Central nervous system (CNS) diseases encompass neurodegenerative disorders, cerebrovascular diseases, central nervous system tumors, and psychiatric disorders, affecting multiple aspects of the patient motor function, sensation, cognition, speech, emotions, and behavior. The early symptoms of these diseases are often subtle, but their pathogenesis is complex, frequently causing devastating neurological damage. Currently, there is no effective curative treatment for CNS diseases, especially in the field of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, and some disease-modifying therapies exhibit an extremely high failure rate in clinical trials, with some studies reporting the failure rate high as 100% [1]. Therefore, exploring novel intervention strategies and identifying non-traditional therapeutic targets are of paramount importance.

The gut-brain axis (GBA) is a multi-pathway bidirectional regulatory system connecting the gut and the brain. Through mechanisms such as microbial metabolites, neurotransmission, immune responses, and endocrine signaling, it facilitates dynamic communication between the gut and the CNS. This axis not only regulates mood and behavior but is closely implicated in the onset and progression of various CNS disorders [2], [3], [4]. Among these, the vagus nerve is the longest and most widely distributed cranial nerve, serving as the core pathway mediating bidirectional gut-brain communication. It functions not only as a “sensor” for the brain to perceive the intestinal status but also as a key route through which the gut microbiota influences the CNS function [5]. Gut microbiota and their metabolites, such as short-chain fatty acids (SCFAs), tryptophan derivatives, and gamma-aminobutyric acid, can transmit signals to the CNS by activating enterochromaffin cells, enteric neurons, or directly acting on vagal nerve endings [6∗], [7]. Conversely, the CNS can also regulate the intestinal microenvironment through vagal efferent activity, influencing microbial composition and function [8] (Figure 1).

The vagus nerve, gut microbiota, and brain form a highly interdependent communication network, supporting the development of novel therapies targeting the GBA.

The vagus nerve is the tenth cranial nerve and one of the most direct and rapid neural pathways connecting the gut to the brain. Its name derives from the Latin word for “wanderer,” vividly describing its anatomical feature of extensively innervating multiple visceral organs [9]. Comprising approximately 80% afferent fibers and 20% efferent fibers, the vagus nerve forms a highly integrated bidirectional communication system. Afferent fibers continuously transmit mechanical, chemical and inflammatory signals from the gastrointestinal (GI) tract, respiratory system, and cardiovascular system to the CNS. Conversely, efferent fibers relay regulatory commands from the CNS to modulate visceral functions, thereby maintaining physiological homeostasis [8].

Afferences are widely distributed throughout the GI wall, capable of detecting various interoceptive stimuli including pressure, pain, temperature, chemicals, and inflammatory mediators. These signals converge at the nucleus of the solitary tract (NST) in the brainstem and project via multisynaptic pathways to multiple brain regions including the hypothalamus, amygdala, and locus coeruleus (LC), participating in the regulation of emotions, stress responses, autonomic nervous function, and cognitive behavior [10∗]. Additionally, the vagus nerve mediates “cumulative sensory input,” integrating weak signals from visceral organs over time to participate in the body's long-term regulation of metabolism, immunity, and behavior [11∗].

The vagus nerve plays a pivotal role in autonomic physiological regulation, encompassing fundamental survival functions such as respiratory rhythm, heart rate variability, drinking, feeding behavior, and disease responses [12], [13], [14]. Furthermore, the vagus nerve-mediated GBA also participates in regulating the mesolimbic reward pathway, offering a potential target for neuromodulatory therapies in affective disorders [15].

VNS, a neuromodulation technique, was first proposed by American neurologist James Corning in the late 19th century for the treatment of epilepsy. He achieved this by compressing the carotid bifurcation and applying direct current to deliver non-specific stimulation to the vagus and sympathetic nerves [16]. As research progresses, VNS has been demonstrated to exert neuromodulatory effects by regulating the electroencephalographic activity and sleep architecture by inducing slow-wave sleep or rapid eye movement sleep in high dependence on stimulation parameters [17]. However, traditional VNS requires surgical implantation of a stimulator, which may potentially cause complications like recurrent laryngeal nerve injury, vocal cord paralysis, and sleep apnea, thus limiting its widespread applications [18], [19].

To overcome these limitations, transcutaneous auricular vagus nerve stimulation (taVNS) was first proposed by Enrique Ventureyra in 2000 [20]. taVNS achieves non-invasive modulation by stimulating the auricular branch of the vagus nerve (ABVN). Stimulation of the ABVN directly connects to the NTS, the terminal point for vagus nerve afferent fibers. NTS is considered a relay station for visceral sensations, playing an intermediary role in receiving signals from the ear and regulating bodily functions[21]. Despite the advantage of easy operation and high safety of taVNS, its frequency, intensity and pulse width remain unstandardized. Research on its action mechanisms is limited, and its broad stimulation range may affect adjacent neural structures[22], [23]. Personalized treatment protocols can be tailored to individual circumstances.

