Identification of Differential Metabolites in Chronic Suppurative Otitis Media With Non-Targeted and Targeted Metabolomics Approach

Lidan Hu , Yifan Zhu , Chengpeng Wu , Xiao Liu , Qi Wang , Yangyiyi Huang , Hongyan Liu , Xiangjun Chen , Wei Wu , Hua Jiang

Smart Medicine ›› 2025, Vol. 4 ›› Issue (3) : e70015

PDF
Smart Medicine ›› 2025, Vol. 4 ›› Issue (3) : e70015 DOI: 10.1002/smmd.70015
RESEARCH ARTICLE

Identification of Differential Metabolites in Chronic Suppurative Otitis Media With Non-Targeted and Targeted Metabolomics Approach

Author information +
History +
PDF

Abstract

Chronic suppurative otitis media (CSOM) is a leading cause of hearing loss and otorrhea, and when associated with cholesteatoma, it can pose a serious threat to patients' lives. This study aims to identify differences in tissue metabolites between patients with CSOM, both with and without cholesteatoma. Metabolomic profiles were measured in tissue samples from 42 surgically treated CSOM patients (35 with cholesteatoma, 7 without cholesteatoma). Significantly altered metabolites associated with CSOM were identified using a non-targeted metabolomics approach and a targeted metabolomics approach. The 42 patients were divided into screening and validation sets. The non-targeted analysis revealed 484 distinct differential metabolites and 32 metabolic pathways that differed between CSOM with and without cholesteatoma in the screening set. Targeted metabolomics confirmed that levels of azobenzene and marimastat in the validation set exhibited trends similar to those observed in the non-targeted analysis. Azobenzene and marimastat were found to be associated with the differences between CSOM with and without cholesteatoma, as well as with bone erosion in the middle ear. This study identified novel potential metabolic pathways and metabolites, providing insights into their possible roles in the inflammatory processes and bone erosion associated with CSOM and cholesteatoma.

Keywords

bone erosion / chronic suppurative otitis media / metabolomics / middle ear cholesteatoma

Cite this article

Download citation ▾
Lidan Hu, Yifan Zhu, Chengpeng Wu, Xiao Liu, Qi Wang, Yangyiyi Huang, Hongyan Liu, Xiangjun Chen, Wei Wu, Hua Jiang. Identification of Differential Metabolites in Chronic Suppurative Otitis Media With Non-Targeted and Targeted Metabolomics Approach. Smart Medicine, 2025, 4(3): e70015 DOI:10.1002/smmd.70015

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

M. F. Bhutta, A. J. Leach, and C. G. Brennan-Jones, “Chronic Suppurative Otitis Media,” Lancet 403 (2024): 2339–2348.

[2]

S. Mansour, J. Magnan, K. Nicolas, and H. Haidar, “ Chronic Suppurative Otitis Media (CSOM): A Middle Ear Mucosal Disease,” in Middle Ear Diseases (Springer International Publishing, 2018), 205–274.

[3]

D. Bächinger, W. Großmann, R. Mlynski, and N. M. Weiss, “Characteristics of Health-Related Quality of Life in Different Types of Chronic Middle Ear Disease,” European Archives of Oto-Rhino-Laryngology 278 (2021): 3795–3800.

[4]

R. Serban, O. E. Frasinariu, B. Simionescu, et al., “The Impact of Chronic Suppurative Otitis Media With and Without Cholesteatoma in Patients From Northeastern Romania,” Healthcare 11 (2022): 73.

[5]

S. Dhingra, D. Vir, J. Bakshi, and P. Rishi, “Mapping of Audiometric Analysis With Microbiological Findings in Patients With Chronic Suppurative Otitis Media (CSOM): A Neglected Clinical Manifestation,” Critical Reviews in Clinical Laboratory Sciences 60 (2023): 212–232.

[6]

Z. Wang, J. Song, R. Su, et al., “Structure-Aware Deep Learning for Chronic Middle Ear Disease,” Expert Systems With Applications 194 (2022): 116519.

[7]

M. Schürmann, P. Goon, and H. Sudhoff, “Review of Potential Medical Treatments for Middle Ear Cholesteatoma,” Cell Communication and Signaling 20 (2022): 148.

