Association between gut microbiota and urinary tract infection: a two-sample Mendelian randomization study_Chinese Journal of Evidence-Based Medicine

Authors：

LIU Xiang , PENG Cong , WANG Zixin ,  SUN Xiang

Department of Urology, the First Affiliated Hospital of Nanchang University, Nanchang 330006, P. R. China;

Corresponding author：

SUN Xiang, Email: ndyfy01344@ncu.edu.cn

Keywords：

Urinary tract infections; Gut microbiota; Two-sample Mendelian randomization analysis; Single nucleotide polymorphisms

DOI：

10.7507/1672-2531.202403179

Video：

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Objective To explore the causal relationship between gut microbiota and urinary tract infections using data from genome-wide association studies. Methods The gut microbiota data were sourced from the MiBioGen consortium, comprising genetic variables from 18 340 individuals. UTI data (ieu-b-5.65) were derived from the UK Biobank. Six methods including inverse variance weighted (IVW), Mendelian randomization (MR)-Egger, maximum likelihood, simple mode, weighted mode, and weighted median were employed for two-sample MR analysis on these datasets. Additionally, MR-PRESSO was used to detect and correct for heterogeneity and outliers in the analysis. Cochran's Q test and leave-one-out analysis were applied to assess potential heterogeneity and multiple effects. Furthermore, reverse MR analysis was conducted to investigate causal relationships between UTI and gut microbiota. Results According to IVW method analysis results, bacterial genera Eggerthella (OR=1.08, 95%CI 1.01 to 1.16, P=0.034) and Ruminococcaceae (UCG005) (OR=1.10, 95%CI 1.01 to 1.20, P=0.022) were found to increase the risk of UTI, while Defluviitaleaceae (UCG011) (OR=0.90, 95%CI 0.82 to 0.99, P=0.022) appeared to decrease it. Reverse MR analysis did not reveal a significant effect of UTI on these three bacterial genera. Our study found no evidence of heterogeneity or pleiotropy based on the results of Cochran’s Q test, MR-Egger, and MR-PRESSO global test. Conclusion In this MR study, we demonstrate a causal association between Eggerthella, Ruminococcaceae, Defluvitalaceae and the risk of urinary tract infections.

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14.	Sanna S, van Zuydam NR, Mahajan A, et al. Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases. Nat Genet, 2019, 51(4): 600-605.
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19.	Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
20.	Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol, 2017, 46(6): 1985-1998.
21.	Milne RL, Kuchenbaecker KB, Michailidou K, et al. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nat Genet, 2017, 49(12): 1767-1778.
22.	Li P, Wang H, Guo L, et al. Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study. BMC Med, 2022, 20(1): 443.
23.	Burgess S, Davey Smith G, Davies NM, et al. Guidelines for performing Mendelian randomization investigations: update for summer 2023. Wellcome Open Res, 2023, 4: 186.
24.	Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
25.	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.
26.	Bai X, Wei H, Liu W, et al. Cigarette smoke promotes colorectal cancer through modulation of gut microbiota and related metabolites. Gut, 2022, 71(12): 2439-2450.
27.	Radjabzadeh D, Bosch JA, Uitterlinden AG, et al. Gut microbiome-wide association study of depressive symptoms. Nat Commun, 2022, 13(1): 7128.
28.	Lohia S, Vlahou A, Zoidakis J. Microbiome in chronic kidney disease (CKD): an omics perspective. Toxins (Basel), 2022, 14(3): 176.
29.	Peter-Bibb TK, Tokeshi J. Hawai'i's first published case of Eggerthella lenta sepsis. Hawaii J Health Soc Welf, 2020, 79(11): 326-328.
30.	Jiang S, E J, Wang D, et al. Eggerthella lenta bacteremia successfully treated with ceftizoxime: case report and review of the literature. Eur J Med Res, 2021, 26(1): 111.
31.	Alexander M, Ang QY, Nayak RR, et al. Human gut bacterial metabolism drives Th17 activation and colitis. Cell Host Microbe, 2022, 30(1): 17-30.
32.	Henke MT, Kenny DJ, Cassilly CD, et al. Ruminococcus gnavus, a member of the human gut microbiome associated with Crohn's disease, produces an inflammatory polysaccharide. Proc Natl Acad Sci USA, 2019, 116(26): 12672-12677.
33.	Tong Y, Zheng L, Qing P, et al. Oral microbiota perturbations are linked to high risk for rheumatoid arthritis. Front Cell Infect Microbiol, 2020, 9: 475.
34.	Mayer EA, Tillisch K, Gupta A. Gut/brain axis and the microbiota. J Clin Invest, 2015, 125(3): 926-938.
35.	Budden KF, Gellatly SL, Wood DL, et al. Emerging pathogenic links between microbiota and the gut-lung axis. Nat Rev Microbiol, 2017, 15(1): 55-63.
36.	Worby CJ, Schreiber HL, Straub TJ, et al. Longitudinal multi-omics analyses link gut microbiome dysbiosis with recurrent urinary tract infections in women. Nat Microbiol, 2022, 7(5): 630-639.
37.	Magruder M, Sholi AN, Gong C, et al. Gut uropathogen abundance is a risk factor for development of bacteriuria and urinary tract infection. Nat Commun, 2019, 10(1): 5521.
38.	Klein RD, Hultgren SJ. Urinary tract infections: microbial pathogenesis, host-pathogen interactions and new treatment strategies. Nat Rev Microbiol, 2020, 18(4): 211-226.
39.	Smith HS, Hughes JP, Hooton TM, et al. Antecedent antimicrobial use increases the risk of uncomplicated cystitis in young women. Clin Infect Dis, 1997, 25(1): 63-68.
40.	van Nieuwkoop C. Antibiotic treatment of urinary tract infection and its impact on the gut microbiota. Lancet Infect Dis, 2022, 22(3): 307-309.
41.	Biehl LM, Cruz Aguilar R, Farowski F, et al. Fecal microbiota transplantation in a kidney transplant recipient with recurrent urinary tract infection. Infection, 2018, 46(6): 871-874.
42.	Jeney SES, Lane F, Oliver A, et al. Fecal microbiota transplantation for the treatment of refractory recurrent urinary tract infection. Obstet Gynecol, 2020, 136(4): 771-773.
43.	Tariq R, Pardi DS, Tosh PK, et al. Fecal microbiota transplantation for recurrent clostridium difficile infection reduces recurrent urinary tract infection frequency. Clin Infect Dis, 2017, 65(10): 1745-1747.

