The gut microbiota regulates autism-like behavior by mediating vitamin B6 homeostasis in EphB6-deficient mice

Abstract

Background: Autism spectrum disorder (ASD) is a developmental disorder, and the effective pharmacological treatments for the core autistic symptoms are currently limited. Increasing evidence, particularly that from clinical studies on ASD patients, suggests a functional link between the gut microbiota and the development of ASD. However, the mechanisms linking the gut microbiota with brain dysfunctions (gut-brain axis) in ASD have not yet been full elucidated. Due to its genetic mutations and downregulated expression in patients with ASD, EPHB6, which also plays important roles in gut homeostasis, is generally considered a candidate gene for ASD. Nonetheless, the role and mechanism of EPHB6 in regulating the gut microbiota and the development of ASD are unclear. Results: Here, we found that the deletion of EphB6 induced autism-like behavior and disturbed the gut microbiota in mice. More importantly, transplantation of the fecal microbiota from EphB6-deficient mice resulted in autism-like behavior in antibiotic-treated C57BL/6J mice, and transplantation of the fecal microbiota from wild-type mice ameliorated the autism-like behavior in EphB6-deficient mice. At the metabolic level, the disturbed gut microbiota in EphB6-deficient mice led to vitamin B 6 and dopamine defects. At the cellular level, the excitation/inhibition (E/I) balance in the medial prefrontal cortex was regulated by gut microbiota-mediated vitamin B 6 in EphB6-deficient mice. Conclusions: Our study uncovers a key role for the gut microbiota in the regulation of autism-like social behavior by vitamin B 6 , dopamine, and the E/I balance in EphB6-deficient mice, and these findings suggest new strategies for understanding and treating ASD.

Regulation of Neurotransmitters by the Gut Microbiota and Effects on Cognition in Neurological Disorders

“…Deficits in the gut microbial composition and their metabolic contents such as vitamin and neurotransmitters may be involved in the development of autistic-like social behaviors in these autism mice [ 107 ]. Importantly, children with autism showed a significant improvement in autistic and gastrointestinal symptoms after treatment with fecal microbiota transplantation [ 108 ], and these benefits prolong for years as reported in a follow-up study with the same participants [ 109 ].…”

The Dopamine Hypothesis of Autism Spectrum Disorder Revisited: Current Status and Future Prospects

“…Last, in line with the ever-increasing interest of the microbiome as a modulator of social behavior [86], accumulating evidence suggest that gut microbiota is involved in the pathogenesis of ASD [77]. Studies show that microbial degradation products found in individuals with ASD elicit autism-like behaviors in mice, possibly through inducing abnormal dopamine metabolism in key structures such as NAc and PFC [87][88][89][90]. Sgritta et al [91] showed that treatment with Lactobacillus reuteri could rescue the behavioral anomalies through modulation of VTA activity via the oxytocinergic system, whereas Li et al [90] managed to ameliorate social deficits through DRD1 agonism in the PFC of mice with disturbed gut microbiota.…”

Harness the functions of gut microbiome in tumorigenesis for cancer treatment

“…The crosstalk between microbes and host cells is critical for health and regulation of many physiological functions both locally and systemically [ 194 ]. For example, gut microbiota can affect locally regarding the nutrient absorption, vitamin B synthesis [ 195 ], bile acid metabolisms [ 196 ], carbohydrate fermentation [ 197 ], maintenance of barrier integrity [ 55 ], and regulating mucosa immunity [ 198 ] (Figure 6 ). Importantly, the gut microbiota can also systemically impact the host's metabolism, behavioral and cognitive activities [ 199 ], cardiovascular functions [ 200 ], hematopoiesis functions [ 201 ], ageing [ 202 ], inflammation and immunity [ 203 , 204 ], and circadian rhythm [ 205 , 206 ] (Figure 6 ), thereby affecting cancer development and cancer therapeutic efficacy and toxicity [ 140 ].…”