<b>Bidirectional </b><b>AHR-</b><b><i>A. muciniphila </i></b><b>axis </b><b>mediates </b><b>the alleviation of alcohol-induced cognitive and social dysfunction</b>

Alcohol-induced cognitive and social dysfunction (AICSD) constitutes a primary etiology of early-onset dementia but with limited effective therapeutic approaches. Recently, the metabolic interactions between host and gut microbiota have emerged as mechanistic pathways implicated in the development of alcohol-related diseases. Here, we report that activation of the aryl hydrocarbon receptor (AHR) alleviated alcohol-related cognitive and social dysfunction. Moreover, activation of AHR significantly enhanced the abundance of <i>Akkermansia muciniphila</i> (<i>A. muciniphila</i>), which was positively correlated with the host behavioral alterations. Furthermore, treatment with A. muciniphila also effectively ameliorated AICSD. Finally, our findings demonstrate a communication bidirectionally between <i>A. muciniphila</i> and AHR in mediating alcohol-induced cognitive and social impairments. Collectively, our results reveal a bidirectional AHR-<i>A. muciniphila</i> axis for alleviating AICSD, providing valuable insights for developing AHR and microbiome-targeted therapeutic strategies against alcohol-induced neurodegenerative diseases.

酒精诱导的认知与社交功能障碍（Alcohol-induced cognitive and social dysfunction, AICSD）是早发性痴呆的核心病因之一，但目前临床可用的有效治疗手段极为有限。近年来，宿主与肠道菌群之间的代谢互作通路逐渐被揭示为酒精相关疾病发生发展的关键机制。本研究发现，激活芳基烃受体（aryl hydrocarbon receptor, AHR）可显著缓解酒精相关的认知与社交功能障碍。此外，激活AHR可有效提升嗜黏蛋白阿克曼菌（Akkermansia muciniphila，以下简称A. muciniphila）的肠道丰度，且该菌的丰度与宿主的行为学改善呈正相关。进一步实验显示，直接施用A. muciniphila同样能够有效改善AICSD表型。最后，本研究证实A. muciniphila与AHR之间存在双向信号通讯，共同介导酒精诱导的认知与社交功能损伤。综上，本研究揭示了一条可缓解AICSD的双向AHR-嗜黏蛋白阿克曼菌调控轴，为开发靶向AHR与肠道菌群的酒精诱导神经退行性疾病治疗策略提供了重要的理论参考与研究思路。