Transcutaneous vagus nerve stimulation: a new strategy for Alzheimer's disease intervention through the brain-gut-microbiota axis?

Abstract

Transcutaneous vagus nerve stimulation (tVNS) is an emerging non-invasive technique designed to stimulate branches of the vagus nerve distributed over the body surface. Studies suggest a correlation between the brain-gut-microbiota (BGM) axis and the pathogenesis of Alzheimer's disease (AD). The BGM axis represents a complex bidirectional communication system, with the vagus nerve being a crucial component. Therefore, non-invasive electrical stimulation of the vagus nerve might have the potential to modify-most of the time probably in a non-physiological way-the signal transmission within the BGM axis, potentially influencing the progression or symptoms of AD. This review explores the interaction between percutaneous vagus nerve stimulation and the BGM axis, emphasizing its potential effects on AD. It examines various aspects, such as specific brain regions, gut microbiota composition, maintenance of intestinal environmental homeostasis, inflammatory responses, brain plasticity, and hypothalamic-pituitary-adrenal (HPA) axis regulation. The review suggests that tVNS could serve as an effective strategy to modulate the BGM axis and potentially intervene in the progression or treatment of Alzheimer's disease in the future.

Keywords: Alzheimer’s disease; HPA axis; brain-gut-microbiota axis; microbiota; transcutaneous vagus nerve stimulation.

Figure 1

taVNS reduced the levels of Aβ-41, IL-1β, and IL-18 produced by microglia via P2X7R/NLRP3/Caspase-1. It also significantly reduced the levels of apoptotic and necroptotic proteins, which induced microglial phenotypic transformations to protect neurons. Additionally, taVNS improved intestinal permeability, enhancing the diversity of species in the microbiota. Furthermore, enteric glial cells assisted in the exchange of information between the vagus nerve and gut.

Figure 2

Anti-inflammatory mechanisms of taVNS. (A) taVNS induces microglia polarization toward an anti-inflammatory phenotype and reduces levels of pro-inflammatory factors, ameliorating hippocampal neuroinflammation. (B) By upregulating the anti-inflammatory effects of α7nAchR, taVNS has been shown to reduce the production of pro-inflammatory cytokines, such as IL-1β.

Figure 3

taVNS has the potential to improve cognitive dysfunction through afferent neuromodulation. It can also reduce hippocampal neuroinflammation, promote vascular regeneration, and enhance neuroplasticity through efferent nerves. This is achieved by increasing α7nAchR activity and releasing NA, VEGF, and BDNF.