Causal Associations Between Gut Microbiota, Gut Microbiota-Derived Metabolites, and Alzheimer’s Disease: A Multivariable Mendelian Randomization Study

Article type: Research Article

Authors: Ning, Min^{a; 1} | An, Lina^{b; 1} | Dong, Liang^{c; 1} | Zhu, Ranran^b | Hao, Jingjing^b | Liu, Xueyuan^{d; *} | Zhang, Yuanyuan^{e; *}

Affiliations: [a] Department of Geriatrics, Shanghai General Hospital, Clinical Medical College of Nanjing Medical University, Shanghai, China | [b] Department of Geriatrics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China | [c] Department of Spine Surgery, Hong Hui Hospital, Xi’an Jiaotong University School of Medicine, Xi’an, Shaanxi, China | [d] Department of Neurology, Shanghai Tenth People’s Hospital, Clinical Medical College of Nanjing Medical University, Shanghai, China | [e] Department of Cardiovascular Medicine, Hong Hui Hospital, Xi’an Jiaotong University School of Medicine, Xi’an, Shaanxi, China

Correspondence: [*] Correspondence to: Yuanyuan Zhang, Department of Cardiovascular Medicine, Hong Hui Hospital, Xi’an Jiaotong University School of Medicine, Xi’an, Shaanxi, China. E-mail: [email protected] and Xueyuan Liu, Department of Neurology, Shanghai Tenth People’s Hospital, Clinical Medical College of Nanjing Medical University, 301 Yan chang Middle Road, Shanghai, 200072, China. E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: 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.

Keywords: Alzheimer’s disease, gut microbiome, Mendelian randomization, metabolites

DOI: 10.3233/JAD-240082

Journal: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 229-237, 2024