Drosophila E3 Ubiquitin-Protein Ligase TRIP12 Regulates Autism Associated Behaviors Through Modulation of Gut-Brain Axis

Multiple studies have reported various pathogenic mutations in the E3 ubiquitin-protein ligase TRIP12 in individuals affected with autism spectrum disorders (ASD). However, its functional relevance has not been characterized, so far in any model system. Autism spectrum disorders (ASDs) are clinically characterized by the manifestation of either typical or atypical characteristics or both. While typical characteristics include impairment in social interaction and restricted or repetitive behaviors, atypical characteristics include hyperactivity, aggression, high anxiety, feeding problems, and gut associated issues. Here, we report for the first time the role of the Drosophila TRIP12 gene, ctrip, in gut-brain interaction and autism-associated behaviors.Using ctrip mutant and with ctrip knockdown male flies, we first show that ctrip is involved in brain and wing size development, we also report that ctrip mutant flies exhibit gut-microbial (GM) dysbiosis and defects in feeding and many ASD-associated behaviors such as locomotion, anxiety, learning, decision-making, and social interaction skills. We also report the involvement of GM dysbiosis in the gut-immune-brain axis through the involvement of Immunodeficiency (IMD) and Toll pathways and impaired expression of Muc11A and LysD genes in the intestine. Finally, we report that microbial recolonization from healthy control flies to germ-free mutant flies reverses impairment in their locomotion, anxiety, and decision-making skills, but not their social interaction. Impaired social interaction was normalized in germ-free mutant flies, suggesting dysbiosis in ctrip mutant flies’ intestines was responsible for impaired social interaction. This study, therefore, proposes that behavioral impairments in the ASD-like Drosophila model are directly coming from GM dysbiosis, and balancing GM communities through probiotic treatment may be a plausible therapeutic approach in the treatment of behavioral impairments in ASD.