[8]

C.-L. Kuo, A.-S. Shiao, M. Yung, et al., “Updates and Knowledge Gaps in Cholesteatoma Research,” BioMed Research International 2015 (2015): 854024.

[9]

J. T. Castle, “Cholesteatoma Pearls: Practical Points and Update,” Head and Neck Pathology 12 (2018): 419–429.

[10]

B. A. Jennings, P. Prinsley, C. Philpott, G. Willis, and M. F. Bhutta, “The Genetics of Cholesteatoma. A Systematic Review Using Narrative Synthesis,” Clinical Otolaryngology 43 (2018): 55–67.

[11]

T. K. Suttle, T. Els, J. Toman, et al., “Chronic Suppurative Otitis Media: A Prospective Descriptive Study of the Microbiology and Antimicrobial Susceptibility Patterns,” Otolaryngology–Head and Neck Surgery 171 (2024): 90–97.

[12]

S. Xie, X. Wang, J. Ren, and W. Liu, “The Role of Bone Resorption in the Etiopathogenesis of Acquired Middle Ear Cholesteatoma,” European Archives of Oto-Rhino-Laryngology 274 (2017): 2071–2078.

[13]

M. Schürmann, F. Oppel, S. Shao, et al., “Chronic Inflammation of Middle Ear Cholesteatoma Promotes Its Recurrence via a Paracrine Mechanism,” Cell Communication and Signaling 19 (2021): 25.

[14]

Y. Feng, Z. Li, W. He, Y. Xiong, Y. Si, and Z. Zhang, “Higher Degree of Keratinization Correlated With Severe Bone Destruction in Acquired Cholesteatoma,” Acta Oto-Laryngologica 143 (2023): 147–155.

[15]

K. Shimizu, J. Kikuta, Y. Ohta, et al., “Single-Cell Transcriptomics of Human Cholesteatoma Identifies an Activin A-producing Osteoclastogenic Fibroblast Subset Inducing Bone Destruction,” Nature Communications 14 (2023): 4417.

[16]

M. Yoshikawa, H. Kojima, Y. Yaguchi, N. Okada, H. Saito, and H. Moriyama, “Cholesteatoma Fibroblasts Promote Epithelial Cell Proliferation Through Overexpression of Epiregulin,” PLoS One 8 (2013): e66725.

[17]

S. Raffa, L. Leone, C. Scrofani, S. Monini, M. R. Torrisi, and M. Barbara, “Cholesteatoma-Associated Fibroblasts Modulate Epithelial Growth and Differentiation Through KGF/FGF7 Secretion,” Histochemistry and Cell Biology 138 (2012): 251–269.

[18]

H. Jiang, Y. Si, Z. Li, et al., “TREM-2 Promotes Acquired cholesteatoma-Induced Bone Destruction by Modulating TLR4 Signaling Pathway and Osteoclasts Activation,” Scientific Reports 6 (2016): 38761.

[19]

A. Britze, M. L. Møller, and T. Ovesen, “Incidence, 10-Year Recidivism Rate and Prognostic Factors for Cholesteatoma,” Journal of Laryngology & Otology 131 (2017): 319–328.

[20]

P. R. Møller, C. N. Pedersen, L. R. Grosfjeld, C. E. Faber, and B. D. Djurhuus, “Recurrence of Cholesteatoma—A Retrospective Study Including 1,006 Patients for More than 33 Years,” International Archives of Otorhinolaryngology 24 (2020): e18–e23.

[21]

F. L. J. Cals, H. F. E. van der Toom, R. M. Metselaar, A. van Linge, M. van der Schroeff, and R. Pauw, “Postoperative Surgical Site Infection in Cholesteatoma Surgery With and Without Mastoid Obliteration, What Can We Learn?,” Journal of Otology 17 (2022): 25–30.

[22]

S. Alseekh, A. Aharoni, Y. Brotman, et al., “Mass Spectrometry-Based Metabolomics: A Guide for Annotation, Quantification and Best Reporting Practices,” Nature Methods 18 (2021): 747–756.

[23]

G. J. Patti, O. Yanes, and G. Siuzdak, “Metabolomics: The Apogee of the Omics Trilogy,” Nature Reviews Molecular Cell Biology 13 (2012): 263–269.

