Effect of the Gut Microbiome and Inflammation-related Proteins on Oral Leukoplakia: a Mendelian Randomization Study and Mediation Analysis

Overview

Journal Front Oncol

Specialty Oncology

Date 2024 Oct 10

PMID 39386195

Authors

Junlong Da

Yinting Ren

Shiwei Liu

Nanyan Wang

Lei Wang

Zhifeng Fu

Yongtang Liang

Yu Pan

Jin Li

Jufeng Chen

Affiliations

Soon will be listed here.

Abstract

Background: Oral leukoplakia (OL) is the most common potentially malignant disease of the oral cavity. In recent years, studies have identified a correlation between the gut microbiota (GM) and oral cancer, in addition, inflammation-related proteins have been reported to play an important role in the development of OL. However, the causal relationship between gut microbiota and OL, as well as whether cytokines play a mediating role, remain unclear.

Methods: In this Mendelian randomization (MR) study, the genome-wide association studies (GWAS) (n=18340) of the MiBioGen consortium microbiome was used as exposure data. Genetic variation data related to OL were extracted from the Finngen R9 project (513 cases of OL and 411668 controls). The 91 inflammation-related proteins obtained in the literature serve as potential mediators. Two-sample Mendelian randomization analysis was applied to infer causality using Inverse Variance Weighted (IVW), MR Egger, weighted media, simple mode and weighted mode method. Subsequently, sensitivity analysis was conducted to ensure the robustness of the MR results. In addition, we conducted reverse MR analysis to alleviate reverse causality. Finally, we used mediation analysis to determine the pathway mediated by inflammation-related proteins from the gut microbiota to OL.

Results: The five bacterial taxa in the gut microbiota indicate a potential causal relationship with the development of OL. Notably, was negatively correlated with the risk of OL development, while , , and were positively associated with the risk of OL development. In addition, this study identified a potential causal relationship between interleukin-10 receptor subunit alpha (IL-10RA), interleukin-18 receptor 1(IL18-R1) and the occurrence of OL. In addition, intermediary analysis indicates that IL18-R1 mediated the pathway between the gut microbiota and OL.

Conclusions: In summary, our research emphasize the complex relationship between gut microbiota, inflammation-related proteins and OL. The identified associations and mediating effects provide new insights into potential therapeutic approaches for targeting the gut microbiota in the management of OL, and contribute to its prevention, diagnosis and treatment.

References

Aguirre-Urizar J, Lafuente-Ibanez de Mendoza I, Warnakulasuriya S . Malignant transformation of oral leukoplakia: Systematic review and meta-analysis of the last 5 years. Oral Dis. 2021; 27(8):1881-1895. DOI: 10.1111/odi.13810. View

Lawlor D, Harbord R, Sterne J, Timpson N, Davey Smith G . Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med. 2007; 27(8):1133-63. DOI: 10.1002/sim.3034. View

Kaur J, Jacobs R . Proinflammatory cytokine levels in oral lichen planus, oral leukoplakia, and oral submucous fibrosis. J Korean Assoc Oral Maxillofac Surg. 2015; 41(4):171-5. PMC: 4558184. DOI: 10.5125/jkaoms.2015.41.4.171. View

Ovsyannikova I, Haralambieva I, Kennedy R, OByrne M, Pankratz V, Poland G . Genetic variation in IL18R1 and IL18 genes and Inteferon γ ELISPOT response to smallpox vaccination: an unexpected relationship. J Infect Dis. 2013; 208(9):1422-30. PMC: 3789570. DOI: 10.1093/infdis/jit341. View

Li N, Wang H, Pei H, Wu Y, Li L, Ren Y . and affect osteoporosis by regulating the microbiota-gut-bone axis. Front Microbiol. 2024; 15:1373013. PMC: 11148449. DOI: 10.3389/fmicb.2024.1373013. View

Hashimoto K, Shimizu D, Hirabayashi S, Ueda S, Miyabe S, Oh-Iwa I . Changes in oral microbial profiles associated with oral squamous cell carcinoma vs leukoplakia. J Investig Clin Dent. 2019; 10(4):e12445. DOI: 10.1111/jicd.12445. View

