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Effect of Anti-TNF Therapy on Mucosal Apoptosis Genes Expression in Crohn's Disease.

ABSTRACT: Crohn's disease (CD) is a chronic immune-mediated disorder for which there is not a fully effective treatment. Moreover, biological therapy with anti-tumor necrosis factor-α (anti-TNF-α) monoclonal antibodies leads to an effective response in only 60-70% of patients. Our previous data suggested that specific loci polymorphism of the TNFRSF1B, FCGR3A, IL1R, IL1B, and FAS genes could be a predictor of the primary non-response to anti-TNF therapy in CD patients. In this work, we propose to explain this hypothesis by functional analysis in colon biopsies and in a cell culture model. Using the RT-qPCR analysis, we estimated the FCGR3A, IL1R, TNFRSF1B, IL1B, FAS, and ADAM17 genes mRNA level in colon biopsies material from inflamed and non-inflamed tissue from 21 CD patients (14 responders and 7 non-responders to anti-TNF therapy) and 6 controls, as well as in vitro in a peripheral blood mononuclear cells (PBMCs) from 14 CD patients (seven responders and seven non-responders to anti-TNF therapy) and eight controls cultured for 72 h with 10 μg/ml of anti-TNF antibody. Our findings demonstrated a significant down-regulation of TNFRSF1B gene expression in non-responders both in inflamed and in non-inflamed colon tissue, while the expression of the FCGR3A and IL1B genes was significantly up-regulated in non-responders in the inflamed colon region. In vitro research results indicate that the anti-TNF drug induced a significant decrease in TNFRSF1B, FCGR3A, and FAS gene expression in non-responders. These results show that altered TNFRSF1B, FCGR3A, and IL1B genes expression can be a predictor of the primary non-response to anti-TNF therapy in CD patients.

SUBMITTER: Lykowska-Szuber L

PROVIDER: S-EPMC7985326 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAnti-TNF medications are the first-line treatment for Crohn's Disease (CD), despite the fact that a significant portion of the population continues to be ineffectively treated. This research aims to discover accurate intervention targets for the follow-up of anti-TNF non-responders using bioinformatics technology.MethodsGSE16879, GSE111761, and GSE52746 retrieved from the GEO database. Unbiased differentially expressed genes (DEGs) were discovered utilizing the limma and RobustRankAggreg (RRA) tools. Then, we used weighted gene co-expression network analysis (WGCNA) to identify the module most strongly associated with non responders and subjected this module to Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis with overlapping genes of the DEGs. GSEA analysis applied to check the results of GO and KEGG. Using the Cytoscape program, the protein-protein interaction (PPI) network was constructed. The software's MCODE addon and CytoHubba addon was used to find the most important modules and the hub genes. Subsequently, we employed reverse transcription-polymerase chain reaction (RT-PCR) to confirm hub gene expression from mucosal biopsy specimens.ResultsThere were a total of 142 genes co-upregulated and 65 genes co-downregulated. According to the WGCNA analysis, 42 genes were duplicated inside the light cyan module. GO and KEGG enrichment analyses of overlapped genes in nonresponders demonstrated an increase in the expression of genes associated with inflammation and immune response, consistent with GSEA results. The PPI network was constructed using 41 protein nodes and 177 edges. After validation, 8 of the top 10 genes were verified to be differentially expressed.ConclusionOur investigation is the first to integrate three CD databases after the anti-TNF medication treatment. We identified IL1B, CCL4, CXCL1, CXCL10, CCL3, CSF3, TREM1, and IL1RN as potential therapeutic targets for patients whose anti-TNF treatment failed.

Project description:BackgroundThe impact of the body composition on the pathophysiology and clinical course of Crohn's disease (CD) has not been fully elucidated.AimsTo reveal the correlations among body composition and long-term outcomes in CD after anti-TNF therapy.MethodsNinety-one patients who received anti-TNF therapy as their first biologic treatment were enrolled. The skeletal muscle index (SMI), visceral and subcutaneous fat area (VFA, SFA), and the ratio of the VFA to SFA (mesenteric fat index; MFI) at the 3rd lumbar level were measured using computed tomography (CT) imaging before the induction. The correlation among the body composition and outcomes were retrospectively analyzed.ResultsThe 5-year cumulative secondary failure- and resection-free rates in patients with a low SMI (39.1% and 64.8%) were significantly lower than those with a high SMI (67.5% and 92.7%; p = 0.0071 and 0.0022, respectively). The 5-year cumulative secondary failure-free rate in the patients with low VF (45.0%) was significantly lower than that in those with high VF (77.6%; p = 0.016), and the 5-year cumulative resection-free rate in patients with a high MFI (68.9%) was significantly lower than that in those with a low MFI (83.0%; p = 0.031). Additionally, patients with low age and BMI had significantly lower cumulative secondary failure- and resection-free rates than those with high age and BMI (low age: 37.4% and 71.2%; high age: 70.7% and 88.9%; p = 0.0083 and 0.027, respectively) (low BMI: 27.2% and 64.8%; high BMI: 68.3% and 87.9%; p = 0.014 and 0.030, respectively), respectively. In the multivariate analyses, a low SMI was the only independent risk factor for secondary failure (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.04-4.44), while low age (HR 4.06, 95% CI 1.07-15.4), a low SMI (HR 4.19, 95% CI 1.01-17.3) and high MFI were risk factors for bowel resection (HR 4.31, 95% CI 1.36-13.7).ConclusionThe skeletal muscle mass and ratio of visceral to subcutaneous fat were suggested to reflect the long-term clinical outcome and may be helpful as prognostic markers after anti-TNF therapy in CD.

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Effect of Anti-TNF Therapy on Mucosal Apoptosis Genes Expression in Crohn's Disease.

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