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

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 ApoE3 (common allele)-KI mice. Here, we determined how cadmium interacts with ApoE4 gene variants to modify the gut-liver axis. 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. ApoE4-KI males had the most prominent changes in their gut microbiota, as well as a predicted down-regulation of many essential microbial pathways involved in nutrient and energy homeostasis. In the host liver, cadmium-exposed ApoE4-KI males had the most differentially regulated pathways; specifically, there was enrichment in several pathways involved in platelet activation and drug metabolism. In conclusion, Cd exposure profoundly modified the gut-liver axis in the most susceptible mouse strain to neurological damage namely the ApoE4-KI males, evidenced by an increase in microbial AD biomarkers, reduction in energy supply-related pathways in gut and blood, and an increase in hepatic pathways involved in inflammation and xenobiotic biotransformation.

Acute toxicity, biochemical and transcriptomic analysis of Procambarus clarkii exposed to avermectin

“…CAT decomposes hydrogen peroxide, and SOD catalyzes the dismutation of two superoxide radicals degenerate into molecular oxygen in the antioxidant defense system 47 . The up‐regulation of CAT and SOD activities have also been reported in other aquatic organisms after exposures to pesticides, heavy metals, nanoplastics and other contaminants, 48–52 indicating a universal response of aquatic organisms against environmental pollutants.…”

“…62 A previous study reported that cadmium exposure resulted in the hepatotoxicity of mice through the enrichment of the platelet activation pathway. 51 The Rap1 signaling pathway play key roles in signal transduction. 63 Changes in genes expression profiles were also observed in lambs, mice and human corneal epithelial cells under stress.…”

“…Platelets play an important role in thrombosis, hemostasis, liver homeostasis and directly fuel tumor growth in the liver 62 . A previous study reported that cadmium exposure resulted in the hepatotoxicity of mice through the enrichment of the platelet activation pathway 51 . The Rap1 signaling pathway play key roles in signal transduction 63 .…”

ApoE Mimetic Peptides to Improve the Vicious Cycle of Malnutrition and Enteric Infections by Targeting the Intestinal and Blood-Brain Barriers

“…[125]. This effect was found along with a reduction in IgG/IgA-producing Bacteroide ovatus (decreased serum IgG/IgA have been found among AD patients) and increases in several pro-inflammatory taxa [126].…”

The function of omega-3 polyunsaturated fatty acids in response to cadmium exposure

“…After Cd enters the human body, it can cause damage to a series of important organs such as liver, kidney, bone, brain and lung, as well as nervous system, reproductive system, immune system, and other systems, among which liver and kidney are the most important target organs. It is reported that the toxicity of Cd is obviously time-dependent and concentration-dependent ( 74 – 77 ). The Cd-induced liver injury is mainly due to the competitive replacement of Cd with the metal prosthetic groups in the liver antioxidant enzymes, which inactivates the antioxidant enzymes and reduces the scavenging ability of free radicals, thereby causing cellular lipid peroxidation and oxidative stress ( 78 , 79 ).…”