Two-sample Mendelian randomization analysis of the causal relationship between gut microbiota and cholelithiasis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHAO Hao ^1,2 , NAN Boyuan ¹ ,  ZHANG Wei ¹

1. Department of Hepatobiliary Surgery, General Hospital of Northern Theater Command, Shenyang 110000, P. R. China;
2. Training Base for Graduate, General Hospital of Northern Theater Command, Dalian Medical University, Shenyang 110000, P. R. China;

Corresponding?author：

ZHANG Wei, Email: zhang_wei_1980@163.com

Keywords：

cholelithiasis; gut microbiota; Mendelian randomization; causal relationship; enterohepatic circulation

DOI：

10.7507/1007-9424.202410097

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To investigate the causal relationship between gut microbiota and cholelithiasis using a two-sample Mendelian randomization method. Methods The genome-wide association studies (GWAS) data of gut microbiota from the MiBioGen study and the GWAS data of cholelithiasis from the FinnGen Biobank were utilized. Genetic variants significantly associated with the relative abundance of gut microbiota were identified as instrumental variables (IVs) based on a specified threshold. The inverse variance weighted (IVW) method was employed as the primary analytical approach, with results assessed based on the odds ratio (OR) and 95% confidence interval (CI). The robustness and reliability of the findings were ensured through quality control measures, including sensitivity analysis, assessment of heterogeneity, and evaluation for horizontal gene pleiotropy. Results Clostridiumsensustricto1 [OR=1.160, 95%CI (1.023, 1.314), P=0.020], Coprococcus3 [OR=1.136, 95%CI (1.014, 1.272), P=0.028] and Peptococcus [OR=1.074, 95%CI (1.023, 1.128) , P=0.004] increased the risk of cholelithiasis. Bacilli [OR=0.897, 95%CI (0.818, 0.984), P=0.022], Family Ⅹ ⅢAD3011group [OR=0.908, 95%CI (0.830, 0.992), P=0.033] and Lactobacillales [OR=0.884, 95%CI (0.802, 0.974), P=0.013] were protective factors for cholelithiasis. Conclusion The study has identified 6 kinds of specific gut microbiota that are causally linked to the development of cholelithiasis, providing new ideas for the diagnosis and treatment of cholelithiasis.

Citation： ZHAO Hao, NAN Boyuan, ZHANG Wei. Two-sample Mendelian randomization analysis of the causal relationship between gut microbiota and cholelithiasis. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2025, 32(8): 972-977. doi: 10.7507/1007-9424.202410097 Copy

