Bile acid metabolism is altered in learning and memory impairment induced by chronic lead exposure

Lead is a neurotoxic contaminant that exists widely in the environment. Although lead neurotoxicity has been found to be tightly linked to gut microbiota disturbance, the effect of host metabolic disorders caused by gut microbiota disturbance on lead neurotoxicity has not been investigated. In this work, the results of new object recognition tests and Morris water maze tests showed that chronic low-dose lead exposure caused learning and memory dysfunction in mice. The results of 16 S rRNA sequencing of cecal contents and fecal microbiota transplantation showed that the neurotoxicity of lead could be transmitted through gut microbiota. The results of untargeted metabolomics and bile acid targeted metabolism analysis showed that the serum bile acid metabolism profile of lead-exposed mice was significantly changed. In addition, supplementation with TUDCA or INT-777 significantly alleviated chronic lead exposure-induced learning and memory impairment, primarily through inhibition of the NLRP3 inflammasome in the hippocampus to relieve neuroinflammation. In conclusion, our findings suggested that dysregulation of host bile acid metabolism may be one of the mechanisms of lead-induced neurotoxicity, and supplementation of specific bile acids may be a possible therapeutic strategy for lead-induced neurotoxicity. There are many environmental sources of lead exposure, such as lead pollution in soil, water and indoor air. Therefore, low levels of lead exposure remain a serious threat to public health. Lead is a neurotoxic metal, and learning and memory impairment is a typical neurotoxic manifestation caused by lead exposure. The role of gut microbiota related host metabolism in lead neurotoxicity has also not been elucidated. Here, we find the role of gut microbiota associated host bile acid metabolism in the neurotoxicity of low dose lead exposure, which contributes to understanding the effects and mechanisms of lead exposure.