Causal association between autism spectrum disorder and gut microbiota based on Mendelian randomization analysis

XIAO Lian; LI Xiaofei; WANG Lei

doi:10.11852/zgetbjzz2024-0638

PDF(3922 KB)

Chinese Journal of Child Health Care ›› 2025, Vol. 33 ›› Issue (1) : 27-33. DOI: 10.11852/zgetbjzz2024-0638

Original Articles

Causal association between autism spectrum disorder and gut microbiota based on Mendelian randomization analysis

XIAO Lian¹, LI Xiaofei², WANG Lei²

Author information +

History +

Abstract

Objective To explore the causal relationship between gut microbiota (GM) and autism spectrum disorder (ASD) by Mendelian randomization, in order to provide insight for ASD treatment. Methods GWAS data on gut microbiota from the MiBioGen public database and GWAS data on ASD from the IEU Open GWAS database were utilized. Independent genetic loci significantly associated with the relative abundance of gut microbiota were extracted as instrumental variables (IVs) based on preset thresholds. The effect size odds ratio (OR) and 95%confidence interval (CI) were primarily assessed using the inverse-variance weighted method. The stability and reliability of the results were verified using leave-one-out analysis, heterogeneity tests, and horizontal pleiotropy tests. Results Increased abundances of Dorea (OR=0.811, 95%CI: 0.686 - 0.959), Ruminiclostridium5 (OR=0.812, 95%CI: 0.687 - 0.961), RuminococcaceaeUCG005 (OR=0.776, 95%CI: 0.670 - 0.898), Ruminococcus1(OR=0.831, 95%CI: 0.705 - 0.981), and Sutterella (OR=0.821, 95%CI: 0.684 - 0.987) were associated with a decreased risk of ASD. However, an increase in Turicibacter abundance was associated with an increased risk of ASD (OR =1.140, 95%CI: 1.008 - 1.290). Leave-one-out analysis showed stable results, with no strong influential IVs, and the effects of heterogeneity and horizontal pleiotropy on causal effect estimation could be excluded. Conclusions Among gut microbiota, Dorea, Ruminiclostridium5, RuminococcaceaeUCG005, Ruminococcus1, and Sutterella are protective factors for the occurrence of ASD, and their increased abundances may reduce the incidence of ASD. In contrast, Turicibacter is a risk factor for the occurrence of ASD, and its increased abundance may increase the incidence of ASD.

Key words

gut microbiota / autism spectrum disorder / Mendelian randomization

Cite this article

EndNote

Ris (Procite)

Bibtex

Download Citations

XIAO Lian, LI Xiaofei, WANG Lei. Causal association between autism spectrum disorder and gut microbiota based on Mendelian randomization analysis[J]. Chinese Journal of Child Health Care. 2025, 33(1): 27-33 https://doi.org/10.11852/zgetbjzz2024-0638

