Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer's disease progression.

Abstract

Recently, increasing evidence has suggested the association between gut dysbiosis and Alzheimer's disease (AD) progression, yet the role of gut microbiota in AD pathogenesis remains obscure. Herein, we provide a potential mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression. Using AD mouse models, we discovered that, during AD progression, the alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine, which stimulates the differentiation and proliferation of pro-inflammatory T helper 1 (Th1) cells. The brain-infiltrated peripheral Th1 immune cells are associated with the M1 microglia activation, contributing to AD-associated neuroinflammation. Importantly, the elevation of phenylalanine and isoleucine concentrations and the increase of Th1 cell frequency in the blood were also observed in two small independent cohorts of patients with mild cognitive impairment (MCI) due to AD. Furthermore, GV-971, a sodium oligomannate that has demonstrated solid and consistent cognition improvement in a phase 3 clinical trial in China, suppresses gut dysbiosis and the associated phenylalanine/isoleucine accumulation, harnesses neuroinflammation and reverses the cognition impairment. Together, our findings highlight the role of gut dysbiosis-promoted neuroinflammation in AD progression and suggest a novel strategy for AD therapy by remodelling the gut microbiota.

• Authors: Xinyi Wang, Guangqiang Sun, Teng Feng, Jing Zhang, Xun Huang, Tao Wang, Zuoquan Xie, Xingkun Chu, Jun Yang, Huan Wang, Shuaishuai Chang, Yanxue Gong, Lingfei Ruan, Guanqun Zhang, Siyuan Yan, Wen Lian, Chen Du, Dabing Yang, Qingli Zhang, Feifei Lin, Jia Liu, Haiyan Zhang, Changrong Ge, Shifu Xiao, Jian Ding, Meiyu Geng
• Journal: Cell research (Cell Res) Vol. 29 Issue 10 Pg. 787-803 (Oct 2019) ISSN: 1748-7838 [Electronic] England
• PMID: 31488882 (Publication Type: Journal Article)

Chemical References

• Amino Acids
• Anti-Bacterial Agents
• GV-971
• Oligosaccharides
• Isoleucine
• Phenylalanine
• Mannose

Topics

• Alzheimer Disease (drug therapy, pathology)
• Amino Acids (metabolism)
• Animals
• Anti-Bacterial Agents (pharmacology)
• Bacteria (drug effects, isolation & purification, metabolism)
• Clinical Trials, Phase III as Topic
• Cognitive Dysfunction (drug therapy, pathology)
• Disease Models, Animal
• Disease Progression
• Gastrointestinal Microbiome (drug effects)
• Humans
• Isoleucine (metabolism)
• Mannose (analogs & derivatives, pharmacology, therapeutic use)
• Maze Learning (drug effects)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Microglia (metabolism)
• Oligosaccharides (pharmacology, therapeutic use)
• Phenylalanine (metabolism)
• Th1 Cells (immunology, metabolism)