Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer\u2019s disease progression

Xinyi Wang,Yanxue Gong,Xingkun Chu,Changrong Ge,Lingfei Ruan,Li-Li Wen ,Haiyan Zhang,Teng Feng,Jia Liu,Guanqun Zhang,Jun Yang,Shifu Xiao,Qingli Zhang,Jing Zhang,Guangqiang Sun,Tao Wang,Feifei Lin,Siyuan Yan,Da Yang ,Jian Ding,Shuaishuai Chang,Xun Huang,Zuoquan Xie,Huan Wang,Chen Du,Meiyu Geng

doi:10.1038/s41422-019-0216-x

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.

Highlights

Despite the tremendous efforts made in the treatment of Alzheimer’s disease (AD), the past decades have witnessed the continuous failure of β-amyloid (Aβ)- or tau-centric therapeutic strategies in late-stage clinical trials, which impels the reconsideration of new therapeutic strategy for this complicated disease.[1,2] Recently, a plethora of studies have shown the dynamic interaction between the intestinal microbiota and host innate and adaptive immune system.[3,4] The dysbiosis of gut microbiota could jeopardize host immune responses and promote the development of various inflammatory disorders.[5]
AD progression is associated with the alteration of gut microbiota and immune cell infiltration To assess the role of gut microbiota alteration in AD pathogenesis, we used the 5XFAD transgenic (Tg) mouse model, which is widely used in AD study for faithfully recapitulating AD-associated pathological features including the severely accelerated cognitive impairment, amyloid deposition in the 2nd postnatal month, synaptic degeneration in the 4th postnatal month, and behavioural changes in the 6th month.[20,21,22,23]
Using principal component analysis (PCA), which simplifies the complexity in highdimensional data while retaining trends and patterns upon a series of time points, we revealed a remarkable shift in the gut microbiota composition during AD progression in Tg mice

Summary

Introduction

Despite the tremendous efforts made in the treatment of Alzheimer’s disease (AD), the past decades have witnessed the continuous failure of β-amyloid (Aβ)- or tau-centric therapeutic strategies in late-stage clinical trials, which impels the reconsideration of new therapeutic strategy for this complicated disease.[1,2] Recently, a plethora of studies have shown the dynamic interaction between the intestinal microbiota and host innate and adaptive immune system.[3,4] The dysbiosis of gut microbiota could jeopardize host immune responses and promote the development of various inflammatory disorders.[5] This appears to be the case for AD-associated inflammation Emerging evidence from both animal and human studies supports the association between dysbiosis of the gut microbiota and the microglia activation during AD development.[6,7,8] For example, Minter et al discovered that perturbations in gut microbial diversity influenced neuroinflammation and amyloidosis. Antibiotics-treated mice showed a significant decrease in plaque-localized microglial activation positive for IBA-1.9 Besides, gut microbiota-produced lipopolysaccharide (LPS) was found in the post-mortem brain samples of AD patients,[10] and peripheral injection of LPS could promote microglial activation.[11,12] All the evidence suggests that gut microbiota is likely involved in regulating microglia activation and neuroinflammation in AD

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