Zebrafish (Danio rerio) as a translational model for neuro-immune interactions in the enteric nervous system in autism spectrum disorders

Autism spectrum disorders (ASD) affect about 1% of the population and are strongly associated with gastroin-testinal diseases creating shortcomings in quality of life. Multiple factors contribute to the development of ASD and although neurodevelopmental deficits are central, the pathogenesis of the condition is complex and the high prevalence of intestinal disorders is poorly understood. In agreement with the prominent research establishing clear bidirectional interactions between the gut and the brain, several studies have made it evident that such a relation also exists in ASD. Thus, dysregulation of the gut microbiota and gut barrier integrity may play an important role in ASD. However, only limited research has investigated how the enteric nervous system (ENS) and intestinal mucosal immune factors may impact on the development of ASD-related intestinal disorders. This review focuses on the mechanistic studies that elucidate the regulation and interactions between enteric immune cells, residing gut microbiota and the ENS in models of ASD. Especially the multifaceted properties and appli-cability of zebrafish (Danio rerio) for the study of ASD pathogenesis are assessed in comparison to studies con-ducted in rodent models and humans. Advances in molecular techniques and in vivo imaging, combined with genetic manipulation and generation of germ-free animals in a controlled environment, appear to make zebrafish an underestimated model of choice for the study of ASD. Finally, we establish the research gaps that remain to be explored to further our understanding of the complexity of ASD pathogenesis and associated mechanisms that may lead to intestinal disorders.

Automated summary

Autism spectrum disorders (ASD), affecting about 1% of the population, are strongly associated with gastrointestinal diseases, leading to deficits in quality of life. The development of ASD involves multiple factors, and dysregulation of gut microbiota and gut barrier integrity may play a crucial role. However, limited research has investigated the impact of the enteric nervous system (ENS) and intestinal mucosal immune factors on ASD-related intestinal disorders. This review assesses the regulation and interactions among enteric immune cells, gut microbiota, and ENS in ASD models, and highlights the potential of zebrafish as a valuable model for studying ASD pathogenesis.