Response In Crohn Research Articles

Optimal timeframe for achieving biochemical remission in Crohn's disease patients treated with first-line biologics: A retrospective multicenter study.

Predicting treatment response in Crohn's disease (CD) patients initiating biological therapy is crucial. The first step involves considering symptom control and normalization of C-reactive protein (CRP). However, data on the actual rates of achieving CRP normalization and the appropriate timeframe are lacking. Therefore, we aim to investigate the rate of attaining CRP normalization and identify its optimal timeframe in CD patients initiating biological therapy. In this retrospective multi-center study, we analyzed moderate to severe CD patients initiating biological therapy from January 2012 to July 2023. The primary outcome was the rate and timeframe for achieving CRP normalization. Secondary outcomes included clinical outcomes in patients who achieved CRP normalization and factors associated with early CRP normalization. Of 183 patients, 123 (67.2%) achieved CRP normalization, with a median duration of 3.8 months (interquartile range 1.4 to 7.4 months). The duration and value difference for CRP normalization between anti-tumor necrosis factor agents, ustekinumab, and vedolizumab were statistically insignificant. Cumulative rates of CD-related hospitalization, intestinal resection, and drug discontinuation over 8 years were 11.4%, 2.4%, and 12.2%, respectively. The duration of CRP normalization correlates with drug discontinuation (area under the curve: 0.64). Treatment with 5-aminosalicylic acid (HR 2.77; 95% confidence interval [CI] 1.26-6.11) and high albumin level (HR 1.64, 95% CI 1.04-2.61) favored early CRP normalization, whereas structuring behavior less likely than inflammatory behavior (HR 0.43, 95% CI 0.19-0.96). We have provided the actual rate of achieving CRP normalization and its appropriate timeframe as an initial target in CD treatment.

Dissecting the Mechanisms of Intestinal Immune Homeostasis by Analyzing T-Cell Immune Response in Crohn's Disease and Colorectal Cancer.

Crohn's disease (CD) and colorectal cancer (CRC) represent a group of intestinal disorders characterized by intricate pathogenic mechanisms linked to the disruption of intestinal immune homeostasis. Therefore, comprehending the immune response mechanisms in both categories of intestinal disorders is of paramount significance in the prevention and treatment of these debilitating intestinal ailments. IIn this study, we conducted single-cell analysis on paired samples obtained from primary colorectal tumors and individuals with Crohn's disease, which was aimed at deciphering the factors influencing the composition of the intestinal immune microenvironment. By aligning T cells across different tissues, we identified various T cell subtypes, such as γδ T cell, NK T cell, and regulatory T (Treg) cell, which maintained immune system homeostasis and were confirmed in enrichment analyses. Subsequently, we generated pseudo-time trajectories for subclusters of T cells in both syndromes to delineate their differentiation patterns and identify key driver genes Result: Furthermore, cellular communication and transcription factor regulatory networks are all essential components of the intricate web of mechanisms that regulate intestinal immune homeostasis. The identified complex cellular interaction suggested potential T-lineage immunotherapeutic targets against epithelial cells with high copy number variation (CNV) levels in CD and CRC. Finally, the analysis of regulon networks revealed several promising candidates for cell-specific transcription factors (TFs). This study focused on the immune molecular mechanism under intestinal diseases. It contributed to the novel insight of depicting a detailed immune landscape and revealing T-cell responding mechanisms in CD and CRC.

Developing a Machine-Learning Prediction Model for Infliximab Response in Crohn's Disease: Integrating Clinical Characteristics and Longitudinal Laboratory Trends.