References

[1] Zulauf LM. The Revision and 5th Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5): Consequences for the diagnostic work with children and adolescents[J]. Prax Kinderpsychol Kinderpsychiatr, 2014,63(7):562-576.
[2] Maenner MJ, Warren Z, Williams AR, et al. Prevalence and characteristics of autism spectrum disorder among children aged 8 years-Autism and developmental disabilities monitoring network, 11 Sites, United States, 2020[J]. MMWR Surveill Summ, 2023,72(2):1-14.
[3] Zhou H, Xu X, Yan W, et al. Prevalence of Autism Spectrum Disorder in China: A nationwide multi-center population-based study among children aged 6 to 12 years[J]. Neurosci Bull, 2020, 36(9): 961-971.
[4] Maenner MJ, Shaw KA, Bakian AV, et al. Prevalence and characteristics of autism spectrum disorder among children aged 8 years-Autism and developmental disabilities monitoring network, 11 Sites, United States, 2018[J]. MMWR Surveill Summ, 2021,70(11):1-16.
[5] Li YA, Chen ZJ, Li XD, et al. Epidemiology of autism spectrum disorders: Global burden of disease 2019 and bibliometric analysis of risk factors[J]. Front Pediatr, 2022,10:972809.
[6] Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans[J]. Cell, 2016,164(3):337-340.
[7] Cho J, Park YJ, Gonzales-Portillo B, et al. Gut dysbiosis in stroke and its implications on Alzheimer's disease-like cognitive dysfunction[J]. CNS Neurosci Ther, 2021,27(5):505-514.
[8] Kraneveld AD, Szklany K, de Theije CG, et al. Gut-to-brain axis in autism spectrum disorders: Central role for the microbiome[J]. Int Rev Neurobiol, 2016,131:263-287.
[9] Adams JB, Johansen LJ, Powell LD, et al. Gastrointestinal flora and gastrointestinal status in children with autism--comparisons to typical children and correlation with autism severity[J]. BMC Gastroenterol, 2011,11:22.
[10] McElhanon BO, McCracken C, Karpen S, et al. Gastrointestinal symptoms in autism spectrum disorder: A meta-analysis[J]. Pediatrics, 2014,133(5):872-883.
[11] Fulceri F, Morelli M, Santocchi E, et al. Gastrointestinal symptoms and behavioral problems in preschoolers with autism spectrum disorder[J]. Dig Liver Dis, 2016,48(3):248-854.
[12] Iovene MR, Bombace F, Maresca R, et al. Intestinal dysbiosis and yeast isolation in stool of subjects with autism spectrum disorders[J]. Mycopathologia, 2017,182(3-4):349-363.
[13] Ha S, Oh D, Lee S, et al. Altered gut microbiota in Korean children with autism spectrum disorders[J]. Nutrients, 2021,13(10):3300.
[14] Emdin CA, Khera AV, Kathiresan S. Mendelian randomization[J]. JAMA, 2017,318(19):1925-1926.
[15] Kurilshikov A, Medina-Gomez C, Bacigalupe R, et al. Large-scale association analyses identify host factors influencing human gut microbiome composition[J]. Nat Genet, 2021,53(2):156-165.
[16] Zhang Y, Zhang X, Chen D, et al. Causal associations between gut microbiome and cardiovascular disease: A Mendelian randomization study[J]. Front Cardiovasc Med, 2022,9:971376.
[17] Jin Q, Ren F, Dai D, et al. The causality between intestinal flora and allergic diseases: Insights from a bi-directional two-sample Mendelian randomization analysis[J]. Front Immunol, 2023,14:1121273.
[18] Hartwig FP, Tilling K, Davey Smith G, et al. Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations[J]. Int J Epidemiol, 2021,50(5):1639-1650.
[19] 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[J]. 中国卫生统计, 2021,38(3):471-475,480.
CSCO Expert Committee on Biostatistics RWS Methodology Group. Statistical consensus of Mendelian randomization model and its normalization application[J]. Chinese health statistics, 2021,38(3): 471-475,480.(in Chinese)
[20] Boehm FJ, Zhou X. Statistical methods for Mendelian randomization in genome-wide association studies: A review[J]. Comput Struct Biotechnol J, 2022,20:2338-2351.
[21] 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[J]. PLoS Genet, 2021,17(11):e1009922.
[22] 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[J]. Nat Genet, 2018,50(5):693-698.
[23] Gronau QF, Wagenmakers EJ. Limitations of bayesian leave-one-out cross-validation for model selection[J]. Comput Brain Behav, 2019,2(1):1-11.
[24] Yuan S, Kim JH, Xu P, et al. Causal association between celiac disease and inflammatory bowel disease: A two-sample bidirectional Mendelian randomization study[J]. Front Immunol, 2022,13:1057253.
[25] Zhao X, Kong M, Wang Y, et al. Nicotinamide mononucleotide improves the Alzheimer's disease by regulating intestinal microbiota[J]. Biochem Biophys Res Commun, 2023,670:27-35.
[26] Hooper LV, Gordon JI. Commensal host-bacterial relationships in the gut[J]. Science, 2001,292(5519):1115-1118.
[27] Carabotti M, Scirocco A, Maselli MA, et al. The gut-brain axis: Interactions between enteric microbiota, central and enteric nervous systems[J]. Ann Gastroenterol, 2015,28(2):203-209.
[28] Dinan TG, Stilling RM, Stanton C, et al. Collective unconscious: How gut microbes shape human behavior[J]. J Psychiatr Res, 2015,63:1-9.
[29] Tomova A, Husarova V, Lakatosova S, et al. Gastrointestinal microbiota in children with autism in Slovakia[J]. Physiol Behav, 2015,138:179-187.
[30] Strati F, Cavalieri D, Albanese D, et al. New evidences on the altered gut microbiota in autism spectrum disorders[J]. Microbiome, 2017,5(1):24.
[31] Alshammari MK, AlKhulaifi MM, Al Farraj DA, et al. Incidence of Clostridium perfringens and its toxin genes in the gut of children with autism spectrum disorder[J]. Anaerobe, 2020,61:102114.
[32] Liu J, Liu X, Xiong XQ, et al. Effect of vitamin A supplementation on gut microbiota in children with autism spectrum disorders-a pilot study[J]. BMC Microbiol, 2017,17(1):204.
[33] Liu YW, Liong MT, Chung YE, et al. Effects of Lactobacillus plantarum PS128 on children with autism spectrum disorder in Taiwan: A randomized, double-blind, placebo-controlled trial[J]. Nutrients, 2019,11(4):820.
[34] Kang DW, Adams JB, Gregory AC, et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: An open-label study[J]. Microbiome, 2017,5(1):10.
[35] Kang DW, Adams JB, Coleman DM, et al. Long-term benefit of microbiota transfer therapy on autism symptoms and gut microbiota[J]. Sci Rep, 2019,9(1):5821.