Revealing a Causal Relationship Between Gut Microbiota and Lung Cancer: a Mendelian Randomization Study

Overview

Journal Front Cell Infect Microbiol

Specialties Cell Biology
Infectious Diseases
Microbiology

Date 2023 Oct 13

PMID 37829610

Authors

Yingchen Li

Ke Wang

Yuchong Zhang

Jitao Yang

Ying Wu

Mingfang Zhao

Affiliations

Soon will be listed here.

Abstract

Background: The gut microbiota has been found to be associated with the risk of lung cancer. However, its causal relationship with various types of lung cancer remains unclear.

Methods: We conducted a Mendelian randomization (MR) study using the largest genome-wide association analysis of gut microbiota data to date from the MiBioGen consortium, with pooled statistics for various types of lung cancer from the Transdisciplinary Research in Cancer of the Lung, the International Lung Cancer Consortium, and FinnGen Consortium R7 release data. Inverse variance weighted, weighted model, MR-Egger regression, and weighted median were adapted to assess the causal relationship between gut microbiota and various types of lung cancer. Sensitivity analysis was used to test for the presence of pleiotropy and heterogeneity in instrumental variables. A reverse MR analysis was performed on these bacteria to determine their potential role in causing lung cancer. A reverse MR analysis was performed on these bacteria to determine their potential role in causing lung cancer. Multivariable Mendelian randomization (MVMR) was conducted to assess the direct causal impact of gut microbiota on the risk of various types of lung cancer.

Results: Using IVW as the primary analytical method, we identified a total of 40 groups of gut microbiota with potential causal associations with various subtypes of lung cancer, of which 10 were associated with lung cancer, 10 with lung adenocarcinoma, 9 with squamous cell lung cancer, and 11 groups of bacteria associated with small cell lung cancer. After performing FDR correction, we further found that there was still a significant causal relationship between Peptococcaceae and lung adenocarcinoma. Sensitivity analyses demonstrated the robustness of these results, with no heterogeneity or pleiotropy found.

Conclusions: Our results confirm a causal relationship between specific gut microbiota and lung cancer, providing new insights into the role of gut microbiota in mediating the development of lung cancer.

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References

Li P, Wang H, Guo L, Gou X, Chen G, Lin D . Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study. BMC Med. 2022; 20(1):443. PMC: 9667679. DOI: 10.1186/s12916-022-02657-x. 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

Hao S, Li S, Wang J, Zhao L, Yan Y, Cao Q . Transcriptome Analysis of Phycocyanin-Mediated Inhibitory Functions on Non-Small Cell Lung Cancer A549 Cell Growth. Mar Drugs. 2018; 16(12). PMC: 6316159. DOI: 10.3390/md16120511. View

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

Xu Q, Ni J, Han B, Yan S, Wei X, Feng G . Causal Relationship Between Gut Microbiota and Autoimmune Diseases: A Two-Sample Mendelian Randomization Study. Front Immunol. 2022; 12:746998. PMC: 8819003. DOI: 10.3389/fimmu.2021.746998. View

Lv W, Lin X, Shen H, Liu H, Qiu X, Li B . Human gut microbiome impacts skeletal muscle mass via gut microbial synthesis of the short-chain fatty acid butyrate among healthy menopausal women. J Cachexia Sarcopenia Muscle. 2021; 12(6):1860-1870. PMC: 8718076. DOI: 10.1002/jcsm.12788. View

Young R, Hopkins R, Marsland B . The Gut-Liver-Lung Axis. Modulation of the Innate Immune Response and Its Possible Role in Chronic Obstructive Pulmonary Disease. Am J Respir Cell Mol Biol. 2015; 54(2):161-9. DOI: 10.1165/rcmb.2015-0250PS. View

Verbanck M, Chen C, Neale B, Do R . Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018; 50(5):693-698. PMC: 6083837. DOI: 10.1038/s41588-018-0099-7. View

Ge Y, Wang X, Guo Y, Yan J, Abuduwaili A, Aximujiang K . Gut microbiota influence tumor development and Alter interactions with the human immune system. J Exp Clin Cancer Res. 2021; 40(1):42. PMC: 7829621. DOI: 10.1186/s13046-021-01845-6. View

10.

Zhao Y, Liu Y, Li S, Peng Z, Liu X, Chen J . Role of lung and gut microbiota on lung cancer pathogenesis. J Cancer Res Clin Oncol. 2021; 147(8):2177-2186. PMC: 8236441. DOI: 10.1007/s00432-021-03644-0. View

11.

Budden K, Gellatly S, Wood D, Cooper M, Morrison M, Hugenholtz P . Emerging pathogenic links between microbiota and the gut-lung axis. Nat Rev Microbiol. 2016; 15(1):55-63. DOI: 10.1038/nrmicro.2016.142. View

12.

Hemani G, Tilling K, Davey Smith G . Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet. 2017; 13(11):e1007081. PMC: 5711033. DOI: 10.1371/journal.pgen.1007081. View

13.

Enaud R, Prevel R, Ciarlo E, Beaufils F, Wieers G, Guery B . The Gut-Lung Axis in Health and Respiratory Diseases: A Place for Inter-Organ and Inter-Kingdom Crosstalks. Front Cell Infect Microbiol. 2020; 10:9. PMC: 7042389. DOI: 10.3389/fcimb.2020.00009. View

14.

Liu X, Cheng Y, Zang D, Zhang M, Li X, Liu D . The Role of Gut Microbiota in Lung Cancer: From Carcinogenesis to Immunotherapy. Front Oncol. 2021; 11:720842. PMC: 8417127. DOI: 10.3389/fonc.2021.720842. View

15.

Pierce B, Burgess S . Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am J Epidemiol. 2013; 178(7):1177-84. PMC: 3783091. DOI: 10.1093/aje/kwt084. View

16.

Nam J, Yun Y, Kim H, Kim H, Jung H, Chang Y . Rosacea and its association with enteral microbiota in Korean females. Exp Dermatol. 2017; 27(1):37-42. DOI: 10.1111/exd.13398. View

17.

Wang B, Huang J, Chen H, Lin C, Lin S, Hung W . The comparison between adenocarcinoma and squamous cell carcinoma in lung cancer patients. J Cancer Res Clin Oncol. 2019; 146(1):43-52. DOI: 10.1007/s00432-019-03079-8. View

18.

He J, Chen Q, Wu S, Wang D, Zhang S, Zhang S . Potential Implications of the Lung Microbiota in Patients with Chronic Obstruction Pulmonary Disease and Non-Small Cell Lung Cancer. Front Cell Infect Microbiol. 2022; 12:937864. PMC: 9363884. DOI: 10.3389/fcimb.2022.937864. View

19.

Zhuang Z, Yang R, Wang W, Qi L, Huang T . Associations between gut microbiota and Alzheimer's disease, major depressive disorder, and schizophrenia. J Neuroinflammation. 2020; 17(1):288. PMC: 7532639. DOI: 10.1186/s12974-020-01961-8. View

20.

Soriano-Lerma A, Garcia-Burgos M, Alferez M, Perez-Carrasco V, Sanchez-Martin V, Linde-Rodriguez A . Gut microbiome-short-chain fatty acids interplay in the context of iron deficiency anaemia. Eur J Nutr. 2021; 61(1):399-412. DOI: 10.1007/s00394-021-02645-6. View