Gao Yuan, Zhang Chun-Sheng, Liang Yan, Gao Jie, Liu Yang, Bu Ren, Liu Hong, Du Xiao-Li, Sun Li-Jun, Li Bing, Li Gang
College of Pharmacy, Inner Mongolia Medical University, Hohhot 010110, China.
State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjian 301617, China.
Am J Chin Med. 2025;53(6):1785-1812. doi: 10.1142/S0192415X25500661. Epub 2025 Aug 7.
polysaccharides (CDPS) exhibit a range of pharmacological activities, most notably in immune modulation, anti-oxidation, and gut microbiota regulation. Emerging evidence suggests that restoring gut microbial and metabolic homeostasis may decelerate the progression of Alzheimer's disease (AD). However, the specific effects and underlying mechanisms of CDPS in the context of AD remain incompletely understood. In this study, we employed behavioral tests, 16S rRNA high-throughput sequencing, and time-resolved metabolomic analyses to comprehensively evaluate the therapeutic efficacy of CDPS. CDPS administration significantly ameliorated cognitive impairment, suppressed pro-inflammatory cytokine expression, and reduced A[Formula: see text] deposition and Tau hyperphosphorylation in the brains of APP/PS1 Tg mice. These effects were associated with CDPS-induced modulation of gut microbial composition - especially the / ratio - and regulation of -Proline and Histidine metabolism. Further and validation confirmed that -Proline and Histidine, key CDPS-associated metabolites, protected against A[Formula: see text]-induced apoptosis and oxidative stress. Notably, the cognitive benefits of CDPS were markedly weakened under conditions of gut microbiota disruption or immune suppression, which highlights the importance of microbial and immune system integrity in mediating its therapeutic effects. Collectively, these findings highlight gut microbial and metabolic disturbances as critical contributors to AD pathogenesis, and support CDPS as a promising multi-target therapeutic strategy. The integration of longitudinal microbiota and metabolomic profiling offers novel mechanistic insights into the neuroprotective actions of CDPS in AD.
多糖（CDPS）具有一系列药理活性，最显著的是在免疫调节、抗氧化和肠道微生物群调节方面。新出现的证据表明，恢复肠道微生物和代谢稳态可能会减缓阿尔茨海默病（AD）的进展。然而，CDPS在AD背景下的具体作用和潜在机制仍不完全清楚。在本研究中，我们采用行为测试、16S rRNA高通量测序和时间分辨代谢组学分析来全面评估CDPS的治疗效果。给予CDPS可显著改善APP/PS1转基因小鼠大脑中的认知障碍，抑制促炎细胞因子表达，并减少Aβ沉积和Tau过度磷酸化。这些作用与CDPS诱导的肠道微生物组成调节有关，尤其是/比率，以及脯氨酸和组氨酸代谢的调节。进一步的和验证证实，关键的CDPS相关代谢物脯氨酸和组氨酸可保护细胞免受Aβ诱导的凋亡和氧化应激。值得注意的是，在肠道微生物群破坏或免疫抑制的情况下，CDPS的认知益处明显减弱，这突出了微生物和免疫系统完整性在介导其治疗效果中的重要性。总的来说，这些发现突出了肠道微生物和代谢紊乱是AD发病机制的关键因素，并支持CDPS作为一种有前途的多靶点治疗策略。纵向微生物群和代谢组学分析的整合为CDPS在AD中的神经保护作用提供了新的机制见解。
