Association of lung cancer and gut microbiota: A two-sample Mendelian randomization analysis_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

REN Qinglin ^1,2 , HE Wenbo ² , YUE Jiarui ² , XIAO Hongbi ² ,  SHU Yusheng ²

1. Dalian Medical University, Dalian, 116000, Liaoning, P. R. China;
2. Department of Thoracic Surgery, Northern Jiangsu People's Hospital, Yangzhou, 225001, Jiangsu, P. R. China;

Corresponding author：

SHU Yusheng, Email: shuyusheng65@163.com

Keywords：

Lung cancer; gut microbiota; Mendelian randomization; single nucleotide polymorphisms

DOI：

10.7507/1007-4848.202307033

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To assess any potential associations between lung cancer and gut microbiota. Methods Mendelian randomization (MR) analysis was carried out by utilizing summary data from genome-wide association studies (GWAS) of the gut microbiota and lung cancer. The gut microbiota served as an exposure. Instrumental ariables (IVs) were identified from the GWAS of 18340 participants. The GWAS study of lung cancer from Europe served as an outcome, including 29 266 lung cancer patients and 56450 controls. We used the inverse-variance weighted (IVW) method as the primary analysis. Sensitivity analysis was used to test the reliability of MR analysis results. Results IVW results showed that Genus Parabacteroides (OR=1.258, 95%CI 1.034 to 1.531, P=0.022) and Phylum Bacteroidetes (OR=1.192, 95%CI 1.001 to 1.419, P=0.048) had a positive causal association with lung cancer, and there was a negative causal association between family Bifidobacteriaceae (OR=0.845, 95%CI 0.721 to 0.989, P=0.037) and order Bifidobacteriales (OR=0.865, 95%CI 0.721 to 0.989, P=0.037) with lung cancer. Sensitivity analysis showed no evidence of reverse causality, pleiotropy, and heterogeneity. Conclusion This study demonstrates that Genus Parabacteroides and Phylum Bacteroidetes are related to an increased risk of lung cancer, family Bifidobacteriaceae and order Bifidobacteriales can reduce the risk of lung cancer. Our thorough investigations provide evidence in favor of a potential causal relationship between a number of gut microbiota-taxa and lung cancer. To demonstrate how gut microbiota influences the development of lung cancer, further research is necessary.

Citation： REN Qinglin, HE Wenbo, YUE Jiarui, XIAO Hongbi, SHU Yusheng. Association of lung cancer and gut microbiota: A two-sample Mendelian randomization analysis. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2023, 30(11): 1618-1627. doi: 10.7507/1007-4848.202307033 Copy

