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

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Aug 19, 2020 version files 111.62 GB

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Abstract

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.