Genotype-Associated Molecular Phenotypes Across Brain and Gut Compartments in Male 5xFAD Mice: Shared Latent Structure and the Limits of Individual-Level Inference
10 affiliations
- 1Department of Medical Biology, School of Medicine, Bahçeşehir University, Istanbul 34734, Türkiye
- 2Department of Translational Medicine, Graduate School of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye
- 3Department of Biochemistry and Molecular Biology, Graduate School of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye
- 4Acibadem Labmed Clinical Laboratories, Istanbul 34752, Türkiye
- 5Department of Basic Medical Sciences, Faculty of Medicine, Nakhchivan State University, Nakhchivan AZ7012, Azerbaijan
- 6Department of Biostatistics and Medical Informatics, Faculty of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye
- 7Experimental Animals Application and Research Center, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye
- 8Department of Medical Biochemistry, Faculty of Medicine, Nişantaşı University, Istanbul 34398, Türkiye
- 9Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Haliç University, Istanbul 34060, Türkiye
- 10Department of Medical Biochemistry, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye
Abstract
Whether gut and brain molecular states covary within individual animals, rather than merely co-occurring at the group level, has rarely been tested in Alzheimer’s disease models. We profiled the hippocampus, cortex, cerebellum, intestine and feces of 18 male 5xFAD (5 familial AD mutations) (B6SJL background) mice and wild-type littermates at 3, 6 and 9 months by label-free proteomics, and feces additionally by shotgun metagenomics. The hippocampal proteome reproduced the amyloid-associated signature (App, Apoe, Hexb, Clu, Gfap), and protein-set analysis showed elevated microglial, lysosomal, astrocytic and endoplasmic reticulum chaperone proteins in the hippocampus and cortex, with no detectable difference in synaptic or mitochondrial sets. Fecal Shannon diversity was reduced, and the bile-acid-modifying genera Romboutsia and Turicibacter were nearly absent in all 5xFAD animals from 3 months (cage nested within genotype). Multi-omics factor analysis recovered a genotype-associated factor shared across brain and gut views (exact permutation p = 0.00125) that explained at most 6.3% of variance in any view and was preprocessing-dependent. After removal of group structure, correlation burden did not exceed a within-cell permutation null, and neither did same-animal positive controls. The 5xFAD genotype thus alters every compartment examined, and a modest latent structure links them; because the design excludes only strong or dense individual-level coupling, the null result bounds design resolution rather than showing that gut and brain are uncoupled.
Related
- Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts
- Alzheimer’s disease research must connect vascular molecular phenotypes with physiology
- Applications of OptoProfilin in Living Cells for the Imaging of Focal Adhesions and Stress-Associated Phenotypes
- SLC12A7 promotes malignant phenotypes of gastric cancer cells and is associated with Ezrin-related PI3K/AKT signaling
- SLC35D1 Is Associated with Colorectal Cancer Progression, EMT-Related Phenotypes, and Immune Infiltration
BibTeX
@article{sahin2026genotypeassociated,
title = {{Genotype-Associated Molecular Phenotypes Across Brain and Gut Compartments in Male 5xFAD Mice: Shared Latent Structure and the Limits of Individual-Level Inference}},
author = {Betul Sahin and Yunus Eken and Furkan Sahin and Tayyip Karaman and Osman Uğur Sezerman and Samed Ozer and Zelal Zuhal Kaya and Mustafa Zafer Karagözlü and Muhittin Abdulkadir Serdar and Mustafa Serteser and Ahmet Tarık Baykal},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219879},
url = {https://www.mdpi.com/1422-0067/27/21/9879},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Genotype-Associated Molecular Phenotypes Across Brain and Gut Compartments in Male 5xFAD Mice: Shared Latent Structure and the Limits of Individual-Level Inference
AU - Betul Sahin
AU - Yunus Eken
AU - Furkan Sahin
AU - Tayyip Karaman
AU - Osman Uğur Sezerman
AU - Samed Ozer
AU - Zelal Zuhal Kaya
AU - Mustafa Zafer Karagözlü
AU - Muhittin Abdulkadir Serdar
AU - Mustafa Serteser
AU - Ahmet Tarık Baykal
PY - 2026
DA - 2026/11/04
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219879
UR - https://www.mdpi.com/1422-0067/27/21/9879
AB - Whether gut and brain molecular states covary within individual animals, rather than merely co-occurring at the group level, has rarely been tested in Alzheimer’s disease models. We profiled the hippocampus, cortex, cerebellum, intestine and feces of 18 male 5xFAD (5 familial AD mutations) (B6SJL background) mice and wild-type littermates at 3, 6 and 9 months by label-free proteomics, and feces additionally by shotgun metagenomics. The hippocampal proteome reproduced the amyloid-associated signature (App, Apoe, Hexb, Clu, Gfap), and protein-set analysis showed elevated microglial, lysosomal, astrocytic and endoplasmic reticulum chaperone proteins in the hippocampus and cortex, with no detectable difference in synaptic or mitochondrial sets. Fecal Shannon diversity was reduced, and the bile-acid-modifying genera Romboutsia and Turicibacter were nearly absent in all 5xFAD animals from 3 months (cage nested within genotype). Multi-omics factor analysis recovered a genotype-associated factor shared across brain and gut views (exact permutation p = 0.00125) that explained at most 6.3% of variance in any view and was preprocessing-dependent. After removal of group structure, correlation burden did not exceed a within-cell permutation null, and neither did same-animal positive controls. The 5xFAD genotype thus alters every compartment examined, and a modest latent structure links them; because the design excludes only strong or dense individual-level coupling, the null result bounds design resolution rather than showing that gut and brain are uncoupled.
SN - 1422-0067
ER -