[24]

C. H. Johnson, J. Ivanisevic, and G. Siuzdak, “Metabolomics: Beyond Biomarkers and Towards Mechanisms,” Nature Reviews Molecular Cell Biology 17 (2016): 451–459.

[25]

G. Mirji, A. Worth, S. A. Bhat, et al., “The microbiome-Derived Metabolite TMAO Drives Immune Activation and Boosts Responses to Immune Checkpoint Blockade in Pancreatic Cancer,” Science Immunology 7 (2022): eabn0704.

[26]

A. Valdés, L. O. Moreno, S. R. Rello, A. Orduña, D. Bernardo, and A. Cifuentes, “Metabolomics Study of COVID-19 Patients in Four Different Clinical Stages,” Scientific Reports 12 (2022): 1650.

[27]

E. Wildman, B. Mickiewicz, H. J. Vogel, and G. C. Thompson, “Metabolomics in Pediatric Lower Respiratory Tract Infections and Sepsis: A Literature Review,” Pediatric Research 93 (2023): 492–502.

[28]

H. Jiang, C. Wu, J. Xu, et al., “Bacterial and Fungal Infections Promote the Bone Erosion Progression in Acquired Cholesteatoma Revealed by Metagenomic Next-Generation Sequencing,” Frontiers in Microbiology 12 (2021): 761111.

[29]

O. A. Sukocheva, E. Lukina, E. McGowan, and A. Bishayee, “Sphingolipids as Mediators of Inflammation and Novel Therapeutic Target in Inflammatory Bowel Disease,” Advances in Protein Chemistry and Structural Biology 120 (2020): 123–158.

[30]

M. Maceyka and S. Spiegel, “Sphingolipid Metabolites in Inflammatory Disease,” Nature 510 (2014): 58–67.

[31]

J. Wang, Y. Chen, Y. Li, D. Chen, J. He, and N. Yao, “Functions of Sphingolipids in Pathogenesis During Host-Pathogen Interactions,” Frontiers in Microbiology 12 (2021): 701041.

[32]

Y. Wu, Y. Liu, E. Gulbins, and H. Grassmé, “The Anti-Infectious Role of Sphingosine in Microbial Diseases,” Cells 10 (2021): 1105.

[33]

C. Sirithanakorn and J. E. Cronan, “Biotin, a Universal and Essential Cofactor: Synthesis, Ligation and Regulation,” FEMS Microbiology Reviews 45 (2021): fuab003.

[34]

W. Salaemae, G. W. Booker, and S. W. Polyak, “The Role of Biotin in Bacterial Physiology and Virulence: A Novel Antibiotic Target for Mycobacterium tuberculosis,” Microbiology Spectrum 4 (2016): 797.

[35]

M. Sprenger, T. S. Hartung, S. Allert, et al., “Fungal Biotin Homeostasis Is Essential for Immune Evasion After Macrophage Phagocytosis and Virulence,” Cellular Microbiology 22 (2020): e13197.

[36]

H. Heo, Y. Kim, B. Cha, et al., “A Systematic Exploration of Ginsenoside Rg5 Reveals Anti-Inflammatory Functions in Airway Mucosa Cells,” Journal of Ginseng Research 47 (2023): 97–105.

[37]

X. Zhang, Y. Li, K. Zhu, et al., “Microbiome–Metabolomic Analysis Revealed the Immunoprotective Effects of the Extract of Vanilla planifolia Andrew (EVPA) on Immunosuppressed Mice,” Foods 13 (2024): 701.

[38]

K. L. Liew, J. M. Jee, I. Yap, and P. V. C. Yong, “In Vitro Analysis of Metabolites Secreted During Infection of Lung Epithelial Cells by Cryptococcus neoformans,” PLoS One 11 (2016): e0153356.

[39]

Y. Iwamoto, K. Nishikawa, R. Imai, et al., “Intercellular Communication Between Keratinocytes and Fibroblasts Induces Local Osteoclast Differentiation: A Mechanism Underlying Cholesteatoma-Induced Bone Destruction,” Molecular and Cellular Biology 36 (2016): 1610–1620.

