Parental Gut Microbiota Dysbiosis Drives Transgenerational DNA Methylation Transmission and Autism-like Behaviors in Offspring

Abstract

Abstract Background Autism spectrum disorder (ASD) presents a complex neurodevelopmental disorder whose origins remain elusive. Emerging research underscores the potential impact of parental environmental exposures on ASD risk in offspring. While the interplay between the "microbiota-gut-brain axis" and epigenetics is increasingly acknowledged in ASD pathogenesis, their comprehensive effects and regulatory mechanisms have not yet been fully revealed. Our hypothesis posits that parental dysbiosis in gut microbiota may engender transgenerational transmission of DNA methylation abnormalities to offspring, consequently modulating their gut microbiota composition, gene expression profiles, and metabolites levels through the "microbiota-gut-brain axis". This multifaceted interplay potentially triggers ASD-like behaviors. Results We conducted fecal microbiota transplantations (FMT) from human donors diagnosed with ASD or typically developing (TD) controls into antibiotic-treated mice, revealing that colonization with ASD microbiota triggered distinct autistic-like behaviors in both male and female offspring. These offspring exhibited pathological changes in both the brain and intestines, alongside significant alterations in their gut microbiota, serum metabolome, and brain transcriptome. Notably, colonization with ASD microbiota induced changes in methylation levels of ASD-related genes in parental mice, with some methylation sites being transmitted transgenerationally to the offspring. Employing a multi-omics sequential mediation network, we elucidated potential mechanisms underlying behavioral differences in mice across genders. Conclusions Our findings delineate a link between parental gut microbiota dysbiosis, transgenerational DNA methylation, and the emergence of ASD-like traits, uncovering an epigenetic basis for the clinical observation that parents of children with ASD are typically asymptomatic.