The Relationship Between Gut Microbiota-Related Hippocampal Tryptophan Metabolite and Alzheimer's Disease-Like Neurobehavioral Changes Induced by Chronic Inorganic Arsenic Exposure in Rats.

Arsenic is recognized for its harmful effects on neurodevelopment and cognitive function, and neurodegenerative alterations induced by arsenic exposure may eventually lead to Alzheimer's disease (AD). However, the precise changes in the gut microbiome and tryptophan (Trp) metabolism resulting from arsenic exposure, as well as their role in the "microbiome-tryptophan metabolite-brain axis" in AD, remain poorly understood. In this study, the rats were exposed to arsenic in utero, with continued exposure lasting until 185 days after birth, through free drinking water contaminated with varying concentrations of NaAsO (0, 30 mg/L, and100mg/L). The findings indicated that the arsenic-exposed groups displayed marked neurobehavioral deficits and exhibited typical AD-like pathological alterations. Long-term arsenic exposure led to gut microbiota dysbiosis in the offspring rats, and significant changes were observed in the levels of tryptophan and its metabolites in the hippocampus of the rats. Notably, metabolites within the kynurenine metabolic pathway showed strong correlations with the majority of differential genera in both the control and high arsenic groups. Overall, this study establishes a multimodal association between chronic arsenic exposure, gut microbiota perturbations, tryptophan-kynurenine pathway dysregulation, and AD-like pathology. These findings present a novel perspective for preventing or treating AD.