Achieving long-term clinical remission in Crohn's disease (CD) with antitumor necrosis factor α (anti-TNF-α) agents remains challenging. This study aims to establish a prediction model based on patients' clinical characteristics using a machine-learning approach to predict the long-term efficacy of infliximab (IFX). Three cohorts comprising 746 patients with CD were included from 3 inflammatory bowel disease (IBD) centers between June 2013 and January 2022. Clinical records were collected from baseline, 14-, 30-, and 52-week post-IFX treatment. Three machine-learning approaches were employed to develop predictive models based on 23 baseline predictors. The SHapley Additive exPlanations (SHAP) algorithm was used to dissect underlying predictors, and latent class mixed model (LCMM) was applied for trajectory analysis of the longitudinal change of blood routine tests along with long-term IFX therapy. The XGBoost model exhibited the best discrimination between long-term responders and nonresponders. In the internal training and testing set, the model achieved an AUC of 0.91 (95% CI, 0.86-0.95) and 0.71 (95% CI, 0.66-0.87), respectively. Moreover, it achieved a moderate predictive performance in the independent external cohort, with an AUC of 0.68 (95% CI, 0.59-0.77). The SHAP algorithm revealed disease-relevant laboratory measurements, notably hemoglobin (HB), white blood cells (WBC), erythrocyte sedimentation rate (ESR), albumin (ALB), and platelets (PLT), alongside age at diagnosis and the Montreal classification, as the most influential predictors. Furthermore, 2 distinct patient clusters based on dynamic laboratory tests were identified for monitoring the long-term remission. The established prediction model demonstrated remarkable discriminatory power in distinguishing long-term responders from nonresponders to IFX therapy. The identification of distinct patient clusters further emphasizes the need for tailored therapeutic approaches in CD management.

Single-Cell Transcriptomic and Targeted Genomic Profiling Adjusted for Inflammation and Therapy Bias Reveal CRTAM and PLCB1 as Novel Hub Genes for Anti-Tumor Necrosis Factor Alpha Therapy Response in Crohn's Disease.

The lack of reliable biomarkers in response to anti-TNFα biologicals hinders personalized therapy for Crohn's disease (CD) patients. The motivation behind our study is to shift the paradigm of anti-TNFα biomarker discovery toward specific immune cell sub-populations using single-cell RNA sequencing and an innovative approach designed to uncover PBMCs gene expression signals, which may be masked due to the treatment or ongoing inflammation; Methods: The single-cell RNA sequencing was performed on PBMC samples from CD patients either naïve to biological therapy, in remission while on adalimumab, or while on ustekinumab but previously non-responsive to adalimumab. Sieves for stringent downstream gene selection consisted of gene ontology and independent cohort genomic profiling. Replication and meta-analyses were performed using publicly available raw RNA sequencing files of sorted immune cells and an association analysis summary. Machine learning, Mendelian randomization, and oligogenic risk score methods were deployed to validate DEGs highly relevant to anti-TNFα therapy response; Results: This study found PLCB1 in CD4+ T cells and CRTAM in double-negative T cells, which met the stringent statistical thresholds throughout the analyses. An additional assessment proved causal inference of both genes in response to anti-TNFα therapy; Conclusions: This study, jointly with an innovative design, uncovered novel candidate genes in the anti-TNFα response landscape of CD, potentially obscured by therapy or inflammation.

Prevalence of the Oral Corticosteroid Exposure and Excessive Use in Patients with Inflammatory Bowel Disease: Data from Four French Referral Centers of the International DICE Study.

Background: Corticosteroids used to induce a response in Crohn's disease (CD) and ulcerative colitis (UC) may cause adverse reactions. The DICE study aimed to quantify and investigate factors associated with their use. Methods: This cross-sectional, non-interventional study conducted in seven countries allowed us to collect data on oral corticosteroid exposure and excessive use (cf. British Society of Gastroenterology) over the past 12 months in adult patients with CD or UC for more than a year. The factors associated with these practices were investigated using marginal logistic models. We present the results from the four participating French expert centers. Results: Corticosteroid exposure over the past 12 months was observed in 20.1% of 324 CD patients and 30.2% of 205 UC patients. Excessive use was reported in 13.3% and 17.1% of patients, respectively. Corticosteroid exposure and excessive use were less frequently observed in CD than in UC (OR: 0.56, p < 0.0001, and 0.69, p = 0.0042). A disease activity assessment at patient's last visit was the main factor (p < 0.01) associated with the risk of corticosteroid exposure and excessive use in CD (OR: 3.41 and 3.44) and UC (OR: 7.29 and 6.90). Conclusions: Corticosteroid exposure and excessive use continue to be frequently observed in CD and UC in France.

