Zhou Hongxu, Zhao Jiaming, Liu Caihong, Zhang Zhengfeng, Zhang Yi, Meng Dali
School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China.
Chongqing Institute for Food and Drug Control, Chunlan Road 2, Chongqing 401121, China.
Phytomedicine. 2022 Apr;98:153937. doi: 10.1016/j.phymed.2022.153937. Epub 2022 Jan 14.
Microbial-derived metabolites play important roles in Alzheimer's disease (AD) pathology, yet how intestinal microbes influence AD progression remains uncertain. Xanthoceraside (XAN), a triterpenoid saponin with anti-AD activity, was extracted from the husks of Xanthoceras sorbifolia Bunge. However, it is still unclear that how XAN modulates the gut microbiota community to regulate AD progression through changing the levels of microbial-derived metabolites.
In this study, we investigated the mechanism underlying the anti-AD effect of XAN.
The current combination studies of multiple-targeted metabolomics, natural product chemistry and pharmacology revealed that oral XAN mediated intestinal microbiota to ameliorate Aβ1-42-induced learning and memory deficits in rats, which were confirmed through antibiotic treatments and fecal microbiota transplantation.
As a poor water solubility and low permeability compound that hardly be absorbed into blood-brain barrier, XAN significantly regulated Aβ1-42-induced metabolism disorders directly or indirectly in gut, including neurotransmitters, amino acids, bile acids and SCFAs metabolism that were detected by UHPLC-MS/MS and GC-MS/MS. In particularly, the in vitro evaluation of XAN on SCFAs production not only found a striking increase in the production of SCFAs after fermentation, but revealed the inner relationship among XAN, gut microbiota and SCFAs in vivo. All results demonstrated that XAN could improve AD rats' learning and memory deficits by modulating the community of gut microbiota which was connected through 16S rRNA sequencing and CCA analyses.
Our study provided a novel mechanism for developing XAN as a potential anti-AD drug and revealed that the gut microbiota might be a potential target for AD treatment .
微生物衍生的代谢产物在阿尔茨海默病（AD）病理过程中发挥着重要作用，但肠道微生物如何影响AD进展仍不明确。文冠果苷（XAN）是一种具有抗AD活性的三萜皂苷，从文冠果的果壳中提取。然而，XAN如何通过改变微生物衍生代谢产物的水平来调节肠道微生物群落以调控AD进展仍不清楚。
在本研究中，我们探究了XAN抗AD作用的潜在机制。
当前多靶点代谢组学、天然产物化学和药理学的联合研究表明，口服XAN可介导肠道微生物群改善Aβ1-42诱导的大鼠学习和记忆缺陷，这通过抗生素治疗和粪便微生物群移植得到证实。
作为一种几乎不能被吸收进入血脑屏障的水溶性差且渗透性低的化合物，XAN直接或间接显著调节肠道中Aβ1-42诱导的代谢紊乱，包括通过超高效液相色谱-串联质谱（UHPLC-MS/MS）和气相色谱-质谱联用仪（GC-MS/MS）检测到的神经递质、氨基酸、胆汁酸和短链脂肪酸（SCFA）代谢。特别是，XAN对SCFA产生的体外评估不仅发现发酵后SCFA产量显著增加，还揭示了XAN、肠道微生物群和体内SCFA之间的内在关系。所有结果表明，XAN可通过调节肠道微生物群落来改善AD大鼠的学习和记忆缺陷，这通过16S核糖体RNA测序和典范对应分析得到证实。
我们的研究为开发XAN作为潜在的抗AD药物提供了一种新机制，并揭示肠道微生物群可能是AD治疗的一个潜在靶点。
