Pretorius L, Coetzee J A, Santos A P Dos, Smith C
Experimental Medicine Group, Dept Medicine, Stellenbosch University, Parow, South Africa.
Mol Med. 2025 May 20;31(1):198. doi: 10.1186/s10020-025-01232-3.
Autism spectrum disorder (ASD) affects approximately 1% of the population directly, but also a much higher proportion (family and caregivers) indirectly. Although ASD is characterized by high prevalence of anxiety and poor gastrointestinal health, current treatment strategies are mainly focused on neurological symptomatic treatment, with little to no attention to gut health. Furthermore, many psychiatric drugs used for management of secondary neurological symptoms, are known to exacerbate gut health issues and neurological dysregulation across the gut-brain axis.Trace amines are neurotransmitter-like substances synthesized endogenously in the human brain - in trace amounts - but also in high abundance by the microbiome. Emerging evidence suggests dysregulation of the trace amine system in ASD. Since trace aminergic signalling is central to regulatory system homeostasis, we hypothesize targeting this system in the ASD context. Given the various sources of trace amines, we suggest that normalization of functional dysbiosis in terms of trace aminergic signalling - rather than microbial compositional dysbiosis - should be a focus in medicines development. In addition, a holistic consideration including also other factors at play in determining trace aminergic signalling outcome - such as receptor binding, enzymatic role players, etc. - is required to fully elucidate and therapeutically modify the pathophysiology of regulatory systems implicated in ASD.This review firstly provides a brief overview of trace amine dysregulation in ASD for context. Secondly, we formulate our hypothesis on how this may therapeutically address symptomology, with consideration of cellular and molecular mechanism interplay across the gut-brain axis. Finally, we provide a critical assessment of advances in therapeutics development and drug re-purposing, gaps in knowledge and priorities for medicines development going forward.
自闭症谱系障碍（ASD）直接影响约1%的人口，但间接影响的比例（家庭和照顾者）要高得多。尽管ASD的特点是焦虑患病率高和胃肠道健康状况差，但目前的治疗策略主要集中在神经症状治疗上，很少或根本不关注肠道健康。此外，许多用于治疗继发性神经症状的精神药物已知会加剧肠道健康问题以及肠道-脑轴上的神经调节紊乱。痕量胺是在人脑中内源性合成的类似神经递质的物质——含量微量——但微生物群也能大量合成。新出现的证据表明ASD中痕量胺系统失调。由于痕量胺能信号传导是调节系统稳态的核心，我们假设在ASD背景下针对该系统。鉴于痕量胺的各种来源，我们建议在药物开发中应关注痕量胺能信号传导方面功能性生态失调的正常化——而不是微生物组成生态失调。此外，需要全面考虑包括在确定痕量胺能信号传导结果中起作用的其他因素——如受体结合、酶促作用因子等——以充分阐明并治疗性改变与ASD相关的调节系统的病理生理学。本综述首先简要概述ASD中痕量胺失调的情况以作背景介绍。其次，我们提出关于如何通过治疗解决症状的假设，同时考虑肠道-脑轴上细胞和分子机制的相互作用。最后，我们对治疗学发展和药物重新利用方面的进展、知识空白以及未来药物开发的重点进行批判性评估。
