Ketogenic diet ameliorates autism spectrum disorders-like behaviors via reduced inflammatory factors and microbiota remodeling in BTBR T+Itpr3tf/J mice

Autism Spectrum Disorder (ASD) is increasing, but its complete etiology is still lacking. Recently, application ofketogenic diet (KD) has shown to reduce abnormal behaviors while improving psychological/sociological statusin neurodegenerative diseases. However, KD role on ASD and underlying mechanism remains unknown. In thiswork, KD administered to BTBR T+ Itpr3tf/J (BTBR) and C57BL/6J (C57) mice reduced social deficits (p =0.002), repetitive behaviors (p <0.001) and memory impairments (p =0.001) in BTBR. Behavioral effects wererelated to reduced expression levels of tumor necrosis factor alpha, interleukin-1?, and interleukin-6 in theplasma (p =0.007; p <0.001 and p =0.023, respectively), prefrontal cortex (p =0.006; p =0.04 and p =0.03)and hippocampus (p =0.02; p =0.09 and p =0.03). Moreover, KD accounted for reduced oxidative stress bychanging lipid peroxidation levels and superoxide dismutase activity in BTBR brain areas. Interestingly, KDincreased relative abundances of putatively beneficial microbiota (Akkermansia and Blautia) in BTBR and C57mice while reversing the increase of Lactobacillus in BTBR feces. Overall, our findings suggest that KD has amultifunctional role since it improved inflammatory plus oxidative stress levels together with remodeling gut-brain axis. Hence, KD may turn out be a valuable therapeutic approach for ameliorating ASD-like conditionseven though more evidence is required to evaluate its effectiveness especially on a long term.