Multi-omics joint analysis to explore new therapeutic targets for Crohn's disease

Background: Infliximab (IFX), the mainstay of current treatment for moderate-to-severe Crohn's disease (CD), markedly improved clinical symptoms and quality of life for patients. However, not all patients can benefit from IFX. This study aims to identify new therapeutic targets for primary nonresponders through combination of transcriptomic and proteomic analyses. Methods The plasma and peripheral leukocytes were collected from seven good responders and four primary nonresponders with CD. To identify differentially expressed genes (DEGs) and proteins (DEPs), we performed reference transcriptome analyses and Olink proteomics analyses by Leukocytes and plasma respectively. Immune-related genes (IRGs) were then intersected with DEGs to screen for the differentially expressed immune-related genes (DEIRGs). We subsequently construct the protein-protein interaction (PPI) network with the DEIRGs. We also investigated the expression of DEGs and DEPs in the intestinal mucosa. Results A total of 1170 DEGs were identified, including 533 upregulated and 637 downregulated genes in primary nonresponders. After mapping DEGs to IRGs, 128 DEIRGs were screened. We identified five hub genes in the PPI network mapped by the DEIRGs, namely IL1B, MMP9, CXCL10, CD8A and CCR7 genes. Similarly, the Olink proteomics analysis discovered 13 DEPs. In the intestinal mucosa of primary nonresponders, hub genes IL1B, MMP9, CXCL10, and DEPs SLAFM1, MMP1, CXCL11, HGF, IFN-γ, and CXCL10 were also substantially expressed. Combined analysis of DEGs and DEPs revealed a common enrichment in the IL 17 signaling pathway, with CXCL10 being the only DEGs to overlap. Conclusions We first connected the intestinal biopsy series expression matrix to the peripheral blood transcriptome and proteome, confirming CXCL10 as a new therapeutic target. IL1B, MMP9, SLAFM1, MMP1, CXCL11, HGF, and IFN-γ were also deserving of consideration as prospective therapeutic targets.