1.	Thai AA, Solomon BJ, Sequist LV, et al. Lung cancer. Lancet (London, England), 2021, 398(10299): 535-554.
2.	Cao W, Chen HD, Yu YW, et al. Changing profiles of cancer burden worldwide and in China: A secondary analysis of the global cancer statistics 2020. Chin Med J, 2021, 134(7): 783-791.
3.	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA, 2021, 71(3): 209-249.
4.	Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA, 2022, 72(1): 7-33.
5.	Duma N, Santana-Davila R, Molina JR. Non-small cell lung cancer: Epidemiology, screening, diagnosis, and treatment. Mayo Clinic Proceedings, 2019, 94(8): 1623-1640.
6.	Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization classification of lung tumors: Impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol, 2015, 10(9): 1243-1260.
7.	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin, 2018, 68(1): 7-30.
8.	Kocher F, Hilbe W, Seeber A, et al. Longitudinal analysis of 2293 NSCLC patients: A comprehensive study from the TYROL registry. Lung Cancer (Amsterdam, Netherlands), 2015, 87(2): 193-200.
9.	Chen P, Liu Y, Wen Y, et al. Non-small cell lung cancer in China. Cancer Communications (London, England), 2022, 42(10): 937-970.
10.	Dickson RP, Erb-Downward JR, Huffnagle GB. The role of the bacterial microbiome in lung disease. Expert Rev Respir Med, 2013, 7(3): 245-257.
11.	Shang GS, Liu L, Qin YW. IL-6 and TNF-α promote metastasis of lung cancer by inducing epithelial-mesenchymal transition. Oncology Letters, 2017, 13(6): 4657-4660.
12.	Georgiou K, Marinov B, Farooqi AA, et al. Gut microbiota in lung cancer: Where do we stand? Intern Jo Mole Sci, 2021, 22(19): 10429.
13.	Ge Y, Wang X, Guo Y, et al. Gut microbiota influence tumor development and alter interactions with the human immune system. Jo Exp & Clin Cancer Research, 2021, 40(1): 42.
14.	Goubet AG, Daillère R, Routy B, et al. The impact of the intestinal microbiota in therapeutic responses against cancer. Comptes Rendus Biologies, 2018, 341(5): 284-289.
15.	Cammarota G, Ianiro G. Gut Microbiota and cancer patients: A broad-ranging relationship. Mayo Clinic Proceedings, 2017, 92(11): 1605-1607.
16.	Zheng Y, Fang Z, Xue Y, et al. Specific gut microbiome signature predicts the early-stage lung cancer. Gut Microbes, 2020, 11(4): 1030-1042.
17.	Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA, 2017, 318(19): 1925-1926.
18.	Davey Smith G, Hemani G. Mendelian randomization: Genetic anchors for causal inference in epidemiological studies. Human Molecular Genetics, 2014, 23(R1): R89-R98.
19.	Wei Z, Yang B, Tang T, et al. Gut microbiota and risk of five common cancers: A univariable and multivariable Mendelian randomization study. Cancer Med, 2023, 12(9): 10393-10405.
20.	Ma J, Li J, Jin C, et al. Association of gut microbiome and primary liver cancer: A two-sample mendelian randomization and case-control study. Liver Int, 2023, 43(1): 221-233.
21.	Long Y, Tang L, Zhou Y, et al. Causal relationship between gut microbiota and cancers: A two-sample Mendelian randomisation study. BMC medicine, 2023, 21(1): 66.
22.	McKay JD, Hung RJ, Han Y, et al. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nature Genetics, 2017, 49(7): 1126-1132.
23.	Kurilshikov A, Medina-Gomez C, Bacigalupe R, et al. Large-scale association analyses identify host factors influencing human gut microbiome composition. Nature Genetics, 2021, 53(2): 156-165.