Currently, VNS has been approved for use not only in the treatment of epilepsy and treatment-resistant depression but also shows broad prospects in the field of cardiovascular disease [24], [25], [26], [27]. However, its action mechanism remains incompletely understood. Particularly, numerous uncertainties exist regarding how VNS modulates GBA function by regulating gut microbiota and how microbial metabolites feedback-regulate vagus nerve activity. Therefore, systematically deciphering the bidirectional interaction mechanisms between VNS and gut microbiota will not only deepen our understanding of GBA but also provide a crucial direction for developing novel therapies based on “neuro-microbiome” synergistic interventions.

The gut microbiome is vast and complex, encoding far more genes than the human genome. Through deep sequencing technology, the genetic diversity and core functions of human gut microbes have been revealed, demonstrating their shared nature across individuals and their close association with the host health status [28].

Research has shown that VNS significantly modulates the gut microbiota composition and function (Table 1). In a mouse model of irritable bowel syndrome (IBS-C), taVNS not only substantially increased the fecal pellet count, elevated the fecal water content, and enhanced GI transit, but also reshaped the intestinal microbiome by restoring Lactobacillus abundance, elevating Bifidobacterium levels, reducing potentially pathogenic bacteria such as Staphylococcus, and promoting the growth of SCFAs-producing bacteria like Bacteroides [29]. 10 These beneficial bacteria exert immunomodulatory and neuroprotective effects by producing neuroactive substances like GABA and 5-HT, while inhibiting pro-inflammatory factors such as Lipopolysaccharide (LPS) [30].

Similar results were also validated in patients with IBS-C, showing that taVNS significantly alleviated abdominal pain, increased spontaneous bowel movement frequency, and improved stool consistency and quality of life [31∗]. Multi-omics analysis revealed that following taVNS intervention, the abundance of Campylobacterota, an inflammation-associated phylum, was decreased in patient intestines, while the abundance of Patescibacteria, involved in microbiome restoration, was increased. At the genus level, Bifidobacterium abundance was significantly increased, accompanied with elevated SCFA (acetic acid, butyric acid and propionic acid) levels and decreased tryptophan metabolites (e.g., 3-hydroxy-o-aminobenzoic acid, o-aminobenzoic acid, and L-tryptophan), suggesting a shift toward an anti-inflammatory, homeostatic and metabolic microenvironment [31].

Additionally, minimally invasive VNS has demonstrated significant therapeutic efficacy in ischemic stroke models by suppressing stroke-induced excessive proliferation of gut microbiota, restoring disrupted microbial structure, reversing abnormal Firmicutes/Bacteroidetes (F/B) ratios, and reducing the abundance of pro-inflammatory bacteria, thereby mitigating systemic inflammatory responses and neural damage [32].

Currently, there is no unified standard for VNS parameters, with significant individual variability observed. Different stimulation parameters exert distinct effects on gut microbiota. Although the underlying mechanisms remain unclear, studies have demonstrated that activity in the dorsal motor nucleus of the vagus nerve (DMN) influences intestinal motility and secretion, thereby affecting the composition of gut microbiota [33], [34]. Consequently, it is hypothesized that alterations in VNS parameters may influence the composition of gut microbiota by altering the DMN activity.

The interaction between the vagus nerve and the gut microbiota is not a one-way process. VNS can modulate the composition of gut microbiome, while simultaneously, gut microbiota and its metabolites provide feedback to vagus nerve activity, forming a bidirectionally regulated pathway [35].

Certain probiotics and their metabolites directly act on the vagus nerve. For example, Lactobacillus rhamnosus (JB-1) has been shown to improve anxiety and depression-related behaviors by regulating the GABA (γ aminobutyric acid) system via the vagus nerve, and this improvement disappears after vagus nerve transection [36]. The primary metabolites produced by the microbiota include SCFAs, bile acids, and neuromodulators. Neuromodulators encompass tryptophan precursors and metabolites, serotonin (5-hydroxytryptamine, 5-HT), γ aminobutyric acid (GABA), and catecholamines [8]. SCFAs are the most extensively studied metabolites, comprising acetate, propionate, and butyrate, which account for 95% of total SCFAs. Propionate and butyrate directly activate colonic vagal nerve endings. They transmit satiety signals to the CNS and induce an anti-inflammatory state [37], [38].

