10.5061/DRYAD.W3R2280NJ
Zhang, Angela
0000-0002-4573-0715
University of Washington
Matsushita, Megumi
0000-0002-6874-0836
University of Washington
Xia, Zhengui
University of Washington
Zhang, Liang
University of Washington
Shi, Xiaojian
Arizona State University
Gui, Haiwei
Arizona State University
Cui, Julia Yue
University of Washington
Cadmium exposure persistently modulates the gut-liver axis in an
Alzheimer’s disease mouse model
Dryad
dataset
2020
National Institute of Environmental Health Sciences
https://ror.org/00j4k1h63
R01 ES025708
National Institute of Environmental Health Sciences
https://ror.org/00j4k1h63
R01 ES030197
National Institute of Environmental Health Sciences
https://ror.org/00j4k1h63
R01 ES026591
National Institute of Environmental Health Sciences
https://ror.org/00j4k1h63
T32 ES015459
National Institute of Environmental Health Sciences
https://ror.org/00j4k1h63
P30 ES007033
National Institute of Environmental Health Sciences
https://ror.org/00j4k1h63
T32 ES007032
National Institute of Environmental Health Sciences
https://ror.org/00j4k1h63
P42 ES004696
University of Washington
https://ror.org/00cvxb145
Sheldon Murphy Endowment
2020-08-19T00:00:00Z
2020-08-19T00:00:00Z
en
111620235766 bytes
15
CC0 1.0 Universal (CC0 1.0) Public Domain Dedication
The human Apolipoprotein E4 (ApoE4) variant is the strongest known genetic
risk factor for Alzheimer’s disease (AD). Cadmium (Cd) has been shown to
impair learning and memory at a greater extent in humanized ApoE4 knock-in
(ApoE4-KI) mice as compared to the ApoE3 (common allele)-KI mice. In this
study, we determined the extent that cadmium interacts with the ApoE4 gene
variants to modify the gut-liver axis, which is important for xenobiotic
biotransformation and nutrient homeostasis. Large intestinal content
bacterial 16S rDNA sequencing, serum lipid metabolomics, and hepatic
transcriptomics were analyzed in ApoE3- and ApoE4-KI mice orally exposed
to vehicle, a low dose, or a high dose of Cd in drinking water. Aligning
with the previous report showing that the ApoE4-KI males are more
susceptible to cadmium-induced memory deficit, ApoE4-KI males had the most
prominent changes in gut microbiota, including an up-regulation of A.
muciniciphila, which is a biomarker for AD in humans, as well as predicted
down-regulation of many essential microbial pathways involved in nutrient
and energy homeostasis. Serum lactate was lower only in ApoE4-KI males
following Cd exposure. In the host liver, cadmium-exposed ApoE4-KI males
had the most differentially regulated pathways; specifically there was an
enrichment in several pathways involved in platelet activation, which is
known to amplify liver damage and inflammation. These pathways were
associated with up-regulated Prevotella and A. muciniphila in intestine at
the Cd low dose. Cadmium-exposed ApoE4-KI mice also had the most
differentially regulated hepatic drug processing genes, and in particular,
the up-regulation of Cyp2 family, Ugts, Gsts, and Slco1b2 in liver
associated with the up-regulation of Clostridiaceae in the intestine at
the Cd high dose. In conclusion, Cd exposure profoundly modified the
gut-liver axis in the most susceptible mouse strain to neurological
damage, (ApoE4-KI males) evidenced by up-regulation in microbial AD
biomarkers, reduction in energy supply-related pathways in gut and blood,
and up-regulation in hepatic pathways involved in inflammation and
xenobiotic biotransformation.
Total DNA was isolated from the large intestinal content of male and
female ApoE3-KI and ApoE4-KI mice (n=4-5). Briefly, samples were prepared
using an E.Z.N.A. DNA Stool Kit (Omega Bio-tek Inc., Norcross, GA) per the
manufacturer’s instructions. The V4 hypervariable region of 16S rDNA was
amplified and sequenced using a HiSeq 2500 second generation sequencing
platform (250-bp paired-end) (Novogene Corporation Inc., Sacramento, CA).
Total RNA was isolated from livers of Cd or vehicle exposed ApoE3-KI and
ApoE4-KI mice (n=4 per exposure per sex) using RNA zol Bee reagent
(Tel-Test Inc., Friendswood, TX). cDNA libraries were prepared using a
Clontech cDNA library prep kit (Clontech Laboratories Inc., Mountain View
CA), and were sequenced using a NextSeq 500 sequencing platform (75 bp
paired end).