24.	Liu B, Ye D, Yang H, et al. Assessing the relationship between gut microbiota and irritable bowel syndrome: A two-sample Mendelian randomization analysis. BMC Gastroenterology, 2023, 23(1): 150.
25.	Kamat MA, Blackshaw JA, Young R, et al. PhenoScanner V2: An expanded tool for searching human genotype-phenotype associations. Bioinformatics (Oxford, England), 2019, 35(22): 4851-4853.
26.	Kang HS, Park YM, Ko SH, et al. Impaired lung function and lung cancer incidence: A nationwide population-based cohort study. J Clin Med, 2022, 11(4): 1077.
27.	Bade BC, Dela Cruz CS. Lung cancer 2020: Epidemiology, etiology, and prevention. Clin Chest Med, 2020, 41(1): 1-24.
28.	Palmer TM, Lawlor DA, Harbord RM, et al. Using multiple genetic variants as instrumental variables for modifiable risk factors. Statistic Meth Med Res, 2012, 21(3): 223-242.
29.	Chen L, Yang H, Li H, et al. Insights into modifiable risk factors of cholelithiasis: A Mendelian randomization study. Hepatology (Baltimore, Md. ), 2022, 75(4): 785-796.
30.	Jia Y, Hui L, Sun L, et al. Association between human blood metabolome and the risk of psychiatric disorders. Schizophrenia Bulletin, 2023, 49(2): 428-443.
31.	Yavorska OO, Burgess S. Mendelian randomization: An R package for performing Mendelian randomization analyses using summarized data. Inter J Epidemiol, 2017, 46(6): 1734-1739.
32.	Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol, 2013, 37(7): 658-665.
33.	Goodrich JK, Davenport ER, Clark AG, et al. The relationship between the human genome and microbiome comes into view. Annu Revf Genet, 2017, 51: 413-433.
34.	Brinkmann S, Spohn MS, Schäberle TF. Bioactive natural products from Bacteroidetes. Natural Product Reports, 2022, 39(5): 1045-1065.
35.	McKee LS, La Rosa SL, Westereng B, et al. Polysaccharide degradation by the Bacteroidetes: Mechanisms and nomenclature. Environ Microbiol Rep, 2021, 13(5): 559-581.
36.	Parker BJ, Wearsch PA, Veloo ACM, et al. The genus alistipes: Gut bacteria with emerging implications to inflammation, cancer, and mental health. Front Immunol, 2020, 11: 906.
37.	Hosgood HD, Cai Q, Hua X, et al. Variation in oral microbiome is associated with future risk of lung cancer among never-smokers. Thorax, 2021, 76(3): 256-263.
38.	Kim H, Im WT, Kim M, et al. Parabacteroides chongii sp. nov. , isolated from blood of a patient with peritonitis. J Microbiol (Seoul, Korea), 2018, 56(10): 722-726.
39.	Gomez-Nguyen A, Basson AR, Dark-Fleury L, et al. Parabacteroides distasonis induces depressive-like behavior in a mouse model of Crohn's disease. Brain Behav Immun, 2021, 98: 245-250.
40.	Saltzman ET, Palacios T, Thomsen M, et al. Intestinal microbiome shifts, dysbiosis, inflammation, and non-alcoholic fatty liver disease. Front Microbiol, 2018, 9: 61.
41.	Turroni F, Bottacini F, Foroni E, et al. Genome analysis of Bifidobacterium bifidum PRL2010 reveals metabolic pathways for host-derived glycan foraging. Proc Natl Acad Sci USA, 2010, 107(45): 19514-19519.
42.	Milani C, Lugli GA, Duranti S, et al. Genomic encyclopedia of type strains of the genus Bifidobacterium. Appl Environ Microbiol, 2014, 80(20): 6290-6302.
43.	Geier MS, Butler RN, Howarth GS. Probiotics, prebiotics and synbiotics: A role in chemoprevention for colorectal cancer? Cancer Biol Ther, 2006, 5(10): 1265-1269.
44.	Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science (New York, N. Y. ), 2015, 350(6264): 1084-1089.
45.	Skrypnik K, Suliburska J. Association between the gut microbiota and mineral metabolism. J Sci Food Agric, 2018, 98(7): 2449-2460.

