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

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

doi:10.1038/s41421-024-00725-5

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

Cell Discov. 2024 Nov 19;10(1):115. doi: 10.1038/s41421-024-00725-5.

Authors

Xinyi Wang^#^{1

2}, Zuoquan Xie^#¹, Jie Yuan², Enjing Jin², Wen Lian², Shuaishuai Chang², Guangqiang Sun², Zhengnan Feng², Hui Xu¹, Chen Du², Xinying Yang², Aihua Xia², Ji Qiu², Qingli Zhang³, Feifei Lin³, Jia Liu³, Liang Li², Xiaoguang Du², Zhongping Xiao², Zhou Yi², Zhiyu Luo², Changrong Ge², Rui Li^{4

5

6}, Mingyue Zheng^{5

6}, Yi Jiang⁷, Tao Wang⁸, Jing Zhang², Qihao Guo⁹, Meiyu Geng^{10

11}

Affiliations

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
² Shanghai Green Valley Pharmaceutical Co. Ltd, Shanghai, China.
³ Institutional Technology Service Centre, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁴ School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
⁵ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁶ University of Chinese Academy of Sciences, Beijing, China.
⁷ Lingang Laboratory, Shanghai, China.
⁸ Department of Psychiatry and Affective Disorder Center, Ruijin Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
⁹ Department of Gerontology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
¹⁰ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
¹¹ Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China. [email protected].

^# Contributed equally.

PMID: 39557828
DOI: 10.1038/s41421-024-00725-5

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 (Rib^high-L.m.) particularly enriched in 5XFAD transgenic mice. Mechanistically, Rib^high-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^high-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.

Grants and funding

81821005/National Natural Science Foundation of China (National Science Foundation of China)