Vagal nerve innervation divergence in liver/pancreas: A forgotten key to endocrine recovery after transplantation?

Abstract

As the cross talk of the parasympathetic nervous system, the vagus nerve exerts organ-specific regulatory effects on hepatic and pancreatic endocrine homeostasis, yet its divergent innervation patterns and their implications for post-transplant functional recovery remain understudied. This review summarizes the anatomical and functional differences of the vagus nerve in the liver and pancreas, and discusses how surgical denervation and incomplete re-innervation affect endocrine recovery after liver and pancreatic transplantation. At the anatomical level, vagus nerve fibers in the liver are relatively sparse and travel along the portal tripa, mainly terminating in the perihilar blood vessels and biliary tract ecological loci, with limited direct parenchymal synapses. This structure is conducive to metabolic perception and indirect regulation of liver glucose flux, bile acid-dependent signaling, and inflammatory tension. In contrast, pancreatic vagus nerve input enters through periarterial/periductal channels and is relays through pancreatic ganglia, forming dense cholinergic efferent control over pancreatic islet α/β/δ cells, supporting rapid and precise insulin-glucagon coordination and counterregulation responses. Clinically, recent preclinical trials and translational studies demonstrate that vagal nerve integrity-often compromised during transplant surgery-serves as a pivotal prognostic marker for endocrine recovery: Preserved vagal innervation is associated with accelerated glucose metabolism normalization and reduced post-transplant complications (e.g., insulin resistance, graft rejection). Notably, frontier strategies such as intraoperative vagal nerve-sparing techniques, targeted neuromodulation (e.g., vagus nerve stimulation), and stem cell-derived neurotrophic factor delivery have shown promising potential in mitigating denervation-induced endocrine dysfunction. This review emphasizes that deciphering the organ-specific vagal innervation mechanisms holds great promise for optimizing precision transplant surgery and developing novel neuromodulatory therapies, which may revolutionize the prognosis of liver and pancreatic transplant recipients.

Key Words: Vagal nerve; Liver/pancreas; Transplantation; Endocrine homeostasis; Organ-specific innervation; Neuromodulation

Core Tip: The differences in vagal innervation between the liver and pancreas play an important role in the recovery of endocrine function after transplantation. Cutting-edge strategies such as intraoperative vagus nerve preservation techniques, targeted neuromodulation, and stem cell-derived neurotrophic factor delivery have shown new prospects for improving endocrine dysfunction after transplantation. Future research should focus on the organ-specific mechanisms of vagal innervation, and the development of novel neuromodulatory therapies is of great significance for transplant recipients.

INTRODUCTION

Organ transplantation, especially liver and pancreas transplantation, has become an effective means of treating end-stage organ failure. Despite significant progress in transplant surgery and immunosuppressive strategies, many transplant recipients still face postoperative endocrine dysfunction problems, such as insulin resistance and glucose metabolism disorders. These complications are often associated with damage to the neural regulatory network, especially to the vagus nerve. Within the parasympathetic nervous system (PNS), the vagus nerve plays a significant role in maintaining the body’s homeostasis, especially in regulating the functions of the liver and pancreas, and has gradually received more attention in recent years[1]. At present, the relevant anatomical and functional research on how to restore the endocrine function of transplanted organs is still insufficient. Recent studies have shown that the state of organ denervation caused by transplantation may be one of the key factors in this predicament[2]. For instance, in liver transplantation, the persistent denervation state is associated with the disruption of the metabolic homeostasis of the transplant recipient. As the vagus nerve is an important component of the liver's neural regulatory network, this suggests that neural integrity cannot be ignored in the functional recovery of organ transplantation. This discovery has led the academic community to re-examine a major issue: The separation of the organ's inherent neural network by surgical operations is not insignificant; it determines whether the graft can restore the homeostasis of its internal mechanism. Meanwhile, modern medicine has begun to adopt cutting-edge strategies such as targeted neural regulation and preservation of the vagus nerve during surgery to alleviate the side effects brought about by denervation.

The public’s attention is thus drawn to the vagus nerve that controls these organs. As the main pathway connecting the brain and internal organs, the vagus nerve is the regulator of metabolic homeostasis. Its innervation pattern is not uniform but shows distinct organ-specific characteristics. In the liver, vagus nerve fibers form a macro-regulatory network covering the portal vein and peripheral blood vessels, playing a regulatory role in glucose and lipid metabolism in the liver[3]. In contrast, in the pancreas, the autonomic nerve (including the vagus nerve) directly affects the activity of endocrine island cells and insulin secretion through a rich local neural network. This difference reflects the essential distinctions in anatomical structure and neural regulation patterns. This leads to a pivotal question: Do the fundamental differences in vagal innervation between the liver and pancreas predetermine divergent paths for endocrine recovery following surgical denervation during transplantation? Therefore, an in-depth study of the differences in vagus nerve anatomy and function between the liver and the pancreas can help explain why these two organoids exhibit different patterns in endocrine recovery after transplantation. This review aims to update the latest research achievements in the field of vagus nerve involvement in liver and pancreas transplantation. It further explores how the integrity of the vagus nerve affects the recovery of endocrine function after these transplantations, thereby providing theoretical support for precise transplantation surgery and neuroregulation treatment (Figure 1).

