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Published on: October 15, 2019
Causal Associations Between Gut Microbiota, Gut Microbiota-Derived Metabolites, and Alzheimer's Disease: A
Min Ning1, Lina An2, Liang Dong3
1Department of Geriatrics, Shanghai General Hospital, Clinical Medical College of Nanjing Medical University, Shanghai, China.
Background:
Multiple studies have demonstrated that the gut microbiome is closely related to the onset of Alzheimer's disease, but the causal relationship between the gut microbiome and AD, as well as potential mediating factors, have not been fully explored.
Objective:
Our aim is to validate the causal relationship between the gut microbiome and the onset of AD and determine the key mechanism by which the gut microbiome mediates AD through blood metabolites using Mendelian randomization (MR) analysis methods.
Methods:
We first conducted bidirectional and mediating MR analyses using gut microbiota, blood amino acid metabolites, and AD-related single nucleotide polymorphisms as research data. In the analysis process, the inverse variance-weighted average method was mainly used as the primary method, with other methods serving as supplementary evidence.
Results:
Ultimately, we found that six types of gut bacteria and two blood amino acid metabolites have a causal effect on AD. Subsequent mediation analysis proved that decreased glutamine concentration mediates the negative causal effect of Holdemanella bacteria on AD (mediation ratio of 14.5%), and increased serum alanine concentration mediates the positive causal effect of Parabacteroide bacteria on AD (mediation ratio of 9.4%).
Conclusions:
Our study demonstrates the causality of Holdemanella and Parabacteroides bacteria in the onset of AD and suggests that the reduced glutamine and increased alanine serums concentration may be key nodes in mediating this effect.
Insights
The gut microbiome influences Alzheimer's disease (AD) onset. Specific bacteria, Holdemanella and Parabacteroides, causally impact AD, mediated by glutamine and alanine blood metabolites.
Area of Science:
- Microbiome research
- Neurodegenerative diseases
- Metabolomics
Background:
- Emerging evidence links gut microbiome alterations to Alzheimer's disease (AD) pathogenesis.
- The precise causal pathways and mediating factors between the gut microbiome and AD remain incompletely understood.
Purpose of the Study:
- To establish the causal relationship between gut microbial composition and AD onset.
- To identify key blood metabolites that mediate the gut microbiome's influence on AD.
Main Methods:
- Utilized Mendelian randomization (MR) analysis, including bidirectional and mediation analyses.
- Employed gut microbiota, blood amino acid metabolites, and AD-associated single nucleotide polymorphisms.
- Primarily used the inverse variance-weighted average method, supplemented by other MR techniques.
Main Results:
- Identified six bacterial species and two blood amino acid metabolites with a causal effect on AD.
- Demonstrated that decreased glutamine mediates Holdemanella's negative causal effect on AD (14.5% mediation).
- Showed that increased serum alanine mediates Parabacteroides' positive causal effect on AD (9.4% mediation).
Conclusions:
- Confirmed the causal roles of Holdemanella and Parabacteroides bacteria in AD development.
- Highlighted reduced glutamine and increased alanine serum concentrations as critical mediating factors in the gut-brain axis for AD.
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