Breaking Gut: intestinal microbes and their modulation as a therapy in ASD.

Abstract

Autism Spectrum Disorder (ASD) is a complex and heterogeneous group of neurodevelopmental disorders characterized primarily by deficit in social communication and repetitive behaviors. The prevalence of ASD has increased over the past years, with approximately 1 in 100 children now diagnosed with the condition. Beyond neurological alterations, gastrointestinal issues are frequently observed in individuals with ASD, significantly affecting their quality of life. These gastrointestinal abnormalities are often associated with the severity of ASD symptoms, suggesting a bidirectional communication between the gut and brain, commonly known as the gut-brain axis. The crosstalk between the gut and the brain involves neural, immune, endocrine, and metabolic pathways, and alterations in these pathways have been observed in various neurodevelopmental disorders. Further, imbalances in gut microbiome are commonly presented in ASD subjects and associated to ASD manifestations, which suggests the relevance of understanding the underlying processes along the gut-brain axis in ASD. This study aims to characterize the intestinal and brain barrier, neuroinflammation and enteric nervous system activation in a humanized mouse model for ASD, by transplanting fecal samples from autistic children and their neurotypical siblings in BTBR mice. Besides that, one probiotic diet (diet 1) and two symbiotic diets (diet 2 and 3) were tested in order to study diet-induced gut microbiota changes in the ASD-like phenotype in BTBR mice. Microbiota transplantation from ASD children led to changes in both the intestine and brain of BTBR mice. Neuroinflammation was observed in the prefrontal cortex (PFC) along with impairments in the integrity of the intestinal epithelium and blood-brain barrier. Notably, diet 1 could reduce the neuroinflammation in the PFC of ASD-transplanted mice as well as improving the integrity of the gut barrier in the ileum. Additionally, diet 3 was able to improve the integrity of the blood-brain barrier in the hippocampal tissue. Taken together, ASD-associated gut microbiota is linked with neuroinflammation, and pro- and symbiotic diets were able to modulate different processes across the gut-brain axis, which highlights their potential as targeted-therapy for ASD.