Causal relationship between gut microbiota and amyotrophic lateral sclerosis: sample analysis from the IEU Open GWAS Database

doi:10.12307/2026.686

Abstract

Abstract: BACKGROUND: Recent studies suggest that gut microbiota may have an influence on the progression of amyotrophic lateral sclerosis (ALS), but the exact causal relationship between them is still unclear.
Objective: To explore the causal relationship between gut microbiota and amyotrophic lateral sclerosis using Mendelian randomization analysis.
Methods: Genome-wide association study (GWAS) data on gut microbiota and amyotrophic lateral sclerosis were obtained from the IEU Open GWAS database (an open database developed by the UK Medical Research Council and the Institute of Genetic Epidemiology at the University of Bristol, UK, to provide GWAS data related to various diseases). Gut microbiota was used as the exposure factor and amyotrophic lateral sclerosis as the outcome variable. Inverse variance weighting, MR-Egger regression, weighted median, weighted model, and simple model methods were used to explore the causal relationship between them. Sensitivity analysis was conducted to assess the reliability of the Mendelian randomization results, and reverse Mendelian randomization analysis was further used to validate the causal relationship between the two.
Results and conclusion: (1) The results of the forward Mendelian randomization analysis indicated that there was a causal relationship between six types of gut microbiota and amyotrophic lateral sclerosis. Bilophila [β=0.206, odds ratio (OR)=1.229], Lachnospira (β=0.288, OR=1.333), Marvinbryantia (β=0.196, OR=1.216), RuminococcaceaeUCG010 (β=0.254, OR=1.289), and Tyzzerella3 (β=0.128, OR=1.136) may be potential risk factors for amyotrophic lateral sclerosis, while Intestinibacter (β=-0.203, OR=0.816) may be a protective factor for amyotrophic lateral sclerosis. (2) In the sensitivity analysis, no significant heterogeneity or orizontal pleiotropy was observed (P > 0.05), and the reverse Mendelian randomization analysis also did not reveal a reverse causal relationship between gut microbiota and amyotrophic lateral sclerosis. (3) The findings of this study not only suggest possible biomarkers for treating amyotrophic lateral sclerosis but also provide a foundation for creating new treatments using gut microbiota, with implications for fundamental medical studies in China.

Key words: gut microbiota, amyotrophic lateral sclerosis, Mendelian randomization, causality, inverse variance weighting, genome-wide association study data

CLC Number:

Wang Tao, Min Youjiang, Wang Min, Wang Shunpu, Li Le, Zhang Chen, Xiao Weiping, Yu Yiping. Causal relationship between gut microbiota and amyotrophic lateral sclerosis: sample analysis from the IEU Open GWAS Database[J]. Chinese Journal of Tissue Engineering Research, 2026, 30(12): 3182-3189.

