Sodium oligomannate disrupts the adherence of Ribhigh bacteria to gut epithelia to block SAA-triggered Th1 inflammation in 5XFAD transgenic mice
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<sup>high</sup>-L.m.) particularly enriched in 5XFAD transgenic mice. Mechanistically, Rib<sup>high</sup>-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<sup>high</sup>-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.
Authors
- Jia Liu (ORCID: https://orcid.org/0000-0002-8167-9750)
- Xinying Yang
- Enjing Jin
- Zhiyu Luo
- Guangqiang Sun (ORCID: https://orcid.org/0000-0003-3895-4312)
- Hui Xu (ORCID: https://orcid.org/0000-0002-5212-9012)
- Zuoquan Xie (ORCID: https://orcid.org/0000-0002-1613-3321)
- Chen Du (ORCID: https://orcid.org/0000-0002-0671-7817)
- Zhongping Xiao
- Changrong Ge (ORCID: https://orcid.org/0000-0001-8640-2681)
- Z. Feng
- Meiyu Geng (ORCID: https://orcid.org/0000-0002-7362-0847)
- Yi Jiang (ORCID: https://orcid.org/0000-0002-0723-1413)
- Aihua Xia (ORCID: https://orcid.org/0000-0002-9415-841X)
- Mingyue Zheng (ORCID: https://orcid.org/0000-0002-3323-3092)
- Feifei Lin (ORCID: https://orcid.org/0000-0001-7644-4423)
- Shuaishuai Chang
- Qihao Guo (ORCID: https://orcid.org/0000-0001-5079-8047)
- Yi Zhou (ORCID: https://orcid.org/0000-0001-9616-7283)
- Jing Zhang (ORCID: https://orcid.org/0000-0002-4530-6754)
- Xinyi Wang (ORCID: https://orcid.org/0009-0002-6349-8013)
- Liang Li (ORCID: https://orcid.org/0000-0003-1893-1965)
- Rui Li (ORCID: https://orcid.org/0000-0002-7210-8358)
- Wen Lian
- Qingli Zhang (ORCID: https://orcid.org/0000-0001-9627-6738)
- Jie Yuan (ORCID: https://orcid.org/0009-0002-5303-1137)
- Tao Wang (ORCID: https://orcid.org/0009-0009-8230-5249)
- Xiaoguang Du
- Ji Qiu
Institutions
- China Pharmaceutical University (CN)
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Sciences (CN)
- Shanghai Botanical Garden (CN)
- Ruijin Hospital (CN)
- Shanghai Institute of Materia Medica (CN)
- Drug Discovery Laboratory (Norway) (NO)
- Shanghai Sixth People's Hospital (CN)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Cell Discovery
- Published
- 2024-11-19
- DOI
- https://doi.org/10.1038/s41421-024-00725-5
- Citations
- 10
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 2.34
Funders
- National Natural Science Foundation of China