Indole metabolites produced by Lactobacillus acidophilus impedes bisphenol F- aryl hydrocarbon receptor interaction and ameliorates bisphenol F induced depression-like changes

Bisphenol F (BPF), a major bisphenol A substitute widely used in packaging and pharmaceuticals, poses emerging neuropsychiatric risks with unknown mechanisms. Here, we first linked elevated urinary BPF in newly diagnosed depressed patients to human depressive phenotypes. In mice, we found that BPF exposure resulted in depletion of Lactobacillus acidophilus (L. acidophilus) , whose transplantation obviously reversed the depression-like behaviors. With the Multi-omics (16S rRNA sequencing, untargeted/targeted metabolomics) assays, we revealed the two key reduced target metabolites produced by L. acidophilus , indole-3-lactic acid (ILA) and indole-3-acetic acid (IAA). Exogenous supplementation of ILA/IAA strikingly rescued the BPF-induced depressive behaviors. Mechanistically, the molecular docking and microscale thermophoresis results showed that BPF serves as a novel exogenous aryl hydrocarbon receptor (AHR) ligand, competing with ILA/IAA at MET109/LEU110 to activate cytochrome P450 1B1 (CYP1B1) signaling; Critically, knockout of AHR in mice (AHR -/- ) substantially impeded the BPF induced depression like behaviors, CYP1B1 activation and microglia mediated abnormal synaptic pruning. Collectively, the present study uncovers a novel "microbiota-indole metabolite-AHR-CYP1B1" axis mediating BPF-induced depressive changes, supporting targeted interventions (e.g., L.acidophilus ) transplantation, ILA/IAA supplementation, AHR modulation) as potential therapies for neuropsychiatric disorders induced by BPF.