Figure 1 Organ-specific vagus nerve innervation in liver-pancreas transplantation: Mechanisms and therapeutic interventions. Preganglionic neurons originating from the dorsal motor nucleus and nucleus ambiguus give rise to hepatic and pancreatic branches. The hepatic branches traverse alongside the portal vein, regulating glucose uptake and bile-acid metabolism, while the pancreatic branches synapse with α, β, and δ cells to maintain the balance between insulin and glucagon. Transection of these nerves during organ retrieval and implantation results in hepatic insulin resistance, glucose dysregulation, and cholestasis, subsequently leading to islet dysfunction, endocrine imbalance, and post-transplant diabetes, which increases the risk of rejection and delays recovery. We propose three interventions: Preserving the nerves during dissection; applying low-frequency vagus nerve stimulation to the hepatic branch to enhance metabolic function; and injecting stem-cell-derived neurotrophic factors into the portal vein to facilitate nerve regeneration. Neural elements are depicted in yellow, injury in orange, and therapy in green.

ANATOMICAL DIFFERENCES IN THE VAGAL INNERVATION PATTERNS OF THE LIVER AND PANCREAS

Anatomical mechanism of the vagus nerve innervation pattern in the liver

The vagus nerve innervation of the liver is mainly achieved through the hepatic branches emitted by the anterior and posterior vagus nerve stems. The hepatic branch mainly originates from the anterior vagus nerve trunk, and a small amount of fibers pass through the abdominal branch of the posterior trunk, forming an interlaced plexus with related nerve structures, and then jointly project to the hilar region of the liver. After entering the hepatoduodenal ligament, nerve fibers often travel alongside the hepatic artery and portal vein, forming stable neurovascular bundles, which are distributed along the potential anatomical gap between the Laennec membrane and the Glisson sheath, and then branch out step by step according to the structure of the liver segment[4].

At present, the research results of multimodal imaging, electron microscopy observation and three-dimensional reconstruction basically consistently show that the overall distribution density of vagus nerve fibers in the liver is relatively low, and their terminals are mostly confined to the structures related to the portal region, such as bile ducts, vascular walls and surrounding interstitial tissues, and rarely directly enter the liver lobular parenchyma and form typical synaptic connections with liver cells[5,6]. Based on this phenomenon, while a local direct effect exerted via mechanisms such as non-synaptic chemical transmission cannot be ruled out, existing anatomical evidence provides stronger support for the dominant role of indirect regulation.

Anatomical mechanism of the pancreatic vagus nerve innervation pattern

Pancreatic vagal innervation is organized into vessel-guided anterior and posterior plexuses that converge on intrapancreatic ganglia, thereby enabling region- and compartment-specific control of endocrine islets vs exocrine acini/ducts. Due to the significant functional differences between the endocrine and exocrine parts of the pancreas, the distribution of its neural network not only follows the law of neurovascular co-progression but also form a neural innervation pattern enabling precise regulation[5].

The core pancreatic vagal branches derive from the peritoneal and posterior gastric vagal branches, which first undergo synaptic integration at the peritoneal ganglion and then differentiate into the anterior and posterior pancreatic nerve tracts. The anterior tract runs along the pancreatic upper edge. The posterior tract adheres closely to the posterior pancreatic head, runs parallel to the portal and superior mesenteric veins, and extends toward the pancreatic body and tail. This neurovascular parallelism is not a simple association but underpins precise vagal signal transmission to distinct pancreatic regions[7]. Fluorescence imaging reveals that upon entering the pancreatic parenchyma, vagal fibers exhibit clear functional specialization: One subset projects densely to the islets, while the other distributes in the acini and ductal spaces of the exocrine pancreas[8].

Observation data under electron microscopy show that cholinergic fibers account for approximately 65% of the pancreatic vagus nerve, which directly trigger the insulin secretion activity of pancreatic β cells by releasing acetylcholine. Peptide energy fibers account for 30% and mainly participate in the regulatory process of pancreatic juice synthesis and release[9]. Meanwhile, the pancreas is innervated by a vast array of vagal afferent fibers, which are involved in sensing fluctuations in blood glucose levels, local inflammatory states, and changes in the tissue microenvironment[7,10]. Three-dimensional imaging and optical tracing studies further reveal that the pancreatic neural network presents a highly three-dimensional and cell type-specific tissue pattern in space[11]. For the distinctions between pancreatic and hepatic innervation, refer to Table 1[12-17].

Table 1 The distinctions between pancreatic and hepatic innervation.

Comparative dimensions	Vagus nerve of the liver	Vagus nerve of the pancreas	Ref.
Structural characteristics	Most vagal nerve fibers travel along with the portal vein-hepatic artery-bile duct (the hepatic hilum/portal triad) and their surrounding structures, forming a general distribution pattern of vascular-biliary associated pathways. The liver lacks intrinsic neurons/ganglia, and its neural regulation relies more on the input of exogenous autonomic nerves (including both vagal afferents and efferents)	The pancreas possesses distinct intrapancreatic ganglia/neