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bioRxiv · 10.1101/2025.10.28.685084

Personalised whole-body modelling links gut microbiota to metabolic perturbations in Alzheimer's disease

Hensen, T.·Khatib, L.·Patel, L.·McDonald, D.·Gonzalez, A.·Mahmoudiandehkordi, S.·Blach, C.·Alzheimer Gut Microbiome Project Consortium,·Knight, R.·Kaddurah-Daouk, R.·Thiele, I.
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Abstract

The human gut microbiome has been linked to metabolic disturbances in Alzheimers 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. These in silico models 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 of Bacteroides uniformis and Bacteroides thetaiotamicron were key factors driving the predicted metabolic changes. Furthermore, the predicted altered microbial influences on blood metabolites were also associated with allelic variations in the APOE risk 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.

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Hensen, T., Khatib, L., Patel, L., McDonald, D., Gonzalez, A., Mahmoudiandehkordi, S., Blach, C., Alzheimer Gut Microbiome Project Consortium,, Knight, R., Kaddurah-Daouk, R., Thiele, I.. 2025-10-29. Personalised whole-body modelling links gut microbiota to metabolic perturbations in Alzheimer's disease. https://doi.org/10.1101/2025.10.28.685084

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