1.	吳振坤, 張先卓, 曹潔, 等. 消化道微生態與膽石癥關系研究進展. 中國微生態學雜志, 2023, 35(3): 366-369.
2.	Sekirov I, Russell SL, Antunes LC, et al. Gut microbiota in health and disease. Physiol Rev, 2010, 90(3): 859-904.
3.	CSCO生物統計學專家委員會RWS方法學組. 孟德爾隨機化模型及其規范化應用的統計學共識. 中國衛生統計, 2021, 38(3): 471-475, 480.
4.	孟勇, 蔣維榮, 李瑞, 等. 腸道菌群和代謝相關脂肪性肝病的因果關聯: 一項雙樣本孟德爾隨機化研究. 延安大學學報(醫學科學版), 2023, 21(3): 44-49.
5.	馬瑋瑋, 陳虹谷, 李彤彤, 等. 基于孟德爾隨機化分析腸道菌群與骨密度的因果關系. 中國骨質疏松雜志, 2023, 29(12): 1780-1785.
6.	Burgess S, Thompson SG; CRP CHD Genetics Collaboration. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol, 2011, 40(3): 755-764.
7.	Lin Z, Deng Y, Pan W. Combining the strengths of inverse-variance weighting and Egger regression in Mendelian randomization using a mixture of regressions model. PLoS Genet, 2021, 17(11): e1009922. doi: 10.1371/journal.pgen.1009922.
8.	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.
9.	陳鑫明, 趙平武, 何運勝, 等. 奶酪或茶攝入與胃食管反流病的因果關聯: 兩樣本孟德爾隨機化研究. 中國普外基礎與臨床雜志, 2024, 31(9): 1099-1104.
10.	柴金蓮, 李樹棟, 李威, 等. 腸道菌群與藥物相關性骨壞死: 兩樣本雙向孟德爾隨機化分析. 中國組織工程研究, 2024, 28(27): 4325-4331.
11.	朱儀章, 趙經委, 秦磊. 腸道菌群與急慢性胰腺炎的因果關系: 一項雙樣本孟德爾隨機化研究. 肝膽胰外科雜志, 2024, 36(6): 341-347.
12.	Boursier J, Mueller O, Barret M, et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology, 2016, 63(3): 764-775.
13.	Schneider KM, Mohs A, Gui W, et al. Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment. Nat Commun, 2022, 13(1): 3964. doi: 10.1038/s41467-022-31312-5.
14.	王強, 薛東波. 腸道菌群通過影響膽汁酸代謝參與膽囊膽固醇結石形成. 肝膽胰外科雜志, 2020, 32(1): 6-8, 25.
15.	Jiang L, Zhang H, Xiao D, et al. Farnesoid X receptor (FXR): structures and ligands. Comput Struct Biotechnol J, 2021, 19: 2148-2159.
16.	Liu Y, Lam K, Tang YJ, et al. Anaerobic bacteria and intrahepatic stones: detections of Clostridium sp. and Bacteroides fragilis. Chin Med J (Engl), 2000, 113(9): 858-861.
17.	Berr F, Kullak-Ublick GA, Paumgartner G, et al. 7 alpha-dehydroxylating bacteria enhance deoxycholic acid input and cholesterol saturation of bile in patients with gallstones. Gastroenterology, 1996, 111(6): 1611-1620.
18.	Grigor’eva IN, Romanova TI. Gallstone disease and microbiome. Microorganisms, 2020, 8(6): 835. doi: 10.3390/microorganisms8060835.
19.	Song Z, Cai Y, Lao X, et al. Taxonomic profiling and populational patterns of bacterial bile salt hydrolase (BSH) genes based on worldwide human gut microbiome. Microbiome, 2019, 7(1): 9. doi: 10.1186/s40168-019-0628-3.
20.	Tabata M, Nakayama F. Bacteria and gallstones. Etiological significance. Dig Dis Sci, 1981, 26(3): 218-224.
21.	Song ST, Cai LY, Zeng X, et al. Gut microbial profile in asymptomatic gallstones. Front Microbiol, 2022, 13: 882265. doi: 10.3389/fmicb.2022.882265.
22.	Heaton KW. Review article: epidemiology of gall-bladder disease-role of intestinal transit. Aliment Pharmacol Ther, 2000, 14 Suppl 2: 9-13.
23.	Yu L, Liu Y, Wang S, et al. Cholestasis: exploring the triangular relationship of gut microbiota-bile acid-cholestasis and the potential probiotic strategies. Gut Microbes, 2023, 15(1): 2181930. doi: 10.1080/19490976.2023.2181930.
24.	Choi SB, Lew LC, Yeo SK, et al. Probiotics and the BSH-related cholesterol lowering mechanism: a Jekyll and Hyde scenario. Crit Rev Biotechnol, 2015, 35(3): 392-401.
25.	葉佳怡, 馮金華, 李卡. 膽囊切除術后患者腸道微生物群改變的研究進展. 中國普外基礎與臨床雜志, 2022, 29(12): 1653-1659.
26.	李晶晶, 朱成章, 史新龍, 等. 基于16S rDNA測序分析膽囊結石及膽囊切除對結直腸癌患者腸道菌群的影響. 中國普外基礎與臨床雜志, 2022, 29(12): 1573-1582.

1. 吳振坤, 張先卓, 曹潔, 等. 消化道微生態與膽石癥關系研究進展. 中國微生態學雜志, 2023, 35(3): 366-369.
2. Sekirov I, Russell SL, Antunes LC, et al. Gut microbiota in health and disease. Physiol Rev, 2010, 90(3): 859-904.
3. CSCO生物統計學專家委員會RWS方法學組. 孟德爾隨機化模型及其規范化應用的統計學共識. 中國衛生統計, 2021, 38(3): 471-475, 480.
4. 孟勇, 蔣維榮, 李瑞, 等. 腸道菌群和代謝相關脂肪性肝病的因果關聯: 一項雙樣本孟德爾隨機化研究. 延安大學學報(醫學科學版), 2023, 21(3): 44-49.
5. 馬瑋瑋, 陳虹谷, 李彤彤, 等. 基于孟德爾隨機化分析腸道菌群與骨密度的因果關系. 中國骨質疏松雜志, 2023, 29(12): 1780-1785.
6. Burgess S, Thompson SG; CRP CHD Genetics Collaboration. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol, 2011, 40(3): 755-764.
7. Lin Z, Deng Y, Pan W. Combining the strengths of inverse-variance weighting and Egger regression in Mendelian randomization using a mixture of regressions model. PLoS Genet, 2021, 17(11): e1009922. doi: 10.1371/journal.pgen.1009922.
8. 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.
9. 陳鑫明, 趙平武, 何運勝, 等. 奶酪或茶攝入與胃食管反流病的因果關聯: 兩樣本孟德爾隨機化研究. 中國普外基礎與臨床雜志, 2024, 31(9): 1099-1104.
10. 柴金蓮, 李樹棟, 李威, 等. 腸道菌群與藥物相關性骨壞死: 兩樣本雙向孟德爾隨機化分析. 中國組織工程研究, 2024, 28(27): 4325-4331.
11. 朱儀章, 趙經委, 秦磊. 腸道菌群與急慢性胰腺炎的因果關系: 一項雙樣本孟德爾隨機化研究. 肝膽胰外科雜志, 2024, 36(6): 341-347.
12. Boursier J, Mueller O, Barret M, et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology, 2016, 63(3): 764-775.
13. Schneider KM, Mohs A, Gui W, et al. Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment. Nat Commun, 2022, 13(1): 3964. doi: 10.1038/s41467-022-31312-5.
14. 王強, 薛東波. 腸道菌群通過影響膽汁酸代謝參與膽囊膽固醇結石形成. 肝膽胰外科雜志, 2020, 32(1): 6-8, 25.
15. Jiang L, Zhang H, Xiao D, et al. Farnesoid X receptor (FXR): structures and ligands. Comput Struct Biotechnol J, 2021, 19: 2148-2159.
16. Liu Y, Lam K, Tang YJ, et al. Anaerobic bacteria and intrahepatic stones: detections of Clostridium sp. and Bacteroides fragilis. Chin Med J (Engl), 2000, 113(9): 858-861.
17. Berr F, Kullak-Ublick GA, Paumgartner G, et al. 7 alpha-dehydroxylating bacteria enhance deoxycholic acid input and cholesterol saturation of bile in patients with gallstones. Gastroenterology, 1996, 111(6): 1611-1620.
18. Grigor’eva IN, Romanova TI. Gallstone disease and microbiome. Microorganisms, 2020, 8(6): 835. doi: 10.3390/microorganisms8060835.
19. Song Z, Cai Y, Lao X, et al. Taxonomic profiling and populational patterns of bacterial bile salt hydrolase (BSH) genes based on worldwide human gut microbiome. Microbiome, 2019, 7(1): 9. doi: 10.1186/s40168-019-0628-3.
20. Tabata M, Nakayama F. Bacteria and gallstones. Etiological significance. Dig Dis Sci, 1981, 26(3): 218-224.
21. Song ST, Cai LY, Zeng X, et al. Gut microbial profile in asymptomatic gallstones. Front Microbiol, 2022, 13: 882265. doi: 10.3389/fmicb.2022.882265.
22. Heaton KW. Review article: epidemiology of gall-bladder disease-role of intestinal transit. Aliment Pharmacol Ther, 2000, 14 Suppl 2: 9-13.
23. Yu L, Liu Y, Wang S, et al. Cholestasis: exploring the triangular relationship of gut microbiota-bile acid-cholestasis and the potential probiotic strategies. Gut Microbes, 2023, 15(1): 2181930. doi: 10.1080/19490976.2023.2181930.
24. Choi SB, Lew LC, Yeo SK, et al. Probiotics and the BSH-related cholesterol lowering mechanism: a Jekyll and Hyde scenario. Crit Rev Biotechnol, 2015, 35(3): 392-401.
25. 葉佳怡, 馮金華, 李卡. 膽囊切除術后患者腸道微生物群改變的研究進展. 中國普外基礎與臨床雜志, 2022, 29(12): 1653-1659.
26. 李晶晶, 朱成章, 史新龍, 等. 基于16S rDNA測序分析膽囊結石及膽囊切除對結直腸癌患者腸道菌群的影響. 中國普外基礎與臨床雜志, 2022, 29(12): 1573-1582.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Two-sample Mendelian randomization analysis of the causal relationship between gut microbiota and cholelithiasis

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content