Lactobacillus plantarum enhances cognition through acetate-modulated microglia function

Gut microbiota profoundly influences cognition through immune and metabolic pathways, but how specific strains contribute to these processes remain unclear. Here, we show that supplementation with Lactobacillus plantarum C067 enhanced spatial and fear-associated memory, while restoring hippocampal cytokine expression and microglial morphology in both healthy and antibiotic-treated mice. L. plantarum also reshaped microbial composition and elevated short-chain fatty acids, particularly acetate. Acetate supplementation replicated the cognitive benefits and restored microglial homeostasis. Mechanistically, acetate exerted anti-inflammatory effects via Acetyl-CoA synthetase 2 (ACSS2)-dependent acetyl-CoA production in microglia, reducing mitochondrial oxidative stress and cytokine release. Together, these findings identify an ACSS2-mediated microbe-metabolite-microglia axis that underlies the cognitive benefits of L. plantarum, providing a mechanistic framework for probiotic- and metabolite-based interventions against cognitive decline.