1. Thai AA, Solomon BJ, Sequist LV, et al. Lung cancer. Lancet (London, England), 2021, 398(10299): 535-554.
2. Cao W, Chen HD, Yu YW, et al. Changing profiles of cancer burden worldwide and in China: A secondary analysis of the global cancer statistics 2020. Chin Med J, 2021, 134(7): 783-791.
3. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA, 2021, 71(3): 209-249.
4. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA, 2022, 72(1): 7-33.
5. Duma N, Santana-Davila R, Molina JR. Non-small cell lung cancer: Epidemiology, screening, diagnosis, and treatment. Mayo Clinic Proceedings, 2019, 94(8): 1623-1640.
6. Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization classification of lung tumors: Impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol, 2015, 10(9): 1243-1260.
7. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin, 2018, 68(1): 7-30.
8. Kocher F, Hilbe W, Seeber A, et al. Longitudinal analysis of 2293 NSCLC patients: A comprehensive study from the TYROL registry. Lung Cancer (Amsterdam, Netherlands), 2015, 87(2): 193-200.
9. Chen P, Liu Y, Wen Y, et al. Non-small cell lung cancer in China. Cancer Communications (London, England), 2022, 42(10): 937-970.
10. Dickson RP, Erb-Downward JR, Huffnagle GB. The role of the bacterial microbiome in lung disease. Expert Rev Respir Med, 2013, 7(3): 245-257.
11. Shang GS, Liu L, Qin YW. IL-6 and TNF-α promote metastasis of lung cancer by inducing epithelial-mesenchymal transition. Oncology Letters, 2017, 13(6): 4657-4660.
12. Georgiou K, Marinov B, Farooqi AA, et al. Gut microbiota in lung cancer: Where do we stand? Intern Jo Mole Sci, 2021, 22(19): 10429.
13. Ge Y, Wang X, Guo Y, et al. Gut microbiota influence tumor development and alter interactions with the human immune system. Jo Exp & Clin Cancer Research, 2021, 40(1): 42.
14. Goubet AG, Daillère R, Routy B, et al. The impact of the intestinal microbiota in therapeutic responses against cancer. Comptes Rendus Biologies, 2018, 341(5): 284-289.
15. Cammarota G, Ianiro G. Gut Microbiota and cancer patients: A broad-ranging relationship. Mayo Clinic Proceedings, 2017, 92(11): 1605-1607.
16. Zheng Y, Fang Z, Xue Y, et al. Specific gut microbiome signature predicts the early-stage lung cancer. Gut Microbes, 2020, 11(4): 1030-1042.
17. Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA, 2017, 318(19): 1925-1926.
18. Davey Smith G, Hemani G. Mendelian randomization: Genetic anchors for causal inference in epidemiological studies. Human Molecular Genetics, 2014, 23(R1): R89-R98.
19. Wei Z, Yang B, Tang T, et al. Gut microbiota and risk of five common cancers: A univariable and multivariable Mendelian randomization study. Cancer Med, 2023, 12(9): 10393-10405.
20. Ma J, Li J, Jin C, et al. Association of gut microbiome and primary liver cancer: A two-sample mendelian randomization and case-control study. Liver Int, 2023, 43(1): 221-233.
21. Long Y, Tang L, Zhou Y, et al. Causal relationship between gut microbiota and cancers: A two-sample Mendelian randomisation study. BMC medicine, 2023, 21(1): 66.
22. McKay JD, Hung RJ, Han Y, et al. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nature Genetics, 2017, 49(7): 1126-1132.
23. Kurilshikov A, Medina-Gomez C, Bacigalupe R, et al. Large-scale association analyses identify host factors influencing human gut microbiome composition. Nature Genetics, 2021, 53(2): 156-165.
24. Liu B, Ye D, Yang H, et al. Assessing the relationship between gut microbiota and irritable bowel syndrome: A two-sample Mendelian randomization analysis. BMC Gastroenterology, 2023, 23(1): 150.
25. Kamat MA, Blackshaw JA, Young R, et al. PhenoScanner V2: An expanded tool for searching human genotype-phenotype associations. Bioinformatics (Oxford, England), 2019, 35(22): 4851-4853.
26. Kang HS, Park YM, Ko SH, et al. Impaired lung function and lung cancer incidence: A nationwide population-based cohort study. J Clin Med, 2022, 11(4): 1077.
27. Bade BC, Dela Cruz CS. Lung cancer 2020: Epidemiology, etiology, and prevention. Clin Chest Med, 2020, 41(1): 1-24.
28. Palmer TM, Lawlor DA, Harbord RM, et al. Using multiple genetic variants as instrumental variables for modifiable risk factors. Statistic Meth Med Res, 2012, 21(3): 223-242.
29. Chen L, Yang H, Li H, et al. Insights into modifiable risk factors of cholelithiasis: A Mendelian randomization study. Hepatology (Baltimore, Md. ), 2022, 75(4): 785-796.
30. Jia Y, Hui L, Sun L, et al. Association between human blood metabolome and the risk of psychiatric disorders. Schizophrenia Bulletin, 2023, 49(2): 428-443.
31. Yavorska OO, Burgess S. Mendelian randomization: An R package for performing Mendelian randomization analyses using summarized data. Inter J Epidemiol, 2017, 46(6): 1734-1739.
32. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol, 2013, 37(7): 658-665.
33. Goodrich JK, Davenport ER, Clark AG, et al. The relationship between the human genome and microbiome comes into view. Annu Revf Genet, 2017, 51: 413-433.
34. Brinkmann S, Spohn MS, Schäberle TF. Bioactive natural products from Bacteroidetes. Natural Product Reports, 2022, 39(5): 1045-1065.
35. McKee LS, La Rosa SL, Westereng B, et al. Polysaccharide degradation by the Bacteroidetes: Mechanisms and nomenclature. Environ Microbiol Rep, 2021, 13(5): 559-581.
36. Parker BJ, Wearsch PA, Veloo ACM, et al. The genus alistipes: Gut bacteria with emerging implications to inflammation, cancer, and mental health. Front Immunol, 2020, 11: 906.
37. Hosgood HD, Cai Q, Hua X, et al. Variation in oral microbiome is associated with future risk of lung cancer among never-smokers. Thorax, 2021, 76(3): 256-263.
38. Kim H, Im WT, Kim M, et al. Parabacteroides chongii sp. nov. , isolated from blood of a patient with peritonitis. J Microbiol (Seoul, Korea), 2018, 56(10): 722-726.
39. Gomez-Nguyen A, Basson AR, Dark-Fleury L, et al. Parabacteroides distasonis induces depressive-like behavior in a mouse model of Crohn's disease. Brain Behav Immun, 2021, 98: 245-250.
40. Saltzman ET, Palacios T, Thomsen M, et al. Intestinal microbiome shifts, dysbiosis, inflammation, and non-alcoholic fatty liver disease. Front Microbiol, 2018, 9: 61.
41. Turroni F, Bottacini F, Foroni E, et al. Genome analysis of Bifidobacterium bifidum PRL2010 reveals metabolic pathways for host-derived glycan foraging. Proc Natl Acad Sci USA, 2010, 107(45): 19514-19519.
42. Milani C, Lugli GA, Duranti S, et al. Genomic encyclopedia of type strains of the genus Bifidobacterium. Appl Environ Microbiol, 2014, 80(20): 6290-6302.
43. Geier MS, Butler RN, Howarth GS. Probiotics, prebiotics and synbiotics: A role in chemoprevention for colorectal cancer? Cancer Biol Ther, 2006, 5(10): 1265-1269.
44. Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science (New York, N. Y. ), 2015, 350(6264): 1084-1089.
45. Skrypnik K, Suliburska J. Association between the gut microbiota and mineral metabolism. J Sci Food Agric, 2018, 98(7): 2449-2460.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Association of lung cancer and gut microbiota: A two-sample Mendelian randomization analysis

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content