Role of gut microbiota in lead-induced neural damage in diabetic mice.

BACKGROUND: China has the highest incidence of diabetes among all Asian countries, and environmental factors have a significant impact on the onset of diabetes. Lead is one of the important legacy environmental pollutants that disrupts endocrine function. Both lead and diabetes have damaging effects on the nervous system, while the gut microbiota is considered an important mediator of brain damage. AIM: To determine the effects and underlying mechanisms of environmental lead exposure and diabetes on neural function. METHODS: A mouse model of lead exposure and diabetes was used. Lead levels were measured using inductively coupled plasma mass spectrometry, and blood glucose levels were assessed. Immunofluorescence was used to analyze brain damage in mice. The Morris water maze was used for evaluating neural function. Neurotransmitters including vanillylmandelic acid, 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were quantified with high performance liquid chromatography. Proteomics analysis was conducted on hippocampal brain tissue, and gut microbiota analysis was performed on colonic fecal samples. PI3K and COX2 proteins were detected by Western blotting, and then glutathione (GSH) levels in brain tissue were measured. RESULTS: Mice in the lead-exposure diabetic model exhibited significantly elevated lead and blood glucose levels, with the most severe neural damage observed. The neurotransmitters DOPAC and HVA were markedly increased. Proteomics revealed that differential proteins were primarily involved in neural and metabolic pathways. Correlation analysis between the top 20 gut microbiota and differential proteins identified Sutterella as the most associated gut microbe with proteins. The levels of COX2, PI3K, and GSH in the mouse brain provided preliminary validation of these findings. CONCLUSION: The coexistence of lead exposure and diabetes has an interactive effect on neural damage. This interaction appears to affect the abundance of the gut microbe Sutterella, which, through inflammation, influences the expression of related differential proteins in the brain, ultimately resulting in neural damage.