Huanglian Jiedu decoction remodels the periphery microenvironment to inhibit Alzheimer\u2019s disease progression based on the \u201cbrain-gut\u201d axis through multiple integrated omics

Xiaolu Wei,Wei Ren,Nan Si,Haiyu Zhao,Xiaorui Fan,Jian Yang,Xinru Gu,Hongjie Wang,Baolin Bian,Yanyan Zhou,Junyi Zhou,Wenya Gao,Wei Zhao

doi:10.1186/s13195-021-00779-7

Abstract

BackgroundIn recent years, excellent results have suggested an association between the “brain-gut” axis and Alzheimer’s disease (AD) progression, yet the role of the “brain-gut” axis in AD pathogenesis still remains obscure. Herein, we provided a potential link between the central and peripheral neuroinflammatory disorders in AD progression.MethodsThe Morris water maze (MWM) test, immunohistochemistry, ELISA, ProcartaPlex Multiplex immunoassay, multiple LC-MS/MS methods, and the V3-V4 regions of 16S rRNA genes were applied to explore potential biomarkers.ResultsIn Tg-APP/PS1 mice, gut dysbiosis and lipid metabolism were highly associated with AD-like neuroinflammation. The combination of inflammatory factors (IL-6 and INF-γ), phosphatidylcholines (PCs) and SCFA-producing bacteria were expected to be early diagnostic biomarkers for AD. Huanglian Jiedu decoction (HLJDD) suppressed gut dysbiosis and the associated Aβ accumulation, harnessed neuroinflammation and reversed cognitive impairment.ConclusionTogether, our findings highlighted the roles of neuroinflammation induced by gut dysbiosis and lipid metabolism disorder in AD progression. This integrated metabolomics approach showed its potential to understand the complex mechanisms of HLJDD in the treatment of AD.

Highlights

Alzheimer’s disease (AD), a chronic neurodegenerative disease, is a major cause of disability and mortality if not effectively treated
Amyloid β-protein (Aβ) plaques markedly accumulated in the brain cortex and hippocampus of Tg mice compared with WT mice
Congo red staining has shown that Aβ deposition with higher density and larger area existed in the hippocampus and cortex of Tg mice than that of WT mice (Fig. 2a)

Summary

Introduction

Alzheimer’s disease (AD), a chronic neurodegenerative disease, is a major cause of disability and mortality if not effectively treated. As many as 1141 anti-AD drugs worldwide were in development. Only 6 of them stood out and were approved by the Food and Drug Administration (FDA). These drugs are relatively against a single target and are mainly acetylcholinesterase inhibitors, which is not an optimal choice for AD patients with multipathogenesis. The success of GV971 in anti-AD reveals that multi-target intervention breaks new ground for the drug development of AD. Excellent results have suggested an association between the “brain-gut” axis and Alzheimer’s disease (AD) progression, yet the role of the “brain-gut” axis in AD pathogenesis still remains obscure. We provided a potential link between the central and peripheral neuroinflammatory disorders in AD progression

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