Targeting AQP9 enhanced the anti-TNF therapy response in Crohn's disease by inhibiting LPA-hippo pathway

Although anti-TNF antibodies are extensively used to treat Crohn's disease (CD), a significant proportion of patients, up to 40%, exhibit an inadequate response to this therapy. Our objective was to identify potential targets that could improve the effectiveness of anti-TNF therapy in CD. Through the integration and analysis of transcriptomic data from various CD databases, we found that the expression of AQP9 was significantly increased in anti-TNF therapy-resistant specimens. The response to anti-TNF therapy in the CD mouse model was significantly enhanced by specifically inhibiting AQP9. Further experiments found that the blockade of AQP9, which is dominantly expressed in macrophages, decreased inflamed macrophage functions and cytokine expression. Mechanistic studies revealed that AQP9 transported glycerol into macrophages, where it was metabolized to LPA, which was further metabolized to LPA, resulting in the activation of the LPAR2 receptor and downstream hippo pathway, finally promoting the expression of cytokines, especially IL23 and IL1β⊡ Taken together, the expansion of AQP9+ macrophages is associated with resistance to anti-TNF therapy in Crohn’s disease. These findings indicated that AQP9 could be a potential target for enhancing anti-TNF therapy in Crohn’s disease.

P556 Immunomodulator and advanced therapies for Induction of clinical remission and response in Crohn’s disease: A systematic review and network meta-analysis

Abstract Background Several effective advanced therapies have been approved for the treatment of Crohn’s disease (CD) in the past two decades. Many have used synthesis techniques to study this area, but these rarely consider both advanced and immunomodulator therapy together in the same analysis. Network meta-analysis enables the direct and indirect comparison of these different therapeutic agents, aiding in determining their relative positioning within the treatment algorithm. Methods We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials between inception and October 2023 for randomised controlled trials (RCTs). The outcomes included were clinical remission and response, adverse events (AE), withdrawal due to AE, total and serious AE. We performed random-effects meta-analysis and network meta-analysis (frequentist approach), and estimated relative risk (RRs), 95%CI values. We used GRADE to ascertain certainty of evidence. Results A total of 83 RCTs comprising 19214 patients were eligible. A total of 28 interventions were included in the analysis. Combination of anti-tumor necrosis factor (TNF) and immunomodulators, anti-TNF monotherapy (adalimumab [ADA], infliximab [IFX], BI695501), IL-23 antagonists (ustekinumab [UST], guselkumab, risankizumab [RIS], mirikizumab), anti-integrins (vedolizumab, natalizumab) and upadacitinib were effective in inducing clinical remission compared to placebo (Figure 1). There was moderate certainty of evidence for combination of ADA and azathioprine (AZA) (RR 3.1, 95%CI [2.0-4.8]; risk difference [RD]: 40.1%), IFX+AZA (RR 2.5, 95%CI [1.7-3.8]; RD: 28.9%), ADA (RR 2.5, 95%CI [1.8-3.5]; RD:28.5%), and UST (RR 2.0 95%CI, [1.6-2.5]; RD: 19.2%) in induction of clinical remission compared to placebo. For induction of clinical response, there was moderate certainty of evidence for IFX+AZA (RR 2.8, 95%CI [1.6-4.8]), ADA (RR 2.5, 95%CI [1.7-3.9]), IFX (RR 2.8, 95%CI [1.6-4.8]), RIS (RR 1.9, 95%CI [1.3-2.6]). On analysis of serious adverse events all therapies were of no difference to placebo (very low certainty). On sensitivity analysis, the impact of concomitant immunomodulator use and the biological naivety of patients had little effect on these results. Conclusion On network meta-analysis, combination of anti-TNFs and immunomodulators followed by anti-TNF monotherapy had large effect size with moderate certainty for the induction of clinical remission. More novel therapies appear to have examples of similarly important effect sizes, but are currently limited due to the imprecision of the limited evidence base at present and future research should target these therapies in study.

