Cadmium exposure persistently modulates the gut-liver axis in an Alzheimer’s disease mouse model

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.