Campanale Antonella, Siniscalco Dario, Di Marzo Vincenzo
Department of Psychiatry, McGill University, Montreal, QC, H4H 1R2, Canada.
Department of Experimental Medicine, Division of Molecular Biology, Biotechnology and Histology, University of Campania, 80138, Naples, Campania, Italy.
J Biomed Sci. 2025 Jul 2;32(1):60. doi: 10.1186/s12929-025-01145-7.
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.
自闭症谱系障碍（ASD）的特征是肠-脑轴功能紊乱，这会导致行为、精神、代谢和胃肠道症状。有效的ASD治疗方法有限。研究突出了内源性大麻素系统（eCBome）和肠道微生物群（GM）的作用，二者对大脑和肠道功能都至关重要。本综述总结了针对ASD及相关合并症的eCBome-GM-脑轴内治疗靶点的研究。
有证据表明，eCBome介质（如油酰乙醇胺和花生四烯乙醇胺）水平降低以及大麻素1型和2型（CB1和CB2）受体活性改变可能导致ASD症状，使其成为有前景的靶点。用脂肪酸酰胺水解酶（FAAH）抑制剂、瞬时受体电位香草酸受体1和单酰甘油脂肪酶（MAGL）调节eCBome-GM-脑轴可能改善重复、刻板和感觉行为，并减轻社交障碍、抑郁和焦虑。然而，抑制FAAH和MAGL也可能诱发类似注意力缺陷多动障碍（ADHD）的行为，CB1反向激动剂可逆转这种情况。靶向代谢型谷氨酸受体5以增加eCBome介质2-花生四烯酸甘油酯（2-AG）的水平可能有益于与ASD相关的行为。eCBome介质如2-AG、1/2-棕榈酰甘油和棕榈酰乙醇胺也可能有助于管理与ASD和胃肠道相关的症状以及全身炎症。其他值得进一步研究的潜在治疗靶点是与eCBome相关的受体G蛋白偶联受体55和过氧化物酶体增殖物激活受体α和γ，以及环氧合酶-2/前列腺素E2途径，它们可能解决多动和重复行为问题。此外，阿克曼氏菌属和瘤胃球菌属等粘蛋白降解菌属可能改善与ASD相关的胃肠道症状，如过敏和炎症。针对特定梭菌菌株的选择性抗生素可能改善易怒和攻击行为。在伴有ADHD和强迫症的ASD中，治疗可能涉及调节CB1和CB2受体，以及瘤胃球菌科和毛螺菌科等细菌家族。最后，调节普雷沃氏菌属和厌氧原体属等抗炎菌属的丰度，以及与肠道健康相关的分类群（如罗斯氏菌属）也可能具有治疗价值。
eCBome-GM-脑轴是ASD治疗的一个有前景的靶点，值得进一步开展临床和临床前研究。
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