Wang Xinyi, Xie Zuoquan, Yuan Jie, Jin Enjing, Lian Wen, Chang Shuaishuai, Sun Guangqiang, Feng Zhengnan, Xu Hui, Du Chen, Yang Xinying, Xia Aihua, Qiu Ji, Zhang Qingli, Lin Feifei, Liu Jia, Li Liang, Du Xiaoguang, Xiao Zhongping, Yi Zhou, Luo Zhiyu, Ge Changrong, Li Rui, Zheng Mingyue, Jiang Yi, Wang Tao, Zhang Jing, Guo Qihao, Geng Meiyu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Shanghai Green Valley Pharmaceutical Co. Ltd, Shanghai, China.
Cell Discov. 2024 Nov 19;10(1):115. doi: 10.1038/s41421-024-00725-5.
Sodium oligomannate (GV-971), an oligosaccharide drug approved in China for treating mild-to-moderate Alzheimer's disease (AD), was previously found to recondition the gut microbiota and limit altered peripheral Th1 immunity in AD transgenic mice. As a follow-up study, we here made advances by pinpointing a Lactobacillus murinus (L.m.) strain that highly expressed a gene encoding a putative adhesin containing Rib repeats (Rib-L.m.) particularly enriched in 5XFAD transgenic mice. Mechanistically, Rib-L.m. adherence to the gut epithelia upregulated fecal metabolites, among which lactate ranked as the top candidate. Excess lactate stimulated the epithelial production of serum amyloid A (SAA) in the gut via the GPR81-NFκB axis, contributing to peripheral Th1 activation. Moreover, GV-971 disrupted the adherence of Rib-L.m. to gut epithelia via direct binding to Rib, which corrected the excess lactate, reduced SAA, and alleviated Th1-skewed inflammation. Together, we gained further insights into the molecular link between gut bacteria and AD progression and the mechanism of GV-971 in treating AD.
寡聚甘露糖酸钠（GV-971）是一种在中国被批准用于治疗轻度至中度阿尔茨海默病（AD）的寡糖药物，此前研究发现它可重塑肠道微生物群，并限制AD转基因小鼠外周Th1免疫的改变。作为一项后续研究，我们在此取得了进展，确定了一株鼠李糖乳杆菌（L.m.），该菌株高度表达一个编码含有Rib重复序列的假定粘附素的基因（Rib-L.m.），这种粘附素在5XFAD转基因小鼠中特别富集。从机制上讲，Rib-L.m.对肠道上皮的粘附上调了粪便代谢产物，其中乳酸是首要候选物。过量的乳酸通过GPR81-NFκB轴刺激肠道上皮产生血清淀粉样蛋白A（SAA），促进外周Th1激活。此外，GV-971通过直接结合Rib破坏了Rib-L.m.与肠道上皮的粘附，从而纠正了过量的乳酸，降低了SAA，并减轻了Th1偏向的炎症。总之，我们进一步深入了解了肠道细菌与AD进展之间的分子联系以及GV-971治疗AD的机制。
