Prediction and Verification of Potential Therapeutic Targets for Non-Responders to Infliximab in Ulcerative Colitis

Xue Lyu; Zhe Zhang; Xia Liu; Li Geng; Muhan Zhang; Baisui Feng

doi:10.2147/JIR.S409290

Prediction and Verification of Potential Therapeutic Targets for Non-Responders to Infliximab in Ulcerative Colitis

J Inflamm Res. 2023 May 15:16:2063-2078. doi: 10.2147/JIR.S409290. eCollection 2023.

Authors

Xue Lyu^#¹, Zhe Zhang^#¹, Xia Liu^#¹, Li Geng¹, Muhan Zhang¹, Baisui Feng¹

Affiliation

¹ Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450014, People's Republic of China.

^# Contributed equally.

Abstract

Background: Infliximab (IFX) has been widely used in ulcerative colitis (UC) patients. However, the subsequent effective treatment of IFX non-response in UC patients remains a challenge. This study aims to predict potential therapeutic targets for non-responders by performing a bioinformatic analysis of the data in the Gene Expression Omnibus (GEO) database and validation by biopsies.

Methods: Colonic mucosal biopsies expression profiles of IFX-treated UC patients (GSE73661, GSE16879) were utilized to predict potential therapeutic targets. Bioinformatics analyses were used to explore potential biological mechanisms. CytoHubba was performed to screen hub genes. We used a validation dataset and colonic mucosal biopsies of UC patients to validate hub genes.

Results: A total of 147 DEGs were identified (119 upregulated genes and 28 downregulated genes). GSEA showed that DEGs in GSE73661 were enriched in the pathways of the cytokine-cytokine receptor, the chemokine, and the adhesion molecules system. Based on the PPI network analysis, we identified four hub genes (and the transcription factor NF-κB). Then, we validate the expression of hub genes by reverse transcription-polymerase chain reaction (RT-PCR). We found higher expression of IL-6, IL1B, CXCL8, and CCL2 in non-responders compared to responders.

Conclusion: In summary, four potential targets (IL-6, IL1B, CXCL8, and CCL2) were finally identified by performing a bioinformatics analysis of the datasets in the GEO database. Their expression was confirmed in colonic mucosal biopsies of patients with UC. These results can help to further explore the mechanism of non-responders to IFX in UC and to provide potential targets for their subsequent treatment.

Keywords: GEO dataset; drug targets; infliximab; ulcerative colitis.

Grants and funding

This project was supported by the Science and Technology Benefiting the People Program of Zhengzhou, 2021 (2021KJHM0018), the Science and Technology Breakthrough Project of Henan Province (222102310531), the Medical Science and Technology Breakthrough Project of Henan Province, China (LHGJ20210409, LHGJ20200396, and LHGJ20210415).