowel Disease

Clinical Gastroenterology and Hepatology ◽

10.1016/j.cgh.2012.10.020 ◽

2013 ◽

Vol 11 (4) ◽

pp. 444-447 ◽

Cited By ~ 201

Author(s):

Shomron Ben–Horin ◽

Matti Waterman ◽

Uri Kopylov ◽

Miri Yavzori ◽

Orit Picard ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Clinical Response ◽

Bowel Disease ◽

Infliximab Therapy ◽

Inflammatory Bowel ◽

Antidrug Antibodies

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Differential Alteration in Intestinal Epithelial Cell Expression of Toll-Like Receptor 3 (TLR3) and TLR4 in Inflammatory Bowel Disease

Infection and Immunity ◽

10.1128/iai.68.12.7010-7017.2000 ◽

2000 ◽

Vol 68 (12) ◽

pp. 7010-7017 ◽

Cited By ~ 883

Author(s):

Elke Cario ◽

Daniel K. Podolsky

Keyword(s):

Inflammatory Bowel Disease ◽

Epithelial Cell ◽

Intestinal Epithelium ◽

Bowel Disease ◽

Intestinal Epithelial Cell ◽

Intestinal Epithelial Cells ◽

Intestinal Epithelial ◽

Innate Response ◽

Response System ◽

Inflammatory Bowel

ABSTRACT Initiation and perpetuation of the inflammatory intestinal responses in inflammatory bowel disease (IBD) may result from an exaggerated host defense reaction of the intestinal epithelium to endogenous lumenal bacterial flora. Intestinal epithelial cell lines constitutively express several functional Toll-like receptors (TLRs) which appear to be key regulators of the innate response system. The aim of this study was to characterize the expression pattern of TLR2, TLR3, TLR4, and TLR5 in primary intestinal epithelial cells from patients with IBD. Small intestinal and colonic biopsy specimens were collected from patients with IBD (Crohn's disease [CD], ulcerative colitis [UC]) and controls. Non-IBD specimens were assessed by immunofluorescence histochemistry using polyclonal antibodies specific for TLR2, TLR3, TLR4, and TLR5. Primary intestinal epithelial cells (IEC) of normal mucosa constitutively expressed TLR3 and TLR5, while TLR2 and TLR4 were only barely detectable. In active IBD, the expression of TLR3 and TLR4 was differentially modulated in the intestinal epithelium. TLR3 was significantly downregulated in IEC in active CD but not in UC. In contrast, TLR4 was strongly upregulated in both UC and CD. TLR2 and TLR5 expression remained unchanged in IBD. These data suggest that IBD may be associated with distinctive changes in selective TLR expression in the intestinal epithelium, implying that alterations in the innate response system may contribute to the pathogenesis of these disorders.

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Surrogate Fecal Biomarkers in Inflammatory Bowel Disease: Rivals or Complementary Tools of Fecal Calprotectin?

Inflammatory Bowel Diseases ◽

10.1093/ibd/izx011 ◽

2017 ◽

Vol 24 (1) ◽

pp. 78-92 ◽

Cited By ~ 17

Author(s):

Mirko Di Ruscio ◽

Filippo Vernia ◽

Antonio Ciccone ◽

Giuseppe Frieri ◽

Giovanni Latella

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Fecal Calprotectin ◽

Response To Therapy ◽

Polymorphonuclear Neutrophil ◽

Cochrane Library ◽

Clinical Relapse ◽

Inflammatory Bowel ◽

Fecal Biomarkers

Abstract Background Current noninvasive methods for assessing intestinal inflammation in inflammatory bowel disease (IBD) remain unsatisfactory. Along with C-reactive protein and erythrocyte sedimentation rate, fecal calprotectin (FC) is the standard test for assessing IBD activity, even though its specificity and accuracy are not optimal and it lacks a validated cutoff. Over the past few decades, several fecal markers released from intestinal inflammatory cells have been investigated in IBD; they are the subject of this systematic review. Methods A systematic electronic search of the English literature up to April 2017 was performed using Medline and the Cochrane Library. Only papers written in English that analyzed fecal biomarkers in IBD were included. In vitro studies, animal studies, studies on blood/serum samples, and studies analyzing FC or fecal lactoferrin alone were excluded. Results Out of 1023 citations, 125 eligible studies were identified. Data were grouped according to each fecal marker including S100A12, high-mobility group box 1, neopterin, polymorphonuclear neutrophil elastase, fecal hemoglobin, alpha1-antitrypsin, human neutrophil peptides, neutrophil gelatinase-associated lipocalin, chitinase 3-like-1, matrix metalloproteinase 9, lysozyme, M2-pyruvate kinase, myeloperoxidase, fecal eosinophil proteins, human beta-defensin-2, and beta-glucuronidase. Some of these markers showed a high sensitivity and specificity and correlated with disease activity, response to therapy, and mucosal healing. Furthermore, they showed a potential utility in the prediction of clinical relapse. Conclusions Several fecal biomarkers have the potential to become useful tools complementing FC in IBD diagnosis and monitoring. However, wide variability in their accuracy in assessment of intestinal inflammation suggests the need for further studies.

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Clinical Pharmacology of Janus Kinase Inhibitors in Inflammatory Bowel Disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjaa014 ◽

2020 ◽

Vol 14 (Supplement_2) ◽

pp. S725-S736 ◽

Cited By ~ 3

Author(s):

Pavine L C Lefevre ◽

Niels Vande Casteele

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Clinical Pharmacology ◽

Gastrointestinal Tract ◽

Bowel Disease ◽

Kinase Inhibitors ◽

Response To Therapy ◽

Janus Kinase ◽

Janus Kinase Inhibitors ◽

Inflammatory Bowel

Abstract Inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, are chronic inflammatory disorders of the gastrointestinal tract which are characterised, in part, by an imbalance in the production of several pro- and anti-inflammatory cytokines. Although various agents are effective for inducing and maintaining remission, approximately 20% of patients are treatment-refractory and require surgery. Parenterally administered monoclonal antibody-based biologics are associated with adverse effects resulting in treatment discontinuation and/or immunogenicity, leading to loss of response to therapy. Approximately 50% of patients who initially respond to treatment with tumour necrosis factor antagonists lose response to therapy within the 1st year of treatment. Incidence of immunogenicity tends to decrease over time, but once present can persist for years, even after treatment discontinuation. Nonimmunogenic oral small molecule therapies, including Janus kinase inhibitors, are currently being developed and have demonstrated efficacy in early phase clinical trials, which has already led to regulatory approval of tofacitinib for the treatment of patients with moderate-to-severe ulcerative colitis. Differentiation of T cells into T helper cells, which are mediators of the inflammatory response in inflammatory bowel disease, is mediated by the Janus kinase signal transducer and activator of the transcription signalling pathway. Absorption and distribution of Janus kinase inhibitors occurs at the site of action in the gastrointestinal tract, and newer compounds are being developed with limited systemic absorption, potentially reducing the risk of adverse effects. The current review describes the clinical pharmacology of approved Janus kinase inhibitors, as well as those in clinical development for the treatment of inflammatory bowel disease.

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