Skip to main content
Log in

Identification of potential predictive biomarkers and biological pathways and the correction with immune infiltration in the activation of Crohn’s disease

  • Original Article
  • Published:
Immunogenetics Aims and scope Submit manuscript

Abstract

Crohn’s disease (CD), a subtype of inflammatory bowel disease (IBD), has increasing prevalence in the world. Due to the lack of cure strategy, most patients with CD develop progressive disease companying with a series of serious complications. Therefore, exploring molecular mechanism differences between active and inactive CD will help in the screening of predict markers and therapeutic targets. In this study, we analyzed differentially expressed genes (DEGs) and molecular pathways through between active and inactive CD patients. In addition, the abundance of 22 immune cell types were assessed by using the CIBERSORT. The hub DEGs were screened out by the CytoHubba in Cytoscape, followed by the least absolute shrinkage and selection operator (LASSO) regression. Finally, the clinical predictive model was constructed by binary logistic regression model. The diagnostic efficacy was tested by receiver operating characteristic (ROC) curve and verified in independent datasets. The results showed that there were 137 DEGs between the active and inactive CD. Most of them were involved in regulating the immunity process. In addition, the decreased abundance of CD8 T cells and the increased abundance of M0, M1 macrophages, and neutrophils were closely related to CD activation. CXCL9, C3AR1, IL1B, and TLR4 were the hub gene and can be applied to the prediction of CD activation. Our results provided important targets for the prediction of CD activation and the selection of therapeutic targets.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The data can be downloaded from GEO dataset (https://www.ncbi.nlm.nih.gov/geo/).

References

  • Agrawal M, Spencer EA, Colombel JF, Ungaro RC (2021) Approach to the management of recently diagnosed inflammatory bowel disease patients: a user’s guide for adult and pediatric gastroenterologists. Gastroenterology 161:47–65

    Article  PubMed  Google Scholar 

  • Aschenbrenner D, Quaranta M, Banerjee S, Ilott N, Jansen J, Steere B, Chen YH, Ho S, Cox K, Arancibia-Cárcamo CV, Coles M, Gaffney E, Travis SP, Denson L, Kugathasan S, Schmitz J, Powrie F, Sansom SN, Uhlig HH (2021) Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance. Gut 70:1023–1036

    Article  PubMed  CAS  Google Scholar 

  • Bhatia K, Ahmad S, Kindelin A, Ducruet AF (2021) Complement C3a receptor-mediated vascular dysfunction: a complex interplay between aging and neurodegeneration. J Clin Invest 131

  • Boucher G, Paradis A, Chabot-Roy G, Coderre L, Hillhouse EE, Bitton A, Des Rosiers C, Levings MK, Schumm LP, Lazarev M, Brant SR, Duerr R, McGovern D, Silverberg MS, Cho J, Lesage S, Rioux JD (2022) Serum analyte profiles associated with Crohn’s disease and disease location. Inflamm Bowel Dis 28:9–20

    Article  PubMed  Google Scholar 

  • Bouguen G, Levesque BG, Feagan BG, Kavanaugh A, Peyrin-Biroulet L, Colombel JF, Hanauer SB, Sandborn WJ (2015) Treat to target: a proposed new paradigm for the management of Crohn’s disease. Clin Gastroenterol Hepatol 13:1042–50.e2

    Article  PubMed  Google Scholar 

  • Caruso R, Warner N, Inohara N, Núñez G (2014) NOD1 and NOD2: signaling, host defense, and inflammatory disease. Immunity 41:898–908

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen H, Chen C, Yuan X, Xu W, Yang MQ, Li Q, Shen Z, Yin L (2020) Identification of immune cell landscape and construction of a novel diagnostic nomogram for Crohn’s disease. Front Genet 11:423

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen H, Sun Q, Zhang C, She J, Cao S, Cao M, Zhang N, Adiila AV, Zhong J, Yao C, Wang Y, Xia H, Lan L (2021) Identification and validation of CYBB, CD86, and C3AR1 as the key genes related to macrophage infiltration of gastric cancer. Front Mol Biosci 8:756085

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chin CH, Chen SH, Wu HH, Ho CW, Ko MT, Lin CY (2014) cytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Syst Biol 8(Suppl 4):S11

    Article  PubMed  PubMed Central  Google Scholar 

  • Cordes F, Foell D, Ding JN, Varga G, Bettenworth D (2020) Differential regulation of JAK/STAT-signaling in patients with ulcerative colitis and Crohn’s disease. World J Gastroenterol 26:4055–4075

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Feki S, Bouzid D, Abida O, Chtourou L, Elloumi N, Toumi A, Hachicha H, Amouri A, Tahri N, Masmoudi H (2017) Genetic association and phenotypic correlation of TLR4 but not NOD2 variants with Tunisian inflammatory bowel disease. J Dig Dis 18:625–633

    Article  PubMed  CAS  Google Scholar 

  • Gionchetti P, Dignass A, Danese S, Magro Dias FJ, Rogler G, Lakatos PL, Adamina M, Ardizzone S, Buskens CJ, Sebastian S, Laureti S, Sampietro GM, Vucelic B, van der Woude CJ, Barreiro-de Acosta M, Maaser C, Portela F, Vavricka SR, Gomollón F (2017) 3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016: part 2: surgical management and special situations. J Crohns Colitis 11:135–149

    Article  PubMed  Google Scholar 

  • Lacher M, Kappler R, Berkholz S, Baurecht H, von Schweinitz D, Koletzko S (2007) Association of a CXCL9 polymorphism with pediatric Crohn’s disease. Biochem Biophys Res Commun 363:701–707

    Article  PubMed  CAS  Google Scholar 

  • Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P (2015) The molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst 1:417–425

