Sodium oligomannate disrupts the adherence of Ribhigh bacteria to gut epithelia to block SAA-triggered Th1 inflammation in 5XFAD transgenic mice.

IF 13 1区 生物学 Q1 CELL BIOLOGY
Xinyi Wang, Zuoquan Xie, Jie Yuan, Enjing Jin, Wen Lian, Shuaishuai Chang, Guangqiang Sun, Zhengnan Feng, Hui Xu, Chen Du, Xinying Yang, Aihua Xia, Ji Qiu, Qingli Zhang, Feifei Lin, Jia Liu, Liang Li, Xiaoguang Du, Zhongping Xiao, Zhou Yi, Zhiyu Luo, Changrong Ge, Rui Li, Mingyue Zheng, Yi Jiang, Tao Wang, Jing Zhang, Qihao Guo, Meiyu Geng
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Abstract

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 (Ribhigh-L.m.) particularly enriched in 5XFAD transgenic mice. Mechanistically, Ribhigh-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 Ribhigh-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.

在 5XFAD 转基因小鼠体内,低聚甘露酸钠能破坏 Ribhigh 细菌对肠道上皮的粘附,从而阻止 SAA 引发的 Th1 炎症。
低聚甘露酸钠(GV-971)是中国批准用于治疗轻度至中度阿尔茨海默病(AD)的一种寡糖药物,以前曾发现它能修复AD转基因小鼠的肠道微生物群并限制外周Th1免疫的改变。作为一项后续研究,我们在本研究中取得了进展,确定了一种鼠乳杆菌(L.m.)菌株,该菌株高表达一种编码含有 Rib 重复序列的假定粘附蛋白(Ribhigh-L.m.)的基因,这种基因在 5XFAD 转基因小鼠中特别富集。从机理上讲,Ribhigh-L.m.粘附在肠道上皮细胞上会上调粪便代谢物,其中乳酸盐是最主要的候选物质。过量的乳酸盐通过GPR81-NFκB轴刺激肠道上皮产生血清淀粉样蛋白A(SAA),导致外周Th1激活。此外,GV-971 通过直接与 Rib 结合,破坏了 Ribhigh-L.m. 与肠道上皮的粘附,从而纠正了过量的乳酸盐,减少了 SAA,并缓解了 Th1 偏向的炎症。通过这些研究,我们进一步了解了肠道细菌与AD进展之间的分子联系以及GV-971治疗AD的机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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