Gut-brain axis and vascular dementia: a review on mechanisms and Chinese herbal medicine therapeutics

Abstract

Vascular dementia (VD), the second most prevalent form of dementia among the elderly population, is a cerebrovascular disorder characterized primarily by cognitive impairment. Emerging evidence has revealed that intestinal flora dysbiosis may be implicated not only in gastrointestinal (GI) pathologies but also in central nervous system (CNS) disorders, including VD. The gut-brain axis (GBA) serves as a critical bidirectional pathway through which intestinal flora influences brain physiology and function. Notably, accumulating studies have demonstrated the therapeutic potential of Chinese herbal medicine (CHM) in VD management via modulation of gut microbial composition. This review synthesizes current understanding of the VD- intestinal flora relationship mediated by the GBA, while systematically evaluating evidence for CHM interventions that ameliorate VD through intestinal flora regulation. These insights may offer novel perspectives and methodological approaches for both fundamental research and clinical management of VD.

Keywords: Chinese herbal medicine; gut-brain axis; intestinal flora; pathogenesis; vascular dementia.

Figure 1

Pathogenesis of VD. The pathogenesis of VD is primarily divided into five aspects: (1) Oxidative stress response. Cerebral hypoxia-ischemia induces a marked elevation in ROS production, which contributes to the damage of BBB and neuronal injury; (2) BBB damage. Under conditions of cerebral hypoperfusion, the resultant the increased BBB permeability facilitates neurotoxic substances to enter the cerebral parenchyma, thereby precipitating neuronal injury; (3) Excitotoxic effects. Excessive release and impaired reuptake of EAAs following CIRI initiates calcium overload, ultimately contributing to the progression of VD; (4) Neuroinflammatory response. Cerebral hypoxia-ischemia triggers the release of inflammatory factors by immune cells, and subsequent inflammatory infiltration of cerebral parenchyma, ultimately culminating in neuronal dysfunction; (5) Genetic mechanisms. Apo E4 gene and the NOTCH3 gene have been identified as major genetic determinants of VD. BBB, blood brain barrier; ATP, adenosine triphosphate; EAAs, excitatory amino acids; CIRI, cerebral ischemia–reperfusion injury; TC, total cholesterol; LDL, low density lipoprotein; ApoE4, apolipoprotein E4; NOTCH3, notch receptor 3 (Created with BioRender.com).

Figure 2

A illustration of the bidirectional communication between the brain and gut microbiota via the GBA. The GBA consists of three principal pathways: vagal nerve pathways, immune regulation pathways and neuroendocrine pathways. Microorganisms in the GI tract can establish direct neural connections with the brain by activating vagal afferents through the enteric nervous system. Additionally, gut microbial, and their synthesized metabolites and neurotransmitters regulate brain physiology by modulating immune cells to produce or release cytokines such as TNF-α. Alternatively, they may influence brain activities by stimulating enteroendocrine cells to release hormones (e.g., GABA). Furthermore, neuroendocrine hormones, particularly cortisol released via the HPA axis, play a significant role in regulating gut microbial homeostasis. GI, gastrointestinal; SCFAs, short-chain fatty acids; TMAO, trimethylamine N-oxide; GABA, γ-aminobutyric acid; NA, noradrenaline; DA, dopamine; PYY, peptideYY; GLP-1, peptide-1; GIP, gastric inhibitory polypeptide; 5-HT, serotonin; ACTH, adrenocorticotropic hormone; CRF, corticotropin-releasing factor (Created with BioRender.com).