Figures/Tables 5

References

[1] NGUYEN L. Updates on Disease Mechanisms and Therapeutics for Amyotrophic Lateral Sclerosis. Cells. 2024;13(11):888.
[2] MEJZINI R, FLYNN LL, PITOUT IL, et al. ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now? Front Neurosci. 2019; 13:1310.
[3] RIZEA RE, CORLATESCU AD, COSTIN HP, et al. Understanding Amyotrophic Lateral Sclerosis: Pathophysiology, Diagnosis, and Therapeutic Advances. Int J Mol Sci. 2024; 25(18):9966.
[4] FONTANA A, MARIN B, LUNA J, et al. Time-trend evolution and determinants of sex ratio in Amyotrophic Lateral Sclerosis: a dose-response meta-analysis. J Neurol. 2021;268(8):2973-2984.
[5] RIVA N, DOMI T, POZZI L, et al. Update on recent advances in amyotrophic lateral sclerosis. J Neurol. 2024;271(7):4693-4723.
[6] KIERNAN MC, KAJI R. Emerging concepts and therapies for amyotrophic lateral sclerosis. Curr Opin Neurol. 2024;37(5): 558-559.
[7] FABI JP. The connection between gut microbiota and its metabolites with neurodegenerative diseases in humans. Metab Brain Dis. 2024;39(5):967-984.
[8] NAKHAL MM, YASSIN LK, ALYAQOUBI R, et al. The Microbiota-Gut-Brain Axis and Neurological Disorders: A Comprehensive Review. Life (Basel). 2024;14(10):1234.
[9] LIU X, LIU Y, LIU J, et al. Correlation between the gut microbiome and neurodegenerative diseases: a review of metagenomics evidence. Neural Regen Res. 2024;19(4):833-845.
[10] KAUL M, MUKHERJEE D, WEINER H L, et al. Gut microbiota immune cross-talk in amyotrophic lateral sclerosis. Neurotherapeutics. 2024;21(6):e00469.
[11] SARESELLA M, PIANCONE F, TORTORELLA P, et al. T helper-17 activation dominates the immunologic milieu of both amyotrophic lateral sclerosis and progressive multiple sclerosis. Clin Immunol. 2013;148(1):79-88.
[12] VAN DER VELDEN L, VAN HOOFT JA, CHAMEAU P. Altered dendritic complexity affects firing properties of cortical layer 2/3 pyramidal neurons in mice lacking the 5-HT3A receptor. J Neurophysiol. 2012; 108(5):1521-1528.
[13] YEUNG S LA, LUO S, IWAGAMI M, et al. Introduction to Mendelian randomization. Ann Clin Epidemiol. 2025;7(1):27-37.
[14] 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.
[15] 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.
[16] VAN RHEENEN W, SHATUNOV A, DEKKER AM, et al. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nat Genet. 2016;48(9):1043-1048.
[17] BURGESS S, DAVIES NM, THOMPSON SG. Bias due to participant overlap in two-sample mendelian randomization. Genet. Epidemiol. 2016;40(7):597-608.
[18] SANDERSON E, GLYMOUR MM, HOLMES MV, et al. Mendelian randomization. Nat Rev Methods Primer. 2022;2:6.
[19] 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.
[20] 汪涛,王顺谱,闵友江,等.肠道菌群与类风湿关节炎的因果关系：GWAS数据欧洲群体资料分析[J].中国组织工程研究,2025,29(35):7663-7668.
[21] PALMER TM, LAWLOR DA, HARBORD RM, et al. Using multiple genetic variants as instrumental variables for modifiable risk factors. Stat Methods Med Res. 2012; 21(3):223-242.
[22] YUAN S, CHEN J, RUAN X, et al. Smoking, alcohol consumption, and 24 gastrointestinal diseases: mendelian randomization analysis. eLife. 2023;12: e84051.
[23] LI J, BAI H, QIAO H, et al. Causal effects of COVID-19 on cancer risk: a mendelian randomization study. J Med Virol. 2023; 95(4):e28722.
[24] 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.
[25] WACHSMUTH HR, WENINGER SN, DUCA FA. Role of the gut-brain axis in energy and glucose metabolism. Exp Mol Med. 2022;54(4):377-392.
[26] CALVO AC, VALLEDOR-MARTÍN I, MORENO-MARTÍNEZ L, et al. Lessons to Learn from the Gut Microbiota: A Focus on Amyotrophic Lateral Sclerosis. Genes. 2022;13(5):865.
[27] BLACHER E, BASHIARDES S, SHAPIRO H, et al. Potential roles of gut microbiome and metabolites in modulating ALS in mice. Nature. 2019;572(7770):474-480.
[28] ZHANG YG, WU S, YI J, et al. Target Intestinal Microbiota to Alleviate Disease Progression in Amyotrophic Lateral Sclerosis. Clin Ther. 2017;39(2):322-336.
[29] GOTKINE M, KVIATCOVSKY D, ELINAV E. Amyotrophic lateral sclerosis and intestinal microbiota-toward establishing cause and effect. Gut Microbes. 2020;11(6):1833-1841.
[30] BROWN GC. The endotoxin hypothesis of neurodegeneration. J Neuroinflammation. 2019;16(1):180.
[31] ROTHHAMMER V, MASCANFRONI ID, BUNSE L, et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med. 2016; 22(6):586-597.
[32] MARTIN-GALLAUSIAUX C, MARINELLI L, BLOTTIÈRE H M, et al. SCFA: mechanisms and functional importance in the gut. Proc Nutr Soc. 2021;80(1):37-49.
[33] BODDY SL, GIOVANNELLI I, SASSANI M, et al. The gut microbiome: a key player in the complexity of amyotrophic lateral sclerosis (ALS). BMC Med. 2021;19(1) 13.
[34] KUNDU P, BLACHER E, ELINAV E, et al. Our Gut Microbiome: The Evolving Inner Self. Cell. 2017;171(7):1481-1493.
[35] 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.
[36] FANG X, WANG X, YANG S, et al. Evaluation of the microbial diversity in amyotrophic lateral sclerosis using high-throughput sequencing. Front Microbiol. 2016;7:1479.
[37] PRIBAC M, MOTATAIANU A, ANDONE S, et al. Bridging the gap: harnessing plant bioactive molecules to target gut microbiome dysfunctions in amyotrophic lateral sclerosis. Curr Issues Mol Biol. 2024; 46(5):4471-4488.
[38] ÖZAYDIN AKSUN Z, ERDOĞAN S, KALKANCI A, et al. Is gut microbiota of patients with ALS different from that of healthy individuals? Turk J Med Sci. 2024;54(3): 579-587.
[39] TAKEWAKI D, KIGUCHI Y, MASUOKA H, et al. Tyzzerella nexilis strains enriched in mobile genetic elements are involved in progressive multiple sclerosis. Cell Rep. 2025;44(1):115228.
[40] ZHANG L, ZHUANG Z, ZHANG G, et al. Assessment of bidirectional relationships between 98 genera of the human gut microbiota and amyotrophic lateral sclerosis: a 2-sample Mendelian randomization study. BMC Neurol. 2022; 22(1):8.
[41] MAZZINI L, MOGNA L, DE MARCHI F, et al. Potential Role of Gut Microbiota in ALS Pathogenesis and Possible Novel Therapeutic Strategies. J Clin Gastroenterol. 2018;52 Suppl 1, Proceedings from the 9th Probiotics, Prebiotics and New Foods, Nutraceuticals and Botanicals for Nutrition&Human and Microbiota Health Meeting, held in Rome, Italy from September 10 to 12, 2017:S68-S70.