Crosstalk between endocannabinoids and gut microbiota in neurodevelopmental disorders

One of the major modulators among the signaling pathways involved in the microbiota–gut–brain axis (MGBA) is the Endocannabinoid System (ECS), whose main components and functions are presented in Chapter 1. The MGBA plays a key role in the pathogenesis of Autism Spectrum Disorder (ASD), with gut dysbiosis contributing to altered neuroimmune signaling and increased intestinal permeability, described in Chapter 2. Probiotic interventions may exert beneficial effects by modulating the ECS. Chapter 3 details the genetic, environmental and idiopathic ASD murine models that are largely used in research to understand the neurobiological aspects of ASD and to test potential therapies In this thesis, three ASD animal models were investigated: a genetic model (Neuroligin-3 R451C knock-in (KI) mice) and two environmental models (pre- and post- natal immune activation mice, and prenatal valproic acid exposure rats, VPA). In Chapter 5, we evaluated the potential therapeutic effects of two selected food-borne Lactiplantibacillus plantarum (Lpb.) strains in the genetic model by 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 UHPLC/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 Lpb. plantarum treatment was investigated also in the MIA model, as shown in Chapter 6. Lastly, Chapter 7 outlines social Anedhonia in ASD throught the ECS in rats prenatally exposed to VPA and treated with fenofibrate. Our results demonstrate that Lpb. strains are capable not only of attenuating behavioral deficits but also of restoring intestinal barrier integrity in both the KI and pre- and post- natal immune activation 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 intervention, through formulation of functional foods enriched with specific Lpb. plantarum strains, and pharmacological therapies aimed at alleviating the core symptoms of ASD.