<p>Recently, modulation of gut microbiota by probiotics treatment has emerged as a promising strategy for treatment of metabolic disorders. In this regarding, <i>Parabacteroides distasonis</i> (<i>P. distasonis</i>) has been shown to play a beneficial role in the treatment of different diseases and also been considered as potential probiotic, but nevertheless, its beneficial effect on central nervous system (CNS) disorders remains to be elucidated. In this study, we demonstrate that treatment with <i>P. distasonis</i> improves high-fat diet (HFD)-induced insulin resistance (IR) and decreases systemic oxidative stress. We further demonstrate that <i>P. distasonis</i> can alleviate HFD-induced brain barrier disruption and neuroinflammation, which was observed to be associated with increased HFD-induced systemic oxidative stress. Additionally, <i>P. distasonis</i> treatment significantly reversed HFD-induced abnormal proliferation and activation of astrocytes and microglia, and their interactions. The improved astrocyte-microglia networks may further contribute to inhibiting HFD-induced excessive synaptic pruning. Our findings suggest that <i>P. distasonis</i> plays a beneficial role in alleviating HFD-induced brain injury and provide possible explanations of how <i>P. distasonis</i> protects against HFD-induced brain injury, identifying the potential probiotic <i>P. distasonis</i> as a potential intervention in CNS disorders.</p><p></p>