Salivary Th17 cytokine, human β-defensin 1–3, and salivary scavenger and agglutinin levels in Crohn’s disease

ObjectivesCrohn’s disease patients, who are prone to develop periodontal diseases, may carry genetic defects in their Th17 cytokine, human beta-defensin (hBD) 1–3, and salivary and scavenger agglutinin (SALSA) expressions. Biochemical composition of saliva reflects the oral consequences of systemic immune response modifications. Our aim was to evaluate the salivary Th17 cytokine, epithelial hBD 1–3, and SALSA levels in relation to Crohn’s disease.Materials and methodsThis cross-sectional study included 42 Crohn’s disease patients and 34 systemically healthy controls. Periodontal and dental indexes were measured, and stimulated saliva samples were collected. Salivary Th17 cytokine levels were analyzed by multiplex technique, and hBD 1–3 and SALSA levels by enzyme-linked immunosorbent assay.ResultsThere were 19 gingivitis and 11 initial periodontitis patients in the Crohn’s disease group, and 15 gingivitis and 4 initial periodontitis in the control group. In comparison to controls, higher salivary Th17 cytokine levels were observed in Crohn’s disease patients. No statistical difference was observed between Crohn’s disease and control groups in terms of their salivary hBD 1–3 and SALSA levels. Based on the regression analysis, there is no independent association between Crohn’s disease and salivary Th17 cytokine levels.ConclusionsCrohn’s disease does not relate to salivary antimicrobial hBD 1–3 or SALSA levels. While Crohn’s disease patients have higher salivary Th17 cytokine levels in comparison to systemically healthy controls, an independent association between Crohn’s disease and Th17 cytokine profile is still missing.Clinical relevanceDiminished Th17 cytokine response in Crohn’s disease, which might be related to genetic susceptibility, can be also visualized in saliva.

Apoptosis in mesenchymal stromal cells activates an immunosuppressive secretome predicting clinical response in Crohn’s disease

Invivo apoptosis of human mesenchymal stromal cells (MSCs) plays a critical role in delivering immunomodulation. Yet, caspase activity not only mediates the dying process but also death-independent functions that may shape the immunogenicity of apoptotic cells. Therefore, a better characterization of the immunological profile of apoptotic MSCs (ApoMSCs) could shed light on their mechanistic action and therapeutic applications. We analyzed the transcriptomes of MSCs undergoing apoptosis and identified several immunomodulatory factors and chemokines dependent on caspase activation following Fas stimulation. The ApoMSC secretome inhibited human Tcell proliferation and activation, and chemoattracted monocytes invitro. Both immunomodulatory activities were dependent on the cyclooxygenase2 (COX2)/prostaglandin E2 (PGE2) axis. To assess the clinical relevance of ApoMSC signature, we used the peripheral blood mononuclear cells (PBMCs) from a cohort of fistulizing Crohn's disease (CD) patients who had undergone MSC treatment (ADMIRE-CD). Compared with healthy donors, MSCs exposed to patients' PBMCs underwent apoptosis and released PGE2 in a caspase-dependent manner. Both PGE2 and apoptosis were significantly associated with clinical responses to MSCs. Our findings identify a new mechanism whereby caspase activation delivers ApoMSC immunosuppression. Remarkably, such molecular signatures could implicate translational tools for predicting patients' clinical responses to MSC therapy in CD.