Kurilshikov A, Medina-Gomez C, Bacigalupe R, Radjabzadeh D, Wang J, Demirkan A . Large-scale association analyses identify host factors influencing human gut microbiome composition. Nat Genet. 2021; 53(2):156-165. PMC: 8515199. DOI: 10.1038/s41588-020-00763-1. View

Carter A, Sanderson E, Hammerton G, Richmond R, Davey Smith G, Heron J . Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur J Epidemiol. 2021; 36(5):465-478. PMC: 8159796. DOI: 10.1007/s10654-021-00757-1. View

Zhao J, Stacey D, Eriksson N, Macdonald-Dunlop E, Hedman A, Kalnapenkis A . Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets. Nat Immunol. 2023; 24(9):1540-1551. PMC: 10457199. DOI: 10.1038/s41590-023-01588-w. View

10.

Evren I, Najim A, Poell J, Brouns E, Wils L, Peferoen L . The value of regular follow-up of oral leukoplakia for early detection of malignant transformation. Oral Dis. 2023; 30(5):2991-3003. DOI: 10.1111/odi.14797. View

11.

Marchetti P, Antonov A, Anemona L, Vangapandou C, Montanaro M, Botticelli A . New immunological potential markers for triple negative breast cancer: IL18R1, CD53, TRIM, Jaw1, LTB, PTPRCAP. Discov Oncol. 2022; 12(1):6. PMC: 8777524. DOI: 10.1007/s12672-021-00401-0. View

12.

Warnakulasuriya S, Johnson N, van der Waal I . Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med. 2007; 36(10):575-80. DOI: 10.1111/j.1600-0714.2007.00582.x. View

13.

Moran C, Walters T, Guo C, Kugathasan S, Klein C, Turner D . IL-10R polymorphisms are associated with very-early-onset ulcerative colitis. Inflamm Bowel Dis. 2012; 19(1):115-23. PMC: 3744177. DOI: 10.1002/ibd.22974. View

14.

Henke M, Kenny D, Cassilly C, Vlamakis H, Xavier R, Clardy J . , a member of the human gut microbiome associated with Crohn's disease, produces an inflammatory polysaccharide. Proc Natl Acad Sci U S A. 2019; 116(26):12672-12677. PMC: 6601261. DOI: 10.1073/pnas.1904099116. View

15.

Romo-Vaquero M, Cortes-Martin A, Loria-Kohen V, Ramirez-de-Molina A, Garcia-Mantrana I, Collado M . Deciphering the Human Gut Microbiome of Urolithin Metabotypes: Association with Enterotypes and Potential Cardiometabolic Health Implications. Mol Nutr Food Res. 2018; 63(4):e1800958. DOI: 10.1002/mnfr.201800958. View

16.

Warnakulasuriya S, Kujan O, Aguirre-Urizar J, Bagan J, Gonzalez-Moles M, Kerr A . Oral potentially malignant disorders: A consensus report from an international seminar on nomenclature and classification, convened by the WHO Collaborating Centre for Oral Cancer. Oral Dis. 2020; 27(8):1862-1880. DOI: 10.1111/odi.13704. View

17.

Mello F, Miguel A, Dutra K, Porporatti A, Warnakulasuriya S, Guerra E . Prevalence of oral potentially malignant disorders: A systematic review and meta-analysis. J Oral Pathol Med. 2018; 47(7):633-640. DOI: 10.1111/jop.12726. View

18.

Ji D, Chen W, Zhang L, Zhang Z, Chen L . Gut microbiota, circulating cytokines and dementia: a Mendelian randomization study. J Neuroinflammation. 2024; 21(1):2. PMC: 10765696. DOI: 10.1186/s12974-023-02999-0. View

19.

Kitamoto S, Nagao-Kitamoto H, Jiao Y, Gillilland 3rd M, Hayashi A, Imai J . The Intermucosal Connection between the Mouth and Gut in Commensal Pathobiont-Driven Colitis. Cell. 2020; 182(2):447-462.e14. PMC: 7414097. DOI: 10.1016/j.cell.2020.05.048. View

20.

Ganly I, Yang L, Giese R, Hao Y, Nossa C, Morris L . Periodontal pathogens are a risk factor of oral cavity squamous cell carcinoma, independent of tobacco and alcohol and human papillomavirus. Int J Cancer. 2019; 145(3):775-784. PMC: 6554043. DOI: 10.1002/ijc.32152. View