The endocannabinoidome-gut microbiome-brain axis as a novel therapeutic target for autism spectrum disorder.

This review looks at how the gut and brain communicate through a system called the endocannabinoidome, and how this might help treat autism. Researchers found that people with autism often have imbalances in gut bacteria and brain chemicals that affect mood, behavior, and digestion. The review suggests that targeting these systems with specific treatments could help with repetitive behaviors, social difficulties, anxiety, and stomach problems common in autism. However, more research is needed to develop safe and effective treatments.

This comprehensive review examines the endocannabinoidome-gut microbiome-brain axis as a novel therapeutic target for autism spectrum disorder. The authors synthesize research showing that disrupted endocannabinoid signaling and altered gut microbiome composition contribute to ASD symptoms including behavioral, gastrointestinal, and psychiatric manifestations. Key therapeutic targets identified include endocannabinoid mediators (anandamide, 2-AG), cannabinoid receptors (CB1/CB2), and specific bacterial genera. The review highlights potential interventions such as FAAH and MAGL inhibitors for improving repetitive behaviors and social impairments, while noting risks of ADHD-like side effects.

Microbiome interventions targeting specific bacterial strains show promise for addressing gastrointestinal symptoms and inflammation. The authors emphasize this axis represents a promising but understudied therapeutic approach requiring further clinical investigation.

The endocannabinoidome-gut microbiome axis represents a novel therapeutic approach for ASD requiring careful clinical investigation. Potential interventions include endocannabinoid modulators and targeted microbiome therapies, but safety profiles need establishment. The complex interactions suggest personalized treatment approaches may be necessary, particularly for managing comorbid conditions like ADHD and gastrointestinal symptoms.

This is a narrative review without systematic methodology or quality assessment of included studies. No sample size reported as this synthesizes existing research rather than presenting original data. The review does not provide detailed analysis of study quality or strength of evidence for individual claims made.

Autism spectrum disorder (ASD) is characterized by disruption of the gut-brain axis, which leads to behavioral, psychiatric, metabolic and gastrointestinal symptoms. Effective ASD treatments are limited. Research highlights the roles of the endocannabinoidome (eCBome) and gut microbiome (GM), both crucial for brain and gut function. This review summarizes research on therapeutic targets within the eCBome-GM-brain axis for ASD and related comorbidities.

Evidence suggests that reduced levels of eCBome mediators, like oleoylethanolamide and anandamide, and altered cannabinoid type 1 and type 2 (CB1 and CB2) receptors activity may contribute to ASD symptoms, making them promising targets. Modulating the eCBome-GM-brain axis with inhibitors of fatty acid amide hydrolase (FAAH), transient receptor potential vanilloid 1, and monoacylglycerol lipase (MAGL) may improve repetitive, stereotypical, and sensory behaviors, and alleviate sociability impairments, depression and anxiety. However, inhibition of FAAH and MAGL may also induce ADHD-like behaviors, which can be reversed by CB1 inverse agonists. Targeting metabotropic glutamate receptor 5 to increase levels of the eCBome mediator 2-arachidonoylglycerol (2-AG) may benefit ASD-related behaviors. eCBome mediators such as 2-AG, 1/2-palmitoylglycerol and palmitoylethanolamide may also help manage ASD- and GI-related symptoms, and systemic inflammation.

Other potential therapeutic targets that deserve further investigation are eCBome-related receptors G-protein-coupled receptor 55 and peroxisome proliferator-activated receptors-alpha and -gamma, and the cyclooxygenase-2/prostaglandin E2 pathway, which may address hyperactivity and repetitive behaviors. Additionally, mucin-degrading genera like Akkermansia and Ruminococcus may improve ASD-related GI symptoms such as hypersensitivity and inflammation. Selective antibiotics against specific Clostridium strains may improve irritability and aggression. In ASD with ADHD and OCD, treatments may involve modulating the CB1 and CB2 receptor, and bacterial families like Ruminococcaceae and Lachnospiraceae.

Lastly, modulating the abundance of anti-inflammatory genera like Prevotella and Anaeroplasma, and taxa associated with gut health such as Roseburia may also offer therapeutic value. The eCBome-GM-brain axis is a promising target for ASD treatment, meriting further clinical and preclinical research.