Yu You, Wang Yujing, Zhang Jie, Li Shucheng, Wang Yulin, You Xin, Chen Xue, Du Mengxuan, Xie Lisheng, Liu Shuang-Jiang
State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
State Key Laboratory of Biopharmaceutical Preparation and Delivery, Chinese Academy of Sciences, Beijing, China.
Front Microbiol. 2025 Aug 22;16:1640149. doi: 10.3389/fmicb.2025.1640149. eCollection 2025.
Autism spectrum disorders (ASD), a group of neurodevelopmental disorders characterized by the core symptoms of impaired social communication and stereotyped behaviors, is strongly associated with dysregulated microbiota-gut-brain axis. Emerging evidence suggests that , which showed reduced abundance in ASD cohorts, holds therapeutic potential, though its interaction with host remain unexplored. Here, we investigated the efficacy and molecular basis of 4P-15 (4P-15) in BTBR /J (BTBR) mice, an idiopathic ASD mouse model. Oral administration of 4P-15 significantly reduced the intestinal levels of indole, indole-3-propionic acid (IPA), and indole-3-acetic acid (IAA), as well as the level of IPA in brain. Furthermore, the decreased levels of IPA in brain contributed to the attenuated aryl hydrocarbon receptor (AhR) signaling characterized by increased expression of downstream elements, including glutamate transporters and GABA receptors. Ultimately, this modulation led to the restoration of excitatory/inhibitory imbalance, a typical pathophysiological feature of ASD, and thereby alleviated ASD core behavioral symptoms. Our findings underscore -mediated AhR modulation as a promising therapeutic strategy for ASD, highlighting the dual potential of -based probiotics and targeted interventions against indole-AhR signaling to address neurodevelopmental disorders.
自闭症谱系障碍（ASD）是一组以社交沟通受损和刻板行为为核心症状的神经发育障碍，与微生物群-肠道-脑轴失调密切相关。新出现的证据表明，在ASD队列中丰度降低的[具体物质未提及]具有治疗潜力，尽管其与宿主的相互作用仍未得到探索。在此，我们研究了4P-15在BTBR T+tf/J（BTBR）小鼠（一种特发性ASD小鼠模型）中的疗效和分子基础。口服4P-15显著降低了肠道中吲哚、吲哚-3-丙酸（IPA）和吲哚-3-乙酸（IAA）的水平，以及脑中IPA的水平。此外，脑中IPA水平的降低导致芳烃受体（AhR）信号减弱，其特征是包括谷氨酸转运体和GABA受体在内的下游元件表达增加。最终，这种调节导致兴奋性/抑制性失衡的恢复，这是ASD的典型病理生理特征，从而减轻了ASD的核心行为症状。我们的研究结果强调基于[具体物质未提及]的AhR调节作为ASD一种有前景的治疗策略，突出了基于[具体物质未提及]的益生菌和针对吲哚-AhR信号的靶向干预在解决神经发育障碍方面的双重潜力。
