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：

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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.	吴振坤, 张先卓, 曹洁, 等. 消化道微生态与胆石症关系研究进展. 中国微生态学杂志, 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生物统计学专家委员会RWS方法学组. 孟德尔随机化模型及其规范化应用的统计学共识. 中国卫生统计, 2021, 38(3): 471-475, 480.
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10.	柴金莲, 李树栋, 李威, 等. 肠道菌群与药物相关性骨坏死: 两样本双向孟德尔随机化分析. 中国组织工程研究, 2024, 28(27): 4325-4331.
11.	朱仪章, 赵经委, 秦磊. 肠道菌群与急慢性胰腺炎的因果关系: 一项双样本孟德尔随机化研究. 肝胆胰外科杂志, 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.	王强, 薛东波. 肠道菌群通过影响胆汁酸代谢参与胆囊胆固醇结石形成. 肝胆胰外科杂志, 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.	叶佳怡, 冯金华, 李卡. 胆囊切除术后患者肠道微生物群改变的研究进展. 中国普外基础与临床杂志, 2022, 29(12): 1653-1659.
26.	李晶晶, 朱成章, 史新龙, 等. 基于16S rDNA测序分析胆囊结石及胆囊切除对结直肠癌患者肠道菌群的影响. 中国普外基础与临床杂志, 2022, 29(12): 1573-1582.

1. 吴振坤, 张先卓, 曹洁, 等. 消化道微生态与胆石症关系研究进展. 中国微生态学杂志, 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生物统计学专家委员会RWS方法学组. 孟德尔随机化模型及其规范化应用的统计学共识. 中国卫生统计, 2021, 38(3): 471-475, 480.
4. 孟勇, 蒋维荣, 李瑞, 等. 肠道菌群和代谢相关脂肪性肝病的因果关联: 一项双样本孟德尔随机化研究. 延安大学学报(医学科学版), 2023, 21(3): 44-49.
5. 马玮玮, 陈虹谷, 李彤彤, 等. 基于孟德尔随机化分析肠道菌群与骨密度的因果关系. 中国骨质疏松杂志, 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. 陈鑫明, 赵平武, 何运胜, 等. 奶酪或茶摄入与胃食管反流病的因果关联: 两样本孟德尔随机化研究. 中国普外基础与临床杂志, 2024, 31(9): 1099-1104.
10. 柴金莲, 李树栋, 李威, 等. 肠道菌群与药物相关性骨坏死: 两样本双向孟德尔随机化分析. 中国组织工程研究, 2024, 28(27): 4325-4331.
11. 朱仪章, 赵经委, 秦磊. 肠道菌群与急慢性胰腺炎的因果关系: 一项双样本孟德尔随机化研究. 肝胆胰外科杂志, 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. 王强, 薛东波. 肠道菌群通过影响胆汁酸代谢参与胆囊胆固醇结石形成. 肝胆胰外科杂志, 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. 叶佳怡, 冯金华, 李卡. 胆囊切除术后患者肠道微生物群改变的研究进展. 中国普外基础与临床杂志, 2022, 29(12): 1653-1659.
26. 李晶晶, 朱成章, 史新龙, 等. 基于16S rDNA测序分析胆囊结石及胆囊切除对结直肠癌患者肠道菌群的影响. 中国普外基础与临床杂志, 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

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