Soy isoflavones mitigate atrazine-induced dopaminergic neuron damage via reshaping short-chain fatty acid-producing bacteria in gut microbiota and modulating the GPR43/GLP-1/GLP-1R axis.

Atrazine (ATR), a widely used herbicide, is linked to dopaminergic neurotoxicity and persistent gut microbiota dysbiosis after early life exposure. However, whether the gut microbiota mediates ATR-induced loss of dopaminergic neurons remains unclear. Mice were exposed to ATR from juvenility (4 week) until adulthood (12 week), after which exposure ceased until the 20 week. The role of gut microbiota was confirmed through fecal microbiota transplantation (FMT), which was classified into different groups based on the donor's ATR treatment status. 16S rRNA sequencing revealed that Akkermansia, which exhibited significant differences across FMT groups, is a classic short-chain fatty acid (SCFA)-producing bacteria. FMT recipients receiving ATR-donor microbiota exhibited reduced colonic G Protein-Coupled Receptor 43 (GPR43), serum Glucagon-like Peptide-1 (GLP-1), and substantia nigra Glucagon-like Peptide-1 receptor (GLP-1R)/Tyrosine hydroxylase (TH) levels. Soy isoflavones (SIF), selected for their dual prebiotic and neuroprotective effects, attenuated ATR-induced dopaminergic neurotoxicity by enriching SCFA-producing gut microbiota and the level of SCFAs, thereby activating the GPR43/GLP-1/GLP-1R axis and reducing neuronal loss. These findings demonstrate the critical role of gut microbiota in ATR-induced dopaminergic neurodegeneration, positioning SIF-mediated microbiota modulation as a promising therapeutic approach within the "food-medicine homology" framework.