Crosstalk between endocannabinoids and gut microbiota in neurodevelopmental disorders

The microbiota–gut–brain axis plays a key role in the pathogenesis of autism spectrum disorder (ASD), with gut dysbiosis contributing to altered neuroimmune signaling and increased intestinal permeability. Probiotic interventions may exert beneficial effects by modulating the endocannabinoid system (ECS). In this study, three ASD animal models were investigated: a genetic model (Neuroligin-3 R451C knock-in (KI) mice) and two environmental models (maternal immune activation mice, MIA, and prenatal valproic acid exposure rats, VPA). In the genetic model, we evaluated the potential therapeutic effects of two selected food-borne Lactiplantibacillus plantarum (LP) strains using a multidisciplinary approach. Behavioral assessments were followed by analyses of intestinal permeability markers (through qRT-PCR), synaptic proteins (by western blotting), circulating endocannabinoid levels (via UPLC/MS-MS) and their brain receptor transcript expression, and gut microbiota composition (16S rRNA gene sequencing). The potential neurobehavioral therapeutic effects as well as the amelioration of the intestinal integrity due to the same LP treatment was investigated also in the MIA model. In the VPA model, the endogenous content of endocannabinoids and endocannabinoid-related lipids was quantified in medial prefrontal cortex and nucleus accumbens in order to verify the role of ECS. Our results demonstrate that LP strains are capable not only of attenuating behavioral deficits but also of restoring intestinal barrier integrity in both the KI and MIA models. The reduction of endocannabinoid levels in the VPA model supports the hypothesis that core ASD deficits may originate from early dysfunctions in the ECS. Additionally, the treatment with fenofibrate revealed a mitigated social impairment in VPA-exposed rats. These findings open new avenues for the development of both dietary and pharmacological therapies aimed at alleviating the core symptoms of ASD. The translational goal is to formulate functional foods enriched with specific LP strains to integrate into the diet of neurodivergent individuals.