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Luo B, Wang L, Gao W, Su Y, Lu Y, Zheng J, Yin J, Zhao Q, Li J, Da Y, Li L (2022) Using a gene network of pyroptosis to quantify the responses to immunotherapy and prognosis for neuroblastoma patients. Front Immunol 13:845757

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ma Y, Zhang X, Yang J, Jin Y, Xu Y, Qiu J (2022) Comprehensive molecular analyses of a TNF family-based gene signature as a potentially novel prognostic biomarker for cervical cancer. Front Oncol 12:854615

    Article  PubMed  PubMed Central  Google Scholar 

  • Nailwal NP, Doshi GM (2021) Role of intracellular signaling pathways and their inhibitors in the treatment of inflammation. Inflammopharmacology 29:617–640

    Article  PubMed  Google Scholar 

  • Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Hoang CD, Diehn M, Alizadeh AA (2015) Robust enumeration of cell subsets from tissue expression profiles. Nat Methods 12:453–457

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, Panaccione R, Ghosh S, Wu JCY, Chan FKL, Sung JJY, Kaplan GG (2017) Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 390:2769–2778

    Article  PubMed  Google Scholar 

  • Nguyen NH, Singh S, Sandborn WJ (2020) Positioning therapies in the management of Crohn’s disease. Clin Gastroenterol Hepatol 18:1268–1279

    Article  PubMed  Google Scholar 

  • Nobel YR, Stier K, Krishnareddy S (2021) STAT signaling in the intestine. Int Rev Cell Mol Biol 361:1–20

    Article  PubMed  Google Scholar 

  • Pan X, Zhu Q, Pan LL, Sun J (2022) Macrophage immunometabolism in inflammatory bowel diseases: from pathogenesis to therapy. Pharmacol Ther 238:108176

    Article  PubMed  CAS  Google Scholar 

  • Peterson LW, Artis D (2014) Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol 14:141–153

    Article  PubMed  CAS  Google Scholar 

  • Roda G, Chien Ng S, Kotze PG, Argollo M, Panaccione R, Spinelli A, Kaser A, Peyrin-Biroulet L, Danese S (2020) Crohn’s Disease Nat Rev Dis Primers 6:22

    Article  PubMed  Google Scholar 

  • Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Smids C, Horjus Talabur Horje CS, Drylewicz J, Roosenboom B, Groenen MJM, van Koolwijk E, van Lochem EG, Wahab PJ (2018) Intestinal T cell profiling in inflammatory bowel disease: linking T cell subsets to disease activity and disease course. J Crohns Colitis 12:465–475

    Article  PubMed  Google Scholar 

  • Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, Santos A, Doncheva NT, Roth A, Bork P, Jensen LJ, von Mering C (2017) The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res 45:D362-d368

    Article  PubMed  CAS  Google Scholar 

  • Tam JSY, Coller JK, Hughes PA, Prestidge CA, Bowen JM (2021) Toll-like receptor 4 (TLR4) antagonists as potential therapeutics for intestinal inflammation. Indian J Gastroenterol 40:5–21

    Article  PubMed  PubMed Central  Google Scholar 

  • Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L (2017) Crohn’s disease. Lancet 389:1741–1755

    Article  PubMed  Google Scholar 

  • Walshe M, Nayeri S, Ji J, Hernandez-Rocha C, Sabic K, Hu L, Giri M, Nayar S, Brant S, McGovern DPB, Rioux JD, Duerr RH, Cho JH, Schumm PL, Lazarev M, Silverberg MS (2021) A role for CXCR3 ligands as biomarkers of post-operative Crohn's disease recurrence. J Crohns Colitis

  • Wéra O, Lancellotti P, Oury C (2016) The dual role of neutrophils in inflammatory bowel diseases. J Clin Med 5

  • Wilkens R, Dolinger M, Burisch J, Maaser C (2022) Point-of-care testing and home testing: pragmatic considerations for widespread incorporation of stool tests, serum tests, and intestinal ultrasound. Gastroenterology 162:1476–1492

    Article  PubMed  Google Scholar 

  • Yang H, Li L, Liu X, Zhao Y (2021) High expression of the component 3a receptor 1 (C3AR1) gene in stomach adenocarcinomas infers a poor prognosis and high immune-infiltration levels. Med Sci Monit 27:e927977

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yu B, Yin YX, Tang YP, Wei KL, Pan ZG, Li KZ, Guo XW, Hu BL (2021) Diagnostic and predictive value of immune-related genes in Crohn’s disease. Front Immunol 12:643036

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yu G, Wang LG, Han Y, He QY (2012) clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16:284–287

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhao Y, Xiang Q, Lin J, Jiang S, Li W (2022) Oxidative stress in intervertebral disc degeneration: new insights from bioinformatic strategies. Oxid Med Cell Longev 2022:2239770

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We sincerely appreciated the data provided by GEO database.

Author information

Authors and Affiliations

Authors

Contributions

Zhong WM and Jin ZW designed and guided the study and provided comments for the study. Zhong WM and Qian XH developed the methodology and analyzed the data. All of the authors discussed the results and approved the manuscript.

Corresponding author

Correspondence to Zhe-Wu Jin.

Ethics declarations

Informed consent

Not applicable.

Conflicts of interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (TIF 295 KB)

Supplementary file2 (XLSX 20 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhong, WM., Qian, XH. & Jin, ZW. Identification of potential predictive biomarkers and biological pathways and the correction with immune infiltration in the activation of Crohn’s disease. Immunogenetics 74, 527–537 (2022). https://doi.org/10.1007/s00251-022-01274-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00251-022-01274-5

Keywords

Navigation