They may also exert effects through intestinal epithelial cell-mediated signaling. Vagus nerve afferent terminals are located near enterochromaffin (EC) cells, which highly express 5-HT3 receptors [39], [40]. EC cells express multiple known and putative microbial metabolite receptors, including SCFA receptors such as FFAR2 and OLFR78, secondary bile acid receptors (GPBAR1), and aromatic acid receptors (GPR35) [41]. Upon metabolite activation, EC cells can modulate sensory pathways such as the vagus nerve by releasing 5-HT via voltage-gated P/Q-type calcium channels [42]. Colonization by indigenous spore-forming bacteria can also specifically increase the expression of tryptophan hydroxylase 1 (TPH1) in colonic EC cells, and elevate 5-HT levels in the colon, feces, and blood [43∗]. Lactobacilli produce tryptophan metabolites including tryptamine and indole, which indirectly regulate vagal activity by influencing intestinal chromaffin cells or enteric neurons [46]. Microbiologically produced GABA may participate in emotional regulation by influencing vagal signaling via the enteric nervous system [47], [48].

These mechanisms collectively demonstrate that VNS-induced microbiota reconfiguration establishes a closed-loop system through microbial metabolite-mediated vagal neuromodulation (Fig. 2).

The vagus nerve, immune system, and gut microbiota and their metabolites interact and influence each other. Following vagus nerve stimulation, acetylcholine (Ach) is released. Vagus nerve efferent fibers activate α7nAChRs on immune cells via cholinergic anti-inflammatory pathways, thereby suppressing the release of pro-inflammatory factors such as tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) from immune cells like macrophages, thus controlling excessive inflammation [49], [25], [50]. The shift from a pro-inflammatory to an anti-inflammatory microenvironment modulates the colonization and composition of distinct microbial communities within the gut, thereby preventing the exacerbation of dysbiosis.Following α7nAChR gene knockout, taVNS failed to reverse depression-like behaviors and neuroinflammation in CUMS model rats, highlighting

the critical role of the α7nAChR/NF-κB signaling pathway [51]. Furthermore, VNS inhibits mast cell degranulation, reduces trypsin secretion, and improves colonic and blood-brain barrier (BBB) integrity. This ultimately enhances locomotor and GI function while reducing systemic inflammation [32].

VNS alters the composition of gut microbiota, acting on host-microbial molecular interactions to regulate immune, metabolic, and neurobehavioral systems, and is closely associated with infections, autoimmune diseases, metabolic disorders, and neurological diseases [52]. SCFAs possess functions such as maintaining intestinal barrier function, regulating GI motility, and influencing hormone secretion and epigenetic regulation [53]。By modulating gut microbiota and maintaining intestinal barrier integrity, they bolster the host's disease resistance [54]. SCFAs also regulate the differentiation of neutrophils, dendritic cells, and T cells, thus reducing systemic inflammation and neuroinflammation [55], [56]. Approximately 90% tryptophan is converted to kynurenine via indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO), which further generates neuroprotective metabolites influencing inflammation and neural function [57]. Vagus nerve afferent fibers detect peripheral inflammatory signals. Upon activation, they project to NTS, which in turn modulates noradrenergic neurons in the locus coeruleus. This regulation reduces proinflammatory factor release and enhances neurotrophic factor expression, among other effects [58], [59].

Certain SCFAs, such as acetate, can directly cross the BBB to reach the CNS, where they act on regulatory centers in regions like the hypothalamus. Although this process does not directly depend on the vagus nerve, it collectively forms a complete regulatory system with vagus nerve afferent signals[56].

Through these intersecting pathways, VNS and gut microbiota interact within a neuro-immune-metabolic framework that forms a self-reinforcing regulatory loop, ultimately promoting physiological homeostasis and recovery.

Although VNS shows promise across multiple disorders, its clinical translation is hampered by surgical risks and a lack of parameter optimization [60]. Thus, VNS is only currently recommended as an adjunct to conventional therapies.

Translational challenges arise from differences between animal models and human patients, as well as the high variability of gut microbiota influenced by diets, environments, and genetics. Future studies should integrate multi-omics technologies with multidimensional analyses to identify microbial biomarkers that can guide VNS applications.

A promising direction is the development of combined VNS-synbiotic regimens, incorporating fecal microbiota transplantation, precision prebiotics, and microbial modulators. Temporal sequencing of these interventions should be optimized to enhance the efficacy and establish a framework for personalized neuromodulation.

VNS helps good gut bacteria to thrive and produce more helpful substances like SCFAs. This alters the community of gut microbes. These bacterial products then adjust vagus nerve signals and brain pathways. This controls immune system activity and reduces inflammation, thus improving gut movement, protecting nerves and restoring immunity. Such processes are the key to making new, gentle treatments for brain and nerve diseases. Future work should explore better stimulation methods, along with helpers such as probiotics or changes in diet.