Effects of herbal medicines and their phytoconstituents on vagus nerve stimulation: a systematic review of in vivo studies.

BACKGROUND: The vagus nerve regulates autonomic, inflammatory, metabolic, and neurobehavioral functions. Although invasive vagus nerve stimulation (VNS) is gaining clinical relevance, herbal medicines may represent accessible, non-invasive modulators of vagal activity. However, the extent and nature of in vivo evidence supporting these effects remain unclear. This systematic review evaluates herbal medicines and phytoconstituents that modulate vagus nerve-related outcomes in animal models. METHODS: A systematic search was conducted in PubMed, Embase, Cochrane Library, ScienceDirect, China National Knowledge Infrastructure (CNKI), Wanfang, Citation Information by National Institute of Informatics (CiNii), Ichushi Web, Research Information Service System (RISS), and Oriental Medicine Advanced Searching Integrated System (OASIS) databases for in vivo studies evaluating the impact of herbal medicines, extracts or phytoconstituents on vagus nerve activity, vagal tone, or vagus-mediated physiological functions. Inclusion criteria included studies using intact animal models with direct assessments of vagally mediated outcomes. Risk of bias was evaluated using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. RESULTS: Out of 10,342 studies screened, 75 studies met inclusion criteria. Interventions included multi-herb prescriptions (n = 22), single-herb extracts (n = 15), phytoconstituents (n = 29), phytoconstituent derivatives or formulations (n = 6), and essential oils (n = 3). Across cardiovascular, neurological, inflammatory, metabolic, and gastrointestinal models, interventions frequently increased acetylcholine (ACh) levels, choline acetyltransferase (ChAT) activity, α7 nicotinic acetylcholine receptor (α7 nAChR) expression, and heart rate variability (HRV) indices, while decreasing acetylcholinesterase (AChE) activity and pro-inflammatory cytokines (p < 0.05-0.001). Proposed mechanisms predominantly involved enhancement of cholinergic neurotransmission, suggesting the involvement of the cholinergic anti-inflammatory pathway. CONCLUSION: Evidence from preclinical studies indicates that certain herbal medicines and phytoconstituents can modulate vagus nerve activity, primarily through anti-inflammatory and autonomic regulation pathways. Rigorous mechanistic studies and translational research are needed to determine the clinical relevance of herbal-induced vagal modulation, particularly given that many preclinical studies employed parenteral administration routes that may not reflect the bioavailability and first-pass metabolism associated with oral herbal use in humans.