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This study identifies Lactobacillus acidophilus LA3 as a potent probiotic strain capable of mitigating neuroinflammation. LA3 demonstrated superior efficacy in suppressing LPS-induced proinflammatory cytokines in BV-2 microglia. In an LPS-induced murine model, LA3 alleviated systemic and neuroinflammation, depressive-like behaviors, and cognitive impairment, while restoring blood-brain and gut-vascular barrier integrity. LA3 reversed gut microbiota dysbiosis, enriched short-chain fatty acid-producing bacteria, and promoted indole-3-acetic acid (IAA) levels in colonic contents and brain. The anti-inflammatory effect of LA3 was AHR-dependent, as confirmed by an AHR inhibitor in BV-2 cells. Notably, both LA3 fermentation supernatant and exogenous IAA (at the same dose as detected in the supernatant) recapitulated key aspects of LA3\u2032s effects. 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