Eriocalyxin B ameliorated Crohn's disease-like colitis by restricting M1 macrophage polarization through JAK2/STAT1 signalling

Background and aimsM1 polarization of macrophages in the intestine is an important maintenance factor of the inflammatory response in Crohn's disease (CD). Eriocalyxin B (EriB) is a natural medicine that antagonizes inflammation. Our study aimed to determine the effects of EriB on CD-like colitis in mice, as well as the possible mechanism. Methods2,4,6-trinitrobenzene sulfonic acid (TNBS) mice and Il-10−/− mice were used as CD animal models, and the therapeutic effect of EriB on CD-like colitis in mice was addressed by the disease activity index (DAI) score, weight change, histological analysis and flow cytometry assay. To assess the direct role of EriB in regulating macrophage polarization, bone marrow-derived macrophages (BMDMs) were induced to M1 or M2 polarization separately. Molecular docking simulations and blocking experiments were performed to explore the potential mechanisms by which EriB regulates the macrophage polarization. ResultsEriB treatment reduced body weight loss, DAI score and histological score, demonstrating the improvement of colitis symptoms in mice. In vivo and in vitro experiments both showed that EriB decreased the M1 polarization of macrophages, and suppressed the release of proinflammatory cytokines (IL-1β, TNF-α and IL-6) in mouse colons and BMDMs. The activation of Janus kinase 2/signal transducer and activator of transcription 1 (JAK2/STAT1) signals could be inhibited by EriB, which may be related to the regulation of EriB on M1 polarization. ConclusionsEriB inhibits the M1 polarization of macrophages by attenuating the JAK2/STAT1 pathway, which partially explains the potential mechanism by which EriB ameliorates colitis in mice, and provides a new regimen for the clinical treatment of CD.

Analysis of Circulating Food Antigen-Specific T-Cells in Celiac Disease and Inflammatory Bowel Disease.

To demonstrate and analyze the specific T-cell response following barrier disruption and antigen translocation, circulating food antigen-specific effector T-cells isolated from peripheral blood were analyzed in patients suffering from celiac disease (CeD) as well as inflammatory bowel disease (IBD). We applied the antigen-reactive T-cell enrichment (ARTE) technique allowing for phenotypical and functional flow cytometric analyses of rare nutritional antigen-specific T-cells, including the celiac disease-causing gliadin (gluten). For CeD, patient groups, including treatment-refractory cases, differ significantly from healthy controls. Even symptom-free patients on a gluten-free diet were distinguishable from healthy controls, without being previously challenged with gluten. Moreover, frequency and phenotype of nutritional antigen-specific T-cells of IBD patients directly correlated to the presence of small intestinal inflammation. Specifically, the frequency of antigen specific T-cells as well as pro-inflammatory cytokines was increased in patients with active CeD or Crohn's disease, respectively. These results suggest active small intestinal inflammation as key for the development of a peripheral food antigen-specific T-cell response in Crohn's disease and celiac disease.

The Serum-Based Endoscopic Healing Index Can Monitor Therapeutic Response in Crohn's Disease.

Journal Article Accepted manuscript The Serum-Based Endoscopic Healing Index Can Monitor Therapeutic Response in Crohn's Disease Get access Dahham Alsoud, Dahham Alsoud Translational Research in Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium https://orcid.org/0000-0002-6795-6328 Search for other works by this author on: Oxford Academic PubMed Google Scholar Jessica Ho, Jessica Ho Prometheus Laboratories Inc, San Diego, California Search for other works by this author on: Oxford Academic PubMed Google Scholar Bram Verstockt Bram Verstockt Translational Research in Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, BelgiumDepartment of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium Corresponding author: Bram Verstockt, MD, PhD , Department of Gastroenterology and Hepatology, University Hospitals Leuven, Herestraat 49 3000 Leuven, Belgium, Phone: 0032 (0)16 34 42 18, E-mail bram.verstockt@uzleuven.be https://orcid.org/0000-0003-3898-7093 Search for other works by this author on: Oxford Academic PubMed Google Scholar Journal of Crohn's and Colitis, jjad077, https://doi.org/10.1093/ecco-jcc/jjad077 Published: 26 April 2023 Article history Received: 30 March 2023 Published: 26 April 2023

How should we/could we optimize the therapeutic response in Crohn’s disease?

