Daxing Research Institute, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, No. 30 XueYuan Road, Haidian District, Beijing 100083, China.
Daxing Research Institute, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, No. 30 XueYuan Road, Haidian District, Beijing 100083, China; Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China.
Brain Behav Immun. 2024 Nov;122:510-526. doi: 10.1016/j.bbi.2024.08.047. Epub 2024 Aug 25.
The intricacy and multifaceted nature of Alzheimer's disease (AD) necessitate therapies that target multiple aspects of the disease. Mesenchymal stromal cells (MSCs) emerge as potential agents to mitigate AD symptoms; however, whether their therapeutic efficacy involves modulation of gut microbiota and the microbiome-gut-brain axis (MGBA) remains unexplored. In this study, we evaluated the effects of three distinct MSCs types-derived from the umbilical cord (UCMSC), dental pulp (SHED), and adipose tissue (ADSC)-in an APP/PS1 mouse model of AD. In comparison to saline control, MSCs administration resulted in a significant reduction of behavioral disturbances, amyloid plaques, and phosphorylated tau in the hippocampus and frontal cortex, accompanied by an increase in neuronal count and Nissl body density across AD-afflicted brain regions. Through 16S rRNA gene sequencing, we identified partial restoration of gut microbial balance in AD mice post-MSCs treatment, evidenced by the elevation of neuroprotective Akkermansia and reduction of the AD-associated Sphingomonas. To examine whether gut microbiota involved in MSCs efficacy in treating AD, SHED with better anti-inflammatory and gut microbiota recovery effects among three MSCs, and another AD model 5 × FAD mice with earlier and more pathological proteins in brain than APP/PS1, were selected for further studies. Antibiotic-mediated gut microbial inactivation attenuated MSCs efficacy in 5 × FAD mice, implicating the involvement of gut microbiota in the therapeutic mechanism. Functional analysis of altered gut microbiota and targeted bile acid metabolism profiling revealed a significant enhancement in bile acid variety following MSCs therapy. A chief bile acid constituent, taurocholic acid (TCA), was orally administered to AD mice and similarly abated AD symptoms. Nonetheless, the disruption of intestinal neuronal integrity with enterotoxin abrogated the ameliorative impact of both MSCs and TCA treatments. Collectively, our findings substantiate that MSCs confer therapeutic benefits in AD within a paradigm that primarily involves regulation of gut microbiota and their metabolites through the MGBA.
阿尔茨海默病（AD）的复杂性和多面性需要针对该疾病的多个方面进行治疗。间充质基质细胞（MSCs）作为减轻 AD 症状的潜在药物出现；然而，它们的治疗效果是否涉及调节肠道微生物群和微生物群-肠-脑轴（MGBA）仍未得到探索。在这项研究中，我们评估了三种不同的 MSC 类型（来自脐带（UCMSC）、牙髓（SHED）和脂肪组织（ADSC））在 AD 模型小鼠中的治疗效果。与生理盐水对照组相比，MSC 给药可显著减轻行为障碍、海马和前额叶皮质中的淀粉样斑块和磷酸化 tau，同时增加 AD 受累脑区的神经元计数和尼氏小体密度。通过 16S rRNA 基因测序，我们发现 MSC 治疗后 AD 小鼠的肠道微生物平衡得到部分恢复，表现为神经保护 Akkermansia 的增加和 AD 相关 Sphingomonas 的减少。为了研究肠道微生物群是否参与 MSC 治疗 AD 的疗效，我们选择了 SHED，因为它在三种 MSC 中具有更好的抗炎和肠道微生物群恢复作用，以及另一种 AD 模型 5×FAD 小鼠，因为它在大脑中的病理蛋白出现更早且更多。抗生素介导的肠道微生物群失活减弱了 5×FAD 小鼠中 MSC 的疗效，表明肠道微生物群参与了治疗机制。改变的肠道微生物群的功能分析和靶向胆汁酸代谢谱分析显示，MSC 治疗后胆汁酸种类显著增加。一种主要的胆汁酸成分，牛磺胆酸（TCA），被口服给予 AD 小鼠，同样减轻了 AD 症状。然而，肠神经元完整性的破坏会消除 MSC 和 TCA 治疗的改善作用。总之，我们的研究结果证实，MSC 通过 MGBA 主要调节肠道微生物群及其代谢物，为 AD 提供治疗益处。
