基于人参皂苷Rg1的肠道代谢处置和AhR/IL-22信号调控诠释其抗抑郁的药动-药效矛盾

Ginsenoside Rg1 (Rg1) has validated anti-depressive efficacy but very poor bioavailability and brain distribution, which suggests that the mechanism behind the central effect is not restricted to the brain. Guided by the in vivo disposition characteristics of ginsenosides and the systems-level pathological network of major depression, we have previously uncovered that peripheral anti-inflammatory and immunomodulation effects may account for the inconsistence between the brain efficacy and concentration of Rg1. Rg1 features a high distribution in the gut, and we further found that the disturbance of gut aryl hydrocarbon receptor (AhR)/interleukin-22 (IL-22) in depressive mice could be attenuated by Rg1, which lead us to hypothesize that ‘Rg1 ameliorated the depressive behavior via modulating the gut AhR/IL-22 signaling’. To validate this proposal, we aim to focus on Rg1 disposition and aryl hydrocarbon receptor (AhR)/IL-22 pathway in the gut of depressive mice induced by chronic unpredictable mild stress (CUMS). Distribution and metabolism profiling of Rg1 in the gut immune barrier, immune cell sorting and functional characterization, and chemical intervention will be applied together to explore the link between gut immune regulation and anti-depression efficacy of Rg1, thus providing in-depth insights into the anti-depression PK-PD paradox of Rg1. By dissecting the peripheral regulatory mechanism underlying the anti-depressive efficacy, our research may exemplify a pharmacokinetics-guided and brain-gut integrative research methodology to mechanistically investigate the central efficacy of poorly-absorbed drugs like Rg1. Moreover, our study may provide potential targets for a holistic therapeutic approach to major depression.

人参皂苷Rg1（Rg1）抗抑郁作用确切，但口服生物利用度低且无法在中枢分布；该“药动-药效矛盾”提示Rg1的抗抑郁机制研究不能局限于脑内。申请人前期研究证实Rg1的中枢效应与其外周作用相关；基于Rg1在肠道高分布的特点，预实验进一步发现Rg1对抑郁小鼠肠道芳香烃受体 (AhR) 及白介素-22(IL-22)水平失调的干预作用。基于以上事实，本项目拟在慢性温和应激诱导的抑郁小鼠模型中，以肠道免疫屏障层面Rg1处置过程及AhR/IL-22 信号轴调控为切入点，综合运用Rg1代谢分布表征、内源性AhR激动剂靶向性分析、免疫细胞体内外功能分析、化学干预等方法，以期构建肠道免疫信号调控与Rg1抗抑郁药效的潜在关联，阐明其抗抑郁“药动-药效矛盾”的科学内涵。本研究将从药物肠道处置和脑肠关联视角为解析Rg1等弱吸收成分的中枢作用机制提供新思路，并为抑郁症的外周干预策略提供潜在靶点。

免疫失衡与代谢紊乱是抑郁症发生、发展中的重要病理特征，解析“免疫代谢”异常参与抑郁症发生、发展的机制是发现抑郁症防治新策略的突破口。本项目聚焦人参皂苷改善抑郁行为的PK-PD矛盾现象，以抑郁模型下色氨酸-犬尿氨酸代谢通路及其免疫调控环节为切入点，开展了系列性研究工作：(1) 基于抑郁模型下色氨酸代谢变化特征，发现犬尿氨酸/芳香烃受体（KYN/AhR）信号轴促进抑郁样行为的作用及机制。KYN可以显著促进CCL2诱导的THP-1单核细胞趋化，并增强其对共培养U251星形胶质细胞的活化能力，以上作用与KYN对AhR的激动作用相关。犬尿氨酸可直接诱导小鼠脑部星形胶质细胞的活化，并加重LPS诱导的小鼠抑郁样行为，而AhR 信号化学抑制剂和单核细胞耗竭可以部分逆转以上作用。以上研究揭示KYN作为免疫调节分子的新功能，通过在中枢-外周的传递而促进了神经免疫互动的信号环路。（2）发现人参皂苷Rg1调节KYN代谢及单核细胞活化发挥抗抑郁作用的机制。在抑郁小鼠模型中，人参皂苷Rg1可以有效干预KYN的代谢紊乱，促进其向犬尿喹啉酸方向转化。在神经炎症及慢性社交应激模型中，人参皂苷Rg1均可有效抑制促炎性单核细胞的浸润，与其抗抑郁作用密切相关, 进一步支持免疫代谢调节在抗抑郁药物研发中的重要价值。以上研究工作揭示了人参皂苷Rg1发挥抗抑郁作用的免疫代谢机制，也提示调控犬尿氨酸-单核细胞功能在抑郁症防治中的潜在价值。