Gut-liver axis through microbiota-metabolite interplay driving age-dependent susceptibility to arsenite-induced liver injury in mice

Arsenic is a highly toxic metalloid that contributes to many chronic diseases. The liver is a primary target organ because it mediates detoxification and metabolism. However, the differences in susceptibility to age-related arsenic-induced liver injury and their underlying mechanisms remain unclear, particularly regarding the involvement of the gut-liver axis. Young, adult, and old mice ingested arsenic via drinking water. We assessed glucose metabolism, liver injury, and intestinal barrier integrity. To investigate the role of the gut microbiota, we performed metagenomic sequencing on fecal samples. Liver metabolic changes and signaling pathways were analyzed using non-targeted metabolomics and transcriptomics technologies, respectively. This study reveals that aged mice exhibit heightened susceptibility to arsenite-induced liver injury and metabolic disorders. Histological examination and reduced occludin expression confirm this is associated with impaired intestinal barrier function. Metagenomic analysis indicated that arsenite exposure was associated with gut microbiota remodeling in aged mice, characterized primarily by genus-level alterations, including reduced Muribaculaceae-related genera and relative enrichment of genera associated with altered mucosal homeostasis and inflammatory signaling. Metagenomic pathway analysis further suggested shifts in microbial metabolic and inflammatory signaling-related pathways, including changes in insulin/glucagon signaling, glycerolipid metabolism, and NOD-like receptor signaling. Metabolomics detection revealed significant accumulation of uridine diphosphate glucose (UDPG) in the livers of arsenite-exposed aged mice. Transcriptomic analysis revealed upregulation of the mitogen-activated protein kinase (MAPK) signaling pathway, while western blotting confirmed its activation in the liver. These findings suggest that aging is associated with increased susceptibility to arsenite-induced liver injury, potentially involving gut microbiota remodeling, intestinal barrier dysfunction, and hepatic UDPG accumulation. UDPG may function as a metabolic stress-associated factor or potential amplifier of MAPK-related inflammatory signaling, thereby potentially contributing to liver injury. Consequently, a novel gut-liver axis mechanism is revealed, elucidating the intrinsic link between aging and susceptibility to environmentally induced toxic diseases.