bioRxiv : the preprint server for biologyNov 24, 2025

Personalized whole-body models connect gut bacteria to metabolism changes in Alzheimer's disease

Gut-Brain Axis Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 4, 2026

Abstract

Altered gut microbiomes in 34 Alzheimer's disease patients are linked to increased production of specific blood metabolites.

AD dementia patients show elevated levels of S-adenosyl-L-methionine, L-arginine, creatine, taurine, and formate in their blood.
Personalized metabolic models were created using gut microbiome data from AD patients, individuals with mild cognitive impairments, and healthy controls.
Increased abundances of certain gut microbes were identified as key factors driving metabolic changes in AD.
Predicted alterations in blood metabolites were also linked to genetic variations in the APOE risk gene in healthy individuals.
The findings suggest a potential role of gut microbiota in influencing metabolic dysfunction associated with Alzheimer's disease.

Simplified

The human gut microbiome has been linked to metabolic disturbances in Alzheimer's disease (AD). However, the mechanisms by which gut microbes might influence metabolic dysfunction in AD remain poorly understood. Previously, we used constraint-based metabolic modelling to associate an increased risk of AD with altered production of microbiome-derived metabolites. In this study, we investigated whether these previous results can also be identified in AD patients. Therefore, we created personalised whole-body metabolic models from gut metagenomics samples from 34 AD dementia patients, 51 individuals with mild cognitive impairments, and 298 healthy controls. Thesemodels were profiled to predict the metabolic influences of gut microbiomes on blood metabolites with previously reported alterations in AD. We found an increased capacity of AD host-microbiome co-metabolism to produce S-adenosyl-L-methionine, L-arginine, creatine, taurine, and formate in the blood of AD dementia patients and patients with mild cognitive impairments. The metabolic predictions were then mechanistically linked to gut microbial changes in AD. This analysis identified that increased relative abundances ofandwere key factors driving the predicted metabolic changes. Furthermore, the predicted altered microbial influences on blood metabolites were also associated with allelic variations in therisk gene in healthy individuals, which confirmed our previous findings. In conclusion, we identified blood metabolites whose perturbations in AD may be influenced by gut microbiota and predicted the key microbial drivers for these metabolic influences. These findings may facilitate the development of microbiome-informed treatments of AD. in silico Bacteroides uniformis Bacteroides thetaiotamicron APOE

Funding

Competing interests

9 Conflict of interest statement Dr. Kaddurah-Daouk is an inventor of a series of patents on the use of metabolomics for the diagnosis and treatment of central nervous system (CNS) diseases and holds equity in Metabolon Inc. and Chymia LLC. Dr. Rob Knight is a scientific advisory board member and consultant for BiomeSense, Inc., has equity, and receives income. He is a scientific advisory board member and has equity in GenCirq. He is a consultant and scientific advisory board member for DayTwo and receives income. He has equity in and acts as a consultant for Cybele. He is a co-founder of Biota, Inc., and has equity. He is a co-founder of Micronoma and has equity and is a scientific advisory board member. The terms of these arrangements have been reviewed and approved by the University of California, San Diego, in accordance with its conflict of interest policies. Daniel McDonald is a consultant for BiomeSense, Inc., has equity, and receives income. The terms of these arrangements have been reviewed and approved by the University of California, San Diego, in accordance with its conflict of interest policies. All other authors have no conflicts of interest to disclose beyond those listed.

PubMed

Personalized whole-body models connect gut bacteria to metabolism changes in Alzheimer's disease

Abstract

Funding

Competing interests

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