How should we/could we optimize the therapeutic response in Crohn’s disease?

Single-Cell Sequencing-Based Validation of T Cell-Associated Diagnostic Model Genes and Drug Response in Crohn's Disease.

Crohn's disease is a highly heterogeneous autoimmune disease with a unique inflammatory phenotype of T cells at the lesion site. We aim to further explore the diagnosis of Crohn's disease and drug prediction of T cell marker gene expression. We obtained single-cell expression profile data from 22 CDs or normal samples and performed cell annotation and cellular communication analysis. Through the intersection of T cell marker genes, differential genes, and WGCNA results, we identified T cell-specific key genes and their immune landscapes and potential pathogenesis, and validated them across multiple datasets and patient tissue samples. We also explored the differentiation characteristics of genes by pseudo-temporal analysis and assessed their diagnostic performance and drug sensitivity by molecular docking. Finally, we extended this study to the prognosis of IBD-associated colon cancer. TNF-centered 5-gene diagnostic model not only has excellent diagnostic efficacy, but is also closely associated with KRAS, P53, and IL6/JAK/STAT3 pathways and physiological processes, such as EMT, coagulation, and apoptosis. In addition, this diagnostic model may have potential synergistic immunotherapeutic effects, with positive correlations with immune checkpoints such as CTLA4, CD86, PDCD1LG2, and CD40. Molecular docking demonstrated that BIRC3 and ANXA1 have strong binding properties to Azathioprine and Glucoocorticoid. Furthermore, the 5-gene model may suggest antagonism to IFX and prognosis for colon cancer associated with inflammatory bowel disease. Single-cell sequencing targeting T cell-related features in patients with Crohn's disease may aid in new diagnostic decisions, as well as the initial exploration of high-potential therapies.

P653 Tight control and Treat to target increase the rates of Transmural remission and Transmural response in Crohn’s disease

Abstract Background increasing evidence support the use of Transmural remission as a treatment target in Crohn’s disease (CD) but few patients can reach it with currently available therapies. Treat-To-Target (T2T) and Tight-Control (TC) strategies may potentially improve these results. Methods Methods: single-center retrospective study including 123 CD patients with active colonoscopy (CN) and magnetic resonance enterography (MRE) at baseline and with available follow-up CN and MRE for reassessment of remission. We evaluated the effects of T2T and TC strategies on the rates of Transmural remission and Transmural response. Patient submitted to bowel surgery between examinations were excluded. Definitions CN activity: ulcers in non-operated patients or Rutgeerts score&amp;gt; i1 in operated patients; MRE activity: bowel thickness &amp;gt;3 mm and enhancement on T1/T2 sequences. Transmural remission: inactive CN and MRE at reassessment; Transmural response: improvement from baseline in either examination. T2T: treatment decisions resulting in both clinical remission (Harvey-Bradshaw &amp;lt;5) and fecal calprotectin remission (Fc &amp;lt;250 ug/g) at reassessment. TC: treatment decisions resulting in persistent Fc remission (≥ 2 consecutive results, including reassessment). Results 48.0% and 42.3% of patients followed a T2T and TC strategy, respectively. Transmural remission and Transmural response were reached by 33.3% and 69.1% of patients, respectively. T2T resulted in higher rates of Transmural remission (55.9% vs 12.5%, P&amp;lt;0.001) and Transmural response (91.5% vs 48.4%, P&amp;lt;0.001). TC was also associated with higher rates of Transmural remission (51.9% vs 19.7%, P&amp;lt;0.001) and Transmural response (90.4% vs 53.5%, P&amp;lt;0.001). In multivariate regression, T2T (OR 9.30 95%CI 2.85-30.30, P&amp;lt;0.001), TC (OR 3.85 95%CI 1.18-12.54, P=0.025) and starting biologic treatment (OR 3.63 95%CI 1.36-9.70, P=0.010) were independent predictors of reaching Transmural response. T2T was the only independent predictor of reaching Transmural remission (OR 6.540 95%CI 2.41-17.74, P&amp;lt;0.001). Conclusion Patients following a T2T and TC strategy presented higher rates of Transmural remission and Transmural response.

