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. 2024 Dec 5:15:1492810.
doi: 10.3389/fimmu.2024.1492810. eCollection 2024.

Common diagnostic biomarkers and molecular mechanisms of Helicobacter pylori infection and inflammatory bowel disease

Minglin Zhang #  1 , Tong Liu #  2 , Lijun Luo  3 , Yi Zhang  4 , Qijiao Chen  5 , Fen Wang  1 , Yuxin Xie  5
Affiliations

Common diagnostic biomarkers and molecular mechanisms of Helicobacter pylori infection and inflammatory bowel disease

Minglin Zhang et al. Front Immunol. .

Abstract

Background: Helicobacter pylori (H. pylori) may be present in the intestinal mucosa of patients with inflammatory bowel disease (IBD), which is a chronic inflammation of the gastrointestinal tract. The role of H. pylori in the pathogenesis of IBD remains unclear. In this study, bioinformatics techniques were used to investigate the correlation and co-pathogenic pathways between H. pylori and IBD.

Methods: The following matrix data were downloaded from the GEO database: H. pylori-associated gastritis, GSE233973 and GSE27411; and IBD, GSE3365 and GSE179285. Differential gene analysis was performed via the limma software package in the R environment. A protein-protein interaction (PPI) network of DEGs was constructed via the STRING database. Cytoscape software, through the CytoHubba plugin, filters the PPI subnetwork and identifies Hub genes. Validation of the Hub genes was performed in the validation set. Immune analysis was conducted via the CIBERSORT algorithm. Transcription factor interaction and small molecule drug analyses of the Hub genes were also performed.

Results: Using the GSE233973 and GSE3365 datasets, 151 differentially expressed genes (DEGs) were identified. GO enrichment analysis revealed involvement in leukocyte migration and chemotaxis, response to lipopolysaccharides, response to biostimulatory stimuli, and regulation of interleukin-8 (IL-8) production. Ten Hub genes (TLR4, IL10, CXCL8, IL1B, TLR2, CXCR2, CCL2, IL6, CCR1 and MMP-9) were identified via the PPI network and Cytoscape software. Enrichment analysis of the Hub genes focused on the lipopolysaccharide response, bacterial molecular response, biostimulatory response and leukocyte movement. Validation using the GSE27411 and GSE179285 datasets revealed that MMP-9 was significantly upregulated in both the H. pylori and IBD groups. The CIBERSORT algorithm revealed immune infiltration differences between the control and disease groups of IBD patients. Additionally, the CMap database identified the top 11 small molecule compounds across 10 cell types, including TPCA-1, AS-703026 and memantine, etc.

Conclusion: Our study revealed the co-pathogenic mechanism between H. pylori and IBD and identified 10 Hub genes related to cellular immune regulation and signal transduction. The expression of MMP-9 is significantly upregulated in both H. pylori infection and IBD. This study provides a new perspective for exploring the prevention and treatment of H. pylori infection and IBD.

Keywords: Helicobacter pylori; bioinformatics analysis; diagnostic biomarkers; inflammatory bowel disease; molecular mechanism.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
DEGs volcano plots, heatmaps and co-expressed genes. (A) Volcano plot representing DEGs from the GSE233973 dataset. (B) Volcano plot representing DEGs from the GSE3365 dataset. (C) Heatmap representing DEGs from the GSE233973 dataset. (D) Heatmap representing DEGs from the GSE3365 dataset. (E) Venn diagram of the coexpressed downregulated DEGs shared between the GSE233973 and GSE3365 datasets. (F) Venn diagram of the coexpressed upregulated DEGs shared between the GSE233973 and GSE3365 datasets. Red represents upregulated genes, green represents downregulated genes, and grey represents genes with no differential expression.
Figure 2
Figure 2
Functional enrichment and pathway enrichment analysis of coexpressed DEGs in H. pylori and IBD. (A–D) GSEA of coexpressed DEGs, with GO and KEGG enrichment analyses of the GSE3365 and GSE233973 datasets. Treat represents disease group. (E) GO analysis of coexpressed DEGs, including BP, biological process; CC, cellular component; MF, molecular function. (F) Circular plot of the GO analysis results. (G) PPI network analysis of coexpressed DEGs. (H) Enrichment analysis of 151 coexpressed DEGs via the Metascape online tool. (I) Transcription factor analysis of coexpressed DEGs.
Figure 3
Figure 3
Identification of hub genes and functional interaction network diagram. (A) PPI network analysis of DEGs (STRING database). (B, E) The top 10 Hub genes identified by the degree and MCC algorithms via the CytoHubba plugin in Cytoscape. (C, D) Visualization of the PPI network and important modules and subnetworks. (F) GeneMANIA diagram showing the coexpression interactions between the 10 identified shared Hub genes and their neighbouring genes. The colour codes indicate the functions shared by the genes.
Figure 4
Figure 4
Enrichment Analysis of Hub Genes. (A) The circular diagram visualizing the results of the GO enrichment analysis is presented below: the left semicircle denotes Hub genes, which represent gene names, whereas the right semicircle indicates GO terms. The different colours correspond to different GO terms. Notably, the connections between the two semicircles illustrate the enrichment of genes within specific GO terms. ***p < 0.001. (B) GO enrichment analysis of the following Hub genes: BP, biological process; CC, cellular component; MF, molecular function. (C) KEGG enrichment analysis of the Hub genes.
Figure 5
Figure 5
Expression of Hub genes in H. pylori and IBD. (A, B) Expression of 10 Hub genes in GSE27411 and GSE179285. (A) Blue represents noninfected individuals, and red represents H. pylori patients. (B) Blue represents normal individuals, and red represents UC+CD patients. *p < 0.05; **p < 0.01; ***p < 0.001; ns, no statistical significance.
Figure 6
Figure 6
Immune cell infiltration analysis of DEGs in IBD. (A, C) These figures represent the extent of infiltration of various immune cells between the IBD disease group and the normal group. (B, D) Violin plots depicting the differences in immune-infiltrating cells between the IBD disease group and the normal group. The horizontal axis represents the names of the immune cells, and the vertical axis represents the content of the immune cells. Green represents the normal group, and red represents the disease group. Treat represents IBD disease group. *p < 0.05; **p < 0.01; ***p < 0.001; ns indicates no statistical significance.
Figure 7
Figure 7
Screening of potential small-molecule compounds for the treatment of H. pylori and IBD via cMAP analysis. (A) Heatmap showing the top 11 compounds with significantly negative enrichment scores (score < -97) in 10 cell lines and a description of those top 11 compounds via cMAP analysis. We choose Perturbagen Type: compound. (B) PPI network diagram of the 11 compounds and Hub genes. (C, E, G) Chemical structures of the 3 compounds (alpha-linolenic acid, dexamethasone and phentolamine). (D, F, H) 3D structures of the 3 compounds. cMAP, Connectivity Map.
Figure 8
Figure 8
Network interaction between Hub genes and transcription factors and validation in H. pylori and IBD. (A) Network interaction diagram of transcription factors and Hub genes. (B, C) Expression of transcription factors in H. pylori-infected and IBD patients, with transcription factors showing significant differences. Blue represents the normal group, and red represents the disease group. *p < 0.05; **p < 0.01; ***p < 0.001.
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