[40]

L. Wu and K. G. Parhofer, “Diabetic Dyslipidemia,” Metabolism 63 (2014): 1469–1479.

[41]

B. Thorsted, M. Bloksgaard, A. Groza, et al., “Biochemical and Bioimaging Evidence of Cholesterol in Acquired Cholesteatoma,” Annals of Otology, Rhinology & Laryngology 125 (2016): 627–633.

[42]

F. A. Jerca, V. V. Jerca, and R. Hoogenboom, “Advances and Opportunities in the Exciting World of Azobenzenes,” Nature Reviews Chemistry 6 (2021): 51–69.

[43]

H. Cheng, S. Zhang, J. Qi, X. Liang, and J. Yoon, “Advances in Application of Azobenzene as a Trigger in Biomedicine: Molecular Design and Spontaneous Assembly,” Advanced Materials 33 (2021): 2007290.

[44]

D. K. Barupal and O. Fiehn, “Generating the Blood Exposome Database Using a Comprehensive Text Mining and Database Fusion Approach,” Environmental Health Perspectives 127 (2019): 097008.

[45]

M. A. Smetanina, M. Y. Pakharukova, S. M. Kurinna, et al., “Ortho-Aminoazotoluene Activates Mouse Constitutive Androstane Receptor (Mcar) and Increases Expression of Mcar Target Genes,” Toxicology and Applied Pharmacology 255 (2011): 76–85.

[46]

M. Sharma, S. Sharma, A. A. M. Alkhanjaf, et al., “Microbial Fuel Cells for Azo Dye Degradation: A Perspective Review,” Journal of Industrial and Engineering Chemistry 142 (2025): 45–67.

[47]

E. George, M. Andrews, and C. Westmoreland, “Effects of Azobenzene and Aniline in the Rodent Bone Marrow Micronucleus Test,” Carcinogenesis 11 (1990): 1551–1556.

[48]

K. Sekihashi, A. Yamamoto, Y. Matsumura, et al., “Comparative Investigation of Multiple Organs of Mice and Rats in the Comet Assay,” Mutation Research/Genetic Toxicology and Environmental Mutagenesis 517 (2002): 53–75.

[49]

N. Sabir, T. Hussain, M. H. Mangi, D. Zhao, and X. Zhou, “Matrix Metalloproteinases: Expression, Regulation and Role in the Immunopathology of Tuberculosis,” Cell Proliferation 52 (2019): e12649.

[50]

A. R. Nelson, B. Fingleton, M. L. Rothenberg, and L. M. Matrisian, “Matrix Metalloproteinases: Biologic Activity and Clinical Implications,” Journal of Clinical Oncology 18 (2000): 1135.

[51]

Y. Wu, X. Tang, W. Shao, and Y. Lu, “Effect of CT Manifestations of Cholesteatoma on MMP-2, MMP-9 and IL-6 in the Serum of Patients,” Experimental and Therapeutic Medicine 17 (2019): 4441–4446.

[52]

E. Cantone, C. Di Nola, E. De Corso, et al., “Endotyping of Cholesteatoma: Which Molecular Biomarkers? A Systematic Review,” Journal of Personalized Medicine 12 (2022): 1347.

[53]

İ. Kaya, Ç. B. Avcı, F. F. Şahin, et al., “Evaluation of Significant Gene Expression Changes in Congenital and Acquired Cholesteatoma,” Molecular Biology Reports 47 (2020): 6127–6133.

[54]

K. Dambergs, G. Sumeraga, and M. Pilmane, “Comparison of Tissue Factors in the Ontogenetic Aspects of Human Cholesteatoma,” Diagnostics 14 (2024): 662.

[55]

G. Khalili-Tanha, E. S. Radisky, D. C. Radisky, and A. Shoari, “Matrix Metalloproteinase-Driven Epithelial-Mesenchymal Transition: Implications in Health and Disease,” Journal of Translational Medicine 23 (2025): 436.

RIGHTS & PERMISSIONS

2025 The Author(s). Smart Medicine published by Wiley-VCH GmbH on behalf of Wenzhou Institute, University of Chinese Academy of Sciences.

AI Summary AI Mindmap
PDF

22

Accesses

0

Citation

Detail

Sections
Recommended

AI思维导图

/