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Assessment of bidirectional relationships between 98 genera of the human gut microbiota and amyotrophic lateral sclerosis: a 2-sample Mendelian randomization study
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Abstract
Background: Growing evidence suggests a mutual interaction between gut microbiome alterations and ALS pathogenesis. However, previous studies were susceptible to potential confounding factors and reverse causation bias, likely leading to inconsistent and biased results. Objectives: To decipher the potentially mutual relationship between gut microbiota and ALS, we used a bidirectional two-sample MR approach to examine the associations between the gut microbiome and ALS. Results: Using the inverse variance-weighted method, OTU10032 unclassified Enterobacteriaceae species-level OTU and unclassified Acidaminococcaceae were associated with a higher risk of ALS (per relative abundance: OR, 1.04; 95% CI, 1.01–1.07; P = 0.011 and OR, 1.02; 95% CI, 1.01–1.04; P = 0.009, respectively). Importantly, Gamma-Glu-Phe was showed potential deleterious effects on the risk of ALS (genetically predicted per a 1-standard deviation increase in the level of Gamma-Glu-Phe: OR, 1.96; 95% CI, 1.50–2.55; P = 0.012). Sensitivity analysis of the two candidate genera and metabolites using the MR-Egger and weighted-median methods produced similar estimates, and no horizontal pleiotropy or outliers were observed. Intriguingly, genetically predicted ALS was associated with an increase in the relative abundance of OTU4607_Sutterella (per 1-unit higher log odds: β, 2.23; 95% CI, 1.27–3.18; P = 0.020) and Lactobacillales_ORDER (per 1-unit higher log odds: β, 0.51; 95% CI, 0.09–0.94; P = 0.019). Conclusions: Our findings provide novel evidence supporting the bidirectional relationship between the gut microbiota and ALS. These results may contribute to designing microbiome- and microbiome-dependent metabolite interventions in future ALS clinical trials.
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γ-glutamyl amino acids may be negatively associated with the risk of developing ALS, while γ-glutamyl phenylalanine is a specific risk factor for the disease.
“Additionally, γ-glutamyl amino acids may be negatively associated with the risk of developing ALS, while γ-glutamyl phenylalanine is a specific risk factor for the disease.”
From Modulation of the gut–brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis (2023) · cites this paper as [82]
In a 2022 genome-wide association study of ALS analyzing data from 20,806 patients and 59,804 control individuals, Enterobacteriaceae and unclassified Acidaminococcaceae were found to be associated with a higher risk of ALS.
“The association between gut flora and ALS was revealed in a 2022 genome-wide association study (GWAS) of ALS (82), which analyzed data from 20,806 patients and 59,804 control individuals. Enterobacteriaceae and unclassified Acidaminococcaceae were found to be associated with a higher risk of ALS.”
From Modulation of the gut–brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis (2023) · cites this paper as [82]
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Metadata
- Authors
- Zhang, L., Zhuang, Z., Zhang, G., Huang, T., & Fan, D.
- Affiliations
- Peking University Third Hospital (CN)
- Peking University (CN)
- Corresponding author
- Huang, Tao
- Fan, Dongsheng
- Venue
- BMC Neurology
- Published
- 2022-01-03
- Volume
- 22
- Issue
- 1
- Pages
- 8-8
- ISSN
- 1471-2377 (ISSN-L)
- PMC
- PMC8721912
- OpenAlex
- W4225262245
- Cited by
- 31
- References
- 41
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 11 · 2023: 3 · 2022: 5
- FWCI
- 2.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- BMC Neurology (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81873784, 81030019)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- amyotrophic lateral sclerosis, gut microbiota, bidirectional relationship, Enterobacteriaceae, Sutterella, Lactobacillales, gut-brain axis, microbiome metabolites, ALS risk
- MeSH terms
- Gastrointestinal Microbiome, Amyotrophic Lateral Sclerosis, Humans, Causality, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Mendelian Randomization Analysis
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