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• Gut microbiota contributes to the cognitive deficits induced by chronic T. gondii infection. • Gut microbiota is a vital player in the impairment of synaptic ultrastructure and cognitive function induced by T. gondii infection. • T. gondii chronic infection induces significant depletion of butyrate-producing bacterial species and decrease of serum butyrate levels. • Dietary butyrate supplementation significantly prevents cognitive decline induced by T. gondii infection. • Manipulation of gut microbiota may represent a promising prophylactic strategy against T. gondii -associated neurodegerative diseases. • Butyrate is a potential metabolite for treating T. gondii -mediated cognitive impairment. Chronic infection with Toxoplasma gondii (T. gondii) emerges as a risk factor for neurodegenerative diseases in animals and humans. However, the underlying mechanisms are largely unknown. We aimed to investigate whether gut microbiota and its metabolites play a role in T. gondii -induced cognitive deficits. We found that T. gondii infection induced cognitive deficits in mice, which was characterized by synaptic ultrastructure impairment and neuroinflammation in the hippocampus. Moreover, the infection led to gut microbiota dysbiosis, barrier integrity impairment, and inflammation in the colon. Interestingly, broad-spectrum antibiotic ablation of gut microbiota attenuated the adverse effects of the parasitic infection on the cognitive function in mice; cognitive deficits and hippocampal pathological changes were transferred from the infected mice to control mice by fecal microbiota transplantation. In addition, the abundance of butyrate-producing bacteria and the production of serum butyrate were decreased in infected mice. Interestingly, dietary supplementation of butyrate ameliorated T. gondii -induced cognitive impairment in mice. Notably, compared to the healthy controls, decreased butyrate production was observed in the serum of human subjects with high levels of anti- T. gondii IgG. Overall, this study demonstrates that gut microbiota is a key regulator of T. gondii -induced cognitive impairment. [ABSTRACT FROM AUTHOR]