1. Wagenlehner FME, Bjerklund Johansen TE, Cai T, et al. Epidemiology, definition and treatment of complicated urinary tract infections. Nat Rev Urol, 2020, 17(10): 586-600.
2. Flores-Mireles AL, Walker JN, Caparon M, et al. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol, 2015, 13(5): 269-284.
3. Qiao LD, Chen S, Yang Y, et al. Characteristics of urinary tract infection pathogens and their in vitro susceptibility to antimicrobial agents in China: data from a multicenter study. BMJ Open, 2013, 3(12): e004152.
4. Adak A, Khan MR. An insight into gut microbiota and its functionalities. Cell Mol Life Sci, 2019, 76(3): 473-493.
5. Paalanne N, Husso A, Salo J, et al. Intestinal microbiome as a risk factor for urinary tract infections in children. Eur J Clin Microbiol Infect Dis, 2018, 37(10): 1881-1891.
6. Magruder M, Edusei E, Zhang L, et al. Gut commensal microbiota and decreased risk for Enterobacteriaceae bacteriuria and urinary tract infection. Gut Microbes, 2020, 12(1): 1805281.
7. Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA, 2017, 318(19): 1925-1931.
8. Kurilshikov A, Medina-Gomez C, Bacigalupe R, et al. Large-scale association analyses identify host factors influencing human gut microbiome composition. Nat Genet, 2021, 53(2): 156-165.
9. Xia D, Wang J, Zhao X, et al. Association between gut microbiota and benign prostatic hyperplasia: a two-sample mendelian randomization study. Front Cell Infect Microbiol, 2023, 13: 1248381.
10. Sanna S, Kurilshikov A, van der Graaf A, et al. Challenges and future directions for studying effects of host genetics on the gut microbiome. Nat Genet, 2022, 54(2): 100-106.
11. Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: The STROBE-MR Statement. JAMA, 2021, 326(16): 1614-1621.
12. Sekula P, Del Greco M F, Pattaro C, et al. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol, 2016, 27(11): 3253-3265.
13. Liu B, Ye D, Yang H, et al. Two-sample Mendelian randomization analysis investigates causal associations between gut microbial genera and inflammatory bowel disease, and specificity causal associations in ulcerative colitis or Crohn's disease. Front Immunol, 2022, 13: 921546.
14. Sanna S, van Zuydam NR, Mahajan A, et al. Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases. Nat Genet, 2019, 51(4): 600-605.
15. Burgess S, Thompson SG. Bias in causal estimates from Mendelian randomization studies with weak instruments. Stat Med, 2011, 30(11): 1312-1323.
16. Papadimitriou N, Dimou N, Tsilidis KK, et al. Physical activity and risks of breast and colorectal cancer: a Mendelian randomisation analysis. Nat Commun, 2020, 11(1): 597.
17. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol, 2013, 37(7): 658-665.
18. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
19. Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
20. Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol, 2017, 46(6): 1985-1998.
21. Milne RL, Kuchenbaecker KB, Michailidou K, et al. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nat Genet, 2017, 49(12): 1767-1778.
22. Li P, Wang H, Guo L, et al. Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study. BMC Med, 2022, 20(1): 443.
23. Burgess S, Davey Smith G, Davies NM, et al. Guidelines for performing Mendelian randomization investigations: update for summer 2023. Wellcome Open Res, 2023, 4: 186.
24. Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
25. 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.
26. Bai X, Wei H, Liu W, et al. Cigarette smoke promotes colorectal cancer through modulation of gut microbiota and related metabolites. Gut, 2022, 71(12): 2439-2450.
27. Radjabzadeh D, Bosch JA, Uitterlinden AG, et al. Gut microbiome-wide association study of depressive symptoms. Nat Commun, 2022, 13(1): 7128.
28. Lohia S, Vlahou A, Zoidakis J. Microbiome in chronic kidney disease (CKD): an omics perspective. Toxins (Basel), 2022, 14(3): 176.
29. Peter-Bibb TK, Tokeshi J. Hawai'i's first published case of Eggerthella lenta sepsis. Hawaii J Health Soc Welf, 2020, 79(11): 326-328.
30. Jiang S, E J, Wang D, et al. Eggerthella lenta bacteremia successfully treated with ceftizoxime: case report and review of the literature. Eur J Med Res, 2021, 26(1): 111.
31. Alexander M, Ang QY, Nayak RR, et al. Human gut bacterial metabolism drives Th17 activation and colitis. Cell Host Microbe, 2022, 30(1): 17-30.
32. Henke MT, Kenny DJ, Cassilly CD, et al. Ruminococcus gnavus, a member of the human gut microbiome associated with Crohn's disease, produces an inflammatory polysaccharide. Proc Natl Acad Sci USA, 2019, 116(26): 12672-12677.
33. Tong Y, Zheng L, Qing P, et al. Oral microbiota perturbations are linked to high risk for rheumatoid arthritis. Front Cell Infect Microbiol, 2020, 9: 475.
34. Mayer EA, Tillisch K, Gupta A. Gut/brain axis and the microbiota. J Clin Invest, 2015, 125(3): 926-938.
35. Budden KF, Gellatly SL, Wood DL, et al. Emerging pathogenic links between microbiota and the gut-lung axis. Nat Rev Microbiol, 2017, 15(1): 55-63.
36. Worby CJ, Schreiber HL, Straub TJ, et al. Longitudinal multi-omics analyses link gut microbiome dysbiosis with recurrent urinary tract infections in women. Nat Microbiol, 2022, 7(5): 630-639.
37. Magruder M, Sholi AN, Gong C, et al. Gut uropathogen abundance is a risk factor for development of bacteriuria and urinary tract infection. Nat Commun, 2019, 10(1): 5521.
38. Klein RD, Hultgren SJ. Urinary tract infections: microbial pathogenesis, host-pathogen interactions and new treatment strategies. Nat Rev Microbiol, 2020, 18(4): 211-226.
39. Smith HS, Hughes JP, Hooton TM, et al. Antecedent antimicrobial use increases the risk of uncomplicated cystitis in young women. Clin Infect Dis, 1997, 25(1): 63-68.
40. van Nieuwkoop C. Antibiotic treatment of urinary tract infection and its impact on the gut microbiota. Lancet Infect Dis, 2022, 22(3): 307-309.
41. Biehl LM, Cruz Aguilar R, Farowski F, et al. Fecal microbiota transplantation in a kidney transplant recipient with recurrent urinary tract infection. Infection, 2018, 46(6): 871-874.
42. Jeney SES, Lane F, Oliver A, et al. Fecal microbiota transplantation for the treatment of refractory recurrent urinary tract infection. Obstet Gynecol, 2020, 136(4): 771-773.
43. Tariq R, Pardi DS, Tosh PK, et al. Fecal microbiota transplantation for recurrent clostridium difficile infection reduces recurrent urinary tract infection frequency. Clin Infect Dis, 2017, 65(10): 1745-1747.

Chinese Journal of Evidence-Based Medicine

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