Multi-omics analyses revealed the effect of fecal microbiota transplantation on alleviating mitochondrial dysfunctions and social deficits in a mouse model of ASD

<strong>Background:</strong> Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder defined by social communication deficiencies and stereotypic behaviors caused by hereditary and environmental risk factors. There are currently no approved medications for treating ASD. Human fecal microbiota transplantation (FMT) can improve autistic symptoms. However, it remains to be determined how the microbiota shift introduced by FMT leads to symptom improvement. <strong>Methods:</strong> Mice were randomely assigned into three groups: B6+Saline, BTBR+Saline, BTBR+FMT. A series of behavior test were performed on mice aftertreatment to determine the effects of FMT. Metagenomics and metabolomic analyses were performed on materials from the mouse feces, the colon contents and the blood plasma, respectively. <strong>Results: </strong>FMT treatment alleviated the sociability index of the BTBR mice. In plasma, the BTBR model displayed a distinct long-chain acylcarnitine profile, suggesting impaired mitochondrial function and fatty acid metabolism. FMT treatment was able to correct such dysfunction and other highly related core functions. Multiple <em>Bacteroides </em>species were involved in the Pyridoxal 5'-phosphate (PLP) biosynthesis I pathway. Prevention against toxicants and PLP biosynthesis were both reported to be associated with mitochondria function, raising the possibility of alleviating ASD and underlying mitochondria dysfunction through modulating vitamin B₆ metabolism and gut barrier integrity. <strong>Conclusions: </strong>These omics data outlined a possible mechanism of FMT centered on mitochondrial function and orchestrated by multiple pathways in alleviating social deficits. Further experiments are required to validate the target of mitochondrial function in addressing autism's social deficiency.