Роль нейромедиаторов в патогенезе воспалительных заболеваний кишечника

Among the diseases of the gastrointestinal tract, inflammatory bowel diseases occupy a special place and are the subject of a thorough, comprehensive study, attracting the attention of scientists and doctors around the world. The relevance of numerous studies is due to the steady increase in incidence, the presence of severe disabling forms, a variety of extraintestinal and systemic manifestations. Social and economic importance is determined by the manifestation of inflammatory bowel diseases mainly among young people of working age. At the same time, the mechanisms that trigger the inflammatory process have not been studied enough. The selection of risk factors also seems to be very arbitrary, which significantly reduces the possibility of preventing these conditions, predicting relapse and, as a result, the quality of life of patients. This literature review is an attempt to collect together the available data on the role of acetylcholine, serotonin, substance P and the vasoactive intestinal peptide in the development of the inflammatory response and modulation of the immune response in Crohn's disease and ulcerative colitis. The study of the content of neurotransmitters in the blood of patients and colon biopsy specimens can be important in developing criteria for laboratory diagnostics, assessing the degree of activity of the pathological process, making a forecast about the effectiveness of the therapy and the outcome of the disease. Key words: acetylcholine, Crohn's disease, inflammatory bowel disease, neurotransmitters, serotonin, substance P, ulcerative colitis, vasointestinal peptide

Identification of Novel Loci Involved in Adalimumab Response in Crohn's Disease Patients Using Integration of Genome Profiling and Isoform-Level Immune-Cell Deconvoluted Transcriptome Profiling of Colon Tissue.

Crohn’s disease is a consequence of dysregulated inflammatory response to the host’s microbiota. Although anti-TNF treatment improves the quality of the patient’s life, a large proportion of patients lose response to the treatment. The past decade of research has led to a continuum of studies showcasing the heterogeneity of anti-TNF response; thus, the aim of the present study was to dissect transcriptome-wide findings to transcript isoform specific levels and combine the analyses with refined information of immune cell landscapes in colon tissue, and subsequently select promising candidates using gene ontology and genomic integration. We enrolled Slovenian Crohn’s disease patients who were naïve with respect to adalimumab treatment. We performed colon tissue RNA sequencing and peripheral blood mononuclear cell DNA genotyping with a subsequent contemporary integrative approach to combine immune cell deconvoluted isoform transcript specific transcriptome analysis, gene ontology layering and genomic data. We identified nine genes (MACF1, CTSE, HDLBP, HSPA9, HLA-DMB, TAP2, LGMN, ANAPC11, ACP5) with 15 transcripts and 16 variants involved in the adalimumab response. Our study identified loci, some of which were previously shown to contribute to inflammatory bowel disease susceptibility, as novel loci involved in adalimumab response in Crohn’s disease patients.

MALT1 reflects inflammatory cytokines, disease activity, and its chronological change could estimate treatment response to infliximab in Crohn's disease patients.

BackgroundMucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1) mediates the immunity and inflammatory response in multiple ways to be intimately involved in the progression of autoimmune diseases. This study intended to explore the linkage of MALT1 with inflammation, disease activity, and its change with infliximab treatment response in Crohn's disease (CD) patients.MethodsMALT1 in peripheral blood mononuclear cell samples from 72 active CD patients (at baseline, 2 weeks [W2], W6, and W12 after infliximab treatment), 20 remissive CD patients (after enrollment), and 20 healthy controls (after enrollment) were detected by RT‐qPCR.ResultsMALT1 was highest in active CD patients, followed by remissive CD patients, and lowest in healthy controls (p < 0.001). MALT1 was positively linked with C‐reactive protein (p = 0.001), erythrocyte sedimentation rate (p = 0.014), clinical disease activity index (p = 0.003), tumor necrosis factor (TNF)‐α (p = 0.006), interleukin (IL)‐1β (p = 0.049), and IL‐17A (p = 0.004), but not other clinical characteristics (all p > 0.05) in active CD patients. After infliximab treatment, MALT1 was decreased from baseline to W12 in active CD patients (p < 0.001), especially in responders (p < 0.001), but not in nonresponders (p = 0.053). The reduction of MALT1 at W6 (p = 0.049) and W12 (p = 0.004) was associated with a good treatment response to infliximab in active CD patients. Moreover, the response rate or MALT1 at any time point was not different between active CD patients with and without TNFi history (all p > 0.05).ConclusionMALT1 reflects aggravated inflammation and disease activity. Meanwhile, the decrement of MALT1 from baseline to W12 could reflect infliximab treatment response in CD patients.

Crohn's Disease Patients Uniquely Contain Inflammatory Responses to Flagellin in a CD4 Effector Memory Subset.

Specific microbial antigens stimulate production of antibodies indicative of the aberrant immune response in Crohn's disease (CD). We tested for T cell reactivity linkage to B cell responses and now report on the prevalence, functionality, and phenotypic differences of flagellin-specific T cells among CD patients, ulcerative colitis (UC) patients, and control subjects and association with clinical features and flagellin seropositivity within CD patients. Sera from non-inflammatory bowel disease control subjects, CD patients, and UC patients were probed for antibody reactivity to gut bacterial recombinant flagellin antigens. Peripheral blood mononuclear cells were measured for flagellin antigen (CBir1, A4 Fla2, FlaX) or control (Candida albicans, and CytoStim) reactivity analyzed by flow cytometry for CD154 and cytokine expression on CD4+ T cells. Supernatants from post-flagellin-stimulated and unstimulated cells were used to measure effects on epithelial barrier function. CD patients had a significantly higher percentage of flagellin-specific CD154+ CD4+ cells that have an effector memory T helper 1 and T helper 17 phenotype compared with UC patients and healthy control subjects. There was a positive correlation between the frequency of flagellin-specific CD154+ CD4+ effector memory T cells and serum levels of anti-flagellin immunoglobulin G in the CD patients. In addition, A4 Fla2-reactive T cells from active CD patients produced cytokines that can decrease barrier function in a gut epithelium. These findings demonstrate a Crohn's-associated flagellin-reactive CD4 cell subset distinct from UC patients and control subjects. There is a link between these cells and flagellin seropositivity. This CD4 cell subset could reflect a particular endophenotype of CD, leading to novel insight into its pathology and treatment.

Pharmacogenetic analysis of canonical versus noncanonical pathway of NF-kB in Crohn's disease patients under anti-tumor necrosis factor-α treatment.

This study explores the potential of gene polymorphisms in the canonical and noncanonical NF-kB signaling pathway as a prediction biomarker of anti-tumor necrosis factor (TNF)α response in Crohn's patients. A total of 109 Greek patients with Crohn's disease (CD) were recruited, and the genotype of TLR2 rs3804099, LTA rs909253, TLR4 rs5030728, and MAP3K14/NIK rs7222094 single nucleotide polymorphisms was investigated for association with response to anti-TNFα therapy. Patient's response to therapy was based on the Crohn's Disease Activity Index, depicting the maximum response within 24 months after initiation of treatment. Seventy-three patients (66.7%) were classified as responders while 36 as nonresponders (33.3%). Comparing allelic frequencies between responders and nonresponders, the presence of TLR2 rs3804099 T allele was associated with nonresponse (P = 0.003), even after stratification by anti-TNFα drugs (infliximab: P = 0.032, adalimumab: P = 0.026). No other association was identified for the rest of the polymorphisms under study. Haplotype analysis further enhanced the association of rs3804099 T allele with loss of response, even though the results were NS (P = 0.073). Our results suggest that polymorphisms in the canonical NF-kB pathway genes could potentially act as a predictive biomarker of anti-TNFα response in CD.