Causal association between gut microbiota and tic disorder: a Mendelian randomization study_West China Medical Journal

Authors：

ZHOU Wenyue ¹ , LIANG Jiahao ¹ , LI Zehao ¹ ,  WANG Hai ^1,2 , LI Yan ^1,2

1. First Clinical Medical College of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P. R. China;
2. Second Department of Pediatrics, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P. R. China;

Corresponding author：

WANG Hai, Email: wanghai@hljucm.net

Keywords：

Mendelian randomization; tic disorder; gut microbiota; causal correlation

DOI：

10.7507/1002-0179.202311179

Video：

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Objective To analyze the causal relationship between gut microbiota and tic disorder based on Mendelian randomization (MR). Methods A total of 196 known microbiota (9 phyla, 16 classes, 20 orders, 32 families, and 119 genera) in the human intestinal microbiota dataset downloaded from the MiBioGen database were selected as the exposure factors, and the dataset of tic disorder (finn-b-KRA_PSY_TIC) containing 172 patients and 218620 controls was downloaded from the genome-wide association study database as the outcome variable. Inverse variance weighted was used as the main analysis method, and the causal relationship between gut microbiota and tic disorder was evaluated using odds ratio (OR) and its 95% confidence interval (CI). Horizontal pleiotropy was tested by MR-Egger intercept and MR-PRESSO global test, heterogeneity was assessed by Cochran’s Q test, and sensitivity analysis was performed by leave-one-out method. Results Inverse variance weighted results showed that the Family Rhodospirillaceae [OR=0.398, 95%CI (0.191, 0.831), P=0.014], Order Rhodospirillales [OR=0.349, 95%CI (0.164, 0.743), P=0.006], and Parasutterella [OR=0.392, 95%CI (0.171, 0.898), P=0.027] had negative causal relationships with tic disorder. The Genus Lachnospira [OR=8.784, 95%CI (1.160, 66.496), P=0.035] and Candidatus Soleaferrea [OR=2.572, 95%CI (1.161, 5.695), P=0.020] had positive causal relationships with tic disorder. In addition, MR-Egger intercept and MR-PRESSO global test showed no horizontal pleiotropy, Cochran’s Q test showed no heterogeneity, and leave-one-out sensitivity analysis showed the results were stable. Conclusions A causal relationship exists between gut microbiota and tic disorder. The Family Rhodospirillaceae, Order Rhodospirillales, and Parasutterella are associated with a decreased risk of tic disorder, while the Genus Lachnospira and Candidatus Soleaverea can increase the risk of tic disorder.

Citation： ZHOU Wenyue, LIANG Jiahao, LI Zehao, WANG Hai, LI Yan. Causal association between gut microbiota and tic disorder: a Mendelian randomization study. West China Medical Journal, 2024, 39(8): 1195-1203. doi: 10.7507/1002-0179.202311179 Copy

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4.	冯春丽, 李春香, 殷丽娟, 等. 抽动障碍致病相关因素及中医健康干预现状分析. 中医儿科杂志, 2021, 17(4): 96-99.
5.	解金娜, 项紫霓, 谭歆, 等. 抽动障碍患儿自我意识及少儿主观生活质量的相关性分析. 中国康复理论与实践, 2016, 22(9): 1052-1055.
6.	Xi W, Gao X, Zhao H, et al. Depicting the composition of gut microbiota in children with tic disorders: an exploratory study. J Child Psychol Psychiatry, 2021, 62(10): 1246-1254.
7.	彭峰, 谭郡, 王丹, 等. 基于“微生物-肠-脑轴”理论从《内经》“脾胃同论”论治小儿抽动障碍. 辽宁中医药大学学报, 2023, 25(6): 118-122.
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12.	Swertz MA, Dijkstra M, Adamusiak T, et al. The MOLGENIS toolkit: rapid prototyping of biosoftware at the push of a button. BMC Bioinformatics, 2010, 11(Suppl 12): S12.
13.	Swertz MA, Jansen RC. Beyond standardization: dynamic software infrastructures for systems biology. Nat Rev Genet, 2007, 8(3): 235-243.
14.	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.
15.	Burgess S, Dudbridge F, Thompson SG. Combining information on multiple instrumental variables in Mendelian randomization: comparison of allele score and summarized data methods. Stat Med, 2016, 35(11): 1880-1906.
16.	Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
17.	Bowden J, Del Greco MF, Minelli C, et al. Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I² statistic. Int J Epidemiol, 2016, 45(6): 1961-1974.
18.	Ooi BNS, Loh H, Ho PJ, et al. The genetic interplay between body mass index, breast size and breast cancer risk: a Mendelian randomization analysis. Int J Epidemiol, 2019, 48(3): 781-794.
19.	Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci, 2011, 12(8): 453-466.
20.	Jin M, Qian Z, Yin J, et al. The role of intestinal microbiota in cardiovascular disease. J Cell Mol Med, 2019, 23(4): 2343-2350.
21.	Carabotti M, Scirocco A, Maselli MA, et al. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol, 2015, 28(2): 203-209.
22.	Erny D, Hrabě de Angelis AL, Jaitin D, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci, 2015, 18(7): 965-977.
23.	Vizcarra JA, Wilson-Perez HE, Espay AJ. The power in numbers: gut microbiota in Parkinson’s disease. Mov Disord, 2015, 30(3): 296-298.
24.	Arneth BM. Gut-brain axis biochemical signalling from the gastrointestinal tract to the central nervous system: gut dysbiosis and altered brain function. Postgrad Med J, 2018, 94(1114): 446-452.
25.	Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science, 2005, 308(5728): 1635-1638.
26.	项金, 白晓红. 文静汤治疗儿童抽动障碍疗效观察及对肠道菌群的影响. 山西中医, 2022, 38(9): 55-58.
27.	张海娥, 汪珍珍, 张海燕. 肠道菌群失调对抽动障碍患儿免疫球蛋白水平的影响. 中国医学工程, 2023, 31(7): 42-45.
28.	Li Y, Wang X, Yang H, et al. Profiles of proinflammatory cytokines and t cells in patients with tourette syndrome: a meta-analysis. Front Immunol, 2022, 26(5): 13: 843247.
29.	Chen YJ, Wu H, Wu SD, et al. Parasutterella, in association with irritable bowel syndrome and intestinal chronic inflammation. J Gastroenterol Hepatol, 2018, 33(11): 1844-1852.
30.	Carding S, Verbeke K, Vipond DT, et al. Dysbiosis of the gut microbiota in disease. Microb Ecol Health Dis, 2015, 26: 26191.
31.	Ju T, Kong JY, Stothard P, et al. Defining the role of Parasutterella, a previously uncharacterized member of the core gut microbiota. ISME J, 2019, 13(6): 1520-1534.
32.	Lee JS, Wang RX, Alexeev EE, et al. Hypoxanthine is a checkpoint stress metabolite in colonic epithelial energy modulation and barrier function. J Biol Chem, 2018, 293(16): 6039-6051.
33.	Ning J, Huang SY, Chen SD, et al. Investigating casual associations among gut microbiota, metabolites, and neurodegenerative diseases: a Mendelian randomization study. J Alzheimers Dis, 2022, 87(1): 211-222.
34.	Mayengbam S, Lambert JE, Parnell JA, et al. Impact of dietary fiber supplementation on modulating microbiota-host-metabolic axes in obesity. J Nutr Biochem, 2019, 64: 228-236.
35.	Forbes JD, Chen CY, Knox NC, et al. A comparative study of the gut microbiota in immune-mediated inflammatory diseases-does a common dysbiosis exist?. Microbiome, 2018, 6(1): 221.
36.	Liu R, Peng C, Jing D, et al. Lachnospira is a signature of antihistamine efficacy in chronic spontaneous urticaria. Exp Dermatol, 2022, 31(2): 242-247.
37.	Jiang H, Zeng W, Zhang X, et al. The role of gut microbiota in patients with benign and malignant brain tumors: a pilot study. Bioengineered, 2022, 13(3): 7847-7859.
38.	Li R, Guo Q, Zhao J, et al. Assessing causal relationships between gut microbiota and asthma: evidence from two sample Mendelian randomization analysis. Front Immunol, 2023, 14: 1148684.
39.	Mao M, Zhai C, Qian G. Gut microbiome relationship with arrhythmias and conduction blocks: a two-sample Mendelian randomization study. J Electrocardiol, 2023, 80: 155-161.

1. 戎萍, 马融, 韩新民, 等. 中医儿科临床诊疗指南·抽动障碍(修订). 中医儿科杂志, 2019, 15(6): 1-6.
2. Pringsheim T, Ganos C, Nilles C, et al. European Society for the Study of Tourette Syndrome 2022 criteria for clinical diagnosis of functional tic-like behaviours: international consensus from experts in tic disorders. Eur J Neurol, 2023, 30(4): 902-910.
3. 姜妍琳, 张蔷, 翟睿, 等. 中国儿童抽动障碍患病率及危险因素系统评价. 中国儿童保健杂志, 2023, 31(6): 661-667.
4. 冯春丽, 李春香, 殷丽娟, 等. 抽动障碍致病相关因素及中医健康干预现状分析. 中医儿科杂志, 2021, 17(4): 96-99.
5. 解金娜, 项紫霓, 谭歆, 等. 抽动障碍患儿自我意识及少儿主观生活质量的相关性分析. 中国康复理论与实践, 2016, 22(9): 1052-1055.
6. Xi W, Gao X, Zhao H, et al. Depicting the composition of gut microbiota in children with tic disorders: an exploratory study. J Child Psychol Psychiatry, 2021, 62(10): 1246-1254.
7. 彭峰, 谭郡, 王丹, 等. 基于“微生物-肠-脑轴”理论从《内经》“脾胃同论”论治小儿抽动障碍. 辽宁中医药大学学报, 2023, 25(6): 118-122.
8. Zheng J, Baird D, Borges MC, et al. Recent developments in mendelian randomization studies. Curr Epidemiol Rep, 2017, 4(4): 330-345.
9. Sekula P, Del Greco MF, Pattaro C, et al. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol, 2016, 27(11): 3253-3265.
10. Hemani G, Zheng J, Elsworth B, et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife, 2018, 7: e34408.
11. van der Velde KJ, Imhann F, Charbon B, et al. MOLGENIS research: advanced bioinformatics data software for non-bioinformaticians. Bioinformatics, 2019, 35(6): 1076-1078.
12. Swertz MA, Dijkstra M, Adamusiak T, et al. The MOLGENIS toolkit: rapid prototyping of biosoftware at the push of a button. BMC Bioinformatics, 2010, 11(Suppl 12): S12.
13. Swertz MA, Jansen RC. Beyond standardization: dynamic software infrastructures for systems biology. Nat Rev Genet, 2007, 8(3): 235-243.
14. 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.
15. Burgess S, Dudbridge F, Thompson SG. Combining information on multiple instrumental variables in Mendelian randomization: comparison of allele score and summarized data methods. Stat Med, 2016, 35(11): 1880-1906.
16. Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
17. Bowden J, Del Greco MF, Minelli C, et al. Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I² statistic. Int J Epidemiol, 2016, 45(6): 1961-1974.
18. Ooi BNS, Loh H, Ho PJ, et al. The genetic interplay between body mass index, breast size and breast cancer risk: a Mendelian randomization analysis. Int J Epidemiol, 2019, 48(3): 781-794.
19. Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci, 2011, 12(8): 453-466.
20. Jin M, Qian Z, Yin J, et al. The role of intestinal microbiota in cardiovascular disease. J Cell Mol Med, 2019, 23(4): 2343-2350.
21. Carabotti M, Scirocco A, Maselli MA, et al. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol, 2015, 28(2): 203-209.
22. Erny D, Hrabě de Angelis AL, Jaitin D, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci, 2015, 18(7): 965-977.
23. Vizcarra JA, Wilson-Perez HE, Espay AJ. The power in numbers: gut microbiota in Parkinson’s disease. Mov Disord, 2015, 30(3): 296-298.
24. Arneth BM. Gut-brain axis biochemical signalling from the gastrointestinal tract to the central nervous system: gut dysbiosis and altered brain function. Postgrad Med J, 2018, 94(1114): 446-452.
25. Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science, 2005, 308(5728): 1635-1638.
26. 项金, 白晓红. 文静汤治疗儿童抽动障碍疗效观察及对肠道菌群的影响. 山西中医, 2022, 38(9): 55-58.
27. 张海娥, 汪珍珍, 张海燕. 肠道菌群失调对抽动障碍患儿免疫球蛋白水平的影响. 中国医学工程, 2023, 31(7): 42-45.
28. Li Y, Wang X, Yang H, et al. Profiles of proinflammatory cytokines and t cells in patients with tourette syndrome: a meta-analysis. Front Immunol, 2022, 26(5): 13: 843247.
29. Chen YJ, Wu H, Wu SD, et al. Parasutterella, in association with irritable bowel syndrome and intestinal chronic inflammation. J Gastroenterol Hepatol, 2018, 33(11): 1844-1852.
30. Carding S, Verbeke K, Vipond DT, et al. Dysbiosis of the gut microbiota in disease. Microb Ecol Health Dis, 2015, 26: 26191.
31. Ju T, Kong JY, Stothard P, et al. Defining the role of Parasutterella, a previously uncharacterized member of the core gut microbiota. ISME J, 2019, 13(6): 1520-1534.
32. Lee JS, Wang RX, Alexeev EE, et al. Hypoxanthine is a checkpoint stress metabolite in colonic epithelial energy modulation and barrier function. J Biol Chem, 2018, 293(16): 6039-6051.
33. Ning J, Huang SY, Chen SD, et al. Investigating casual associations among gut microbiota, metabolites, and neurodegenerative diseases: a Mendelian randomization study. J Alzheimers Dis, 2022, 87(1): 211-222.
34. Mayengbam S, Lambert JE, Parnell JA, et al. Impact of dietary fiber supplementation on modulating microbiota-host-metabolic axes in obesity. J Nutr Biochem, 2019, 64: 228-236.
35. Forbes JD, Chen CY, Knox NC, et al. A comparative study of the gut microbiota in immune-mediated inflammatory diseases-does a common dysbiosis exist?. Microbiome, 2018, 6(1): 221.
36. Liu R, Peng C, Jing D, et al. Lachnospira is a signature of antihistamine efficacy in chronic spontaneous urticaria. Exp Dermatol, 2022, 31(2): 242-247.
37. Jiang H, Zeng W, Zhang X, et al. The role of gut microbiota in patients with benign and malignant brain tumors: a pilot study. Bioengineered, 2022, 13(3): 7847-7859.
38. Li R, Guo Q, Zhao J, et al. Assessing causal relationships between gut microbiota and asthma: evidence from two sample Mendelian randomization analysis. Front Immunol, 2023, 14: 1148684.
39. Mao M, Zhai C, Qian G. Gut microbiome relationship with arrhythmias and conduction blocks: a two-sample Mendelian randomization study. J Electrocardiol, 2023, 80: 155-161.

West China Medical Journal

Causal association between gut microbiota and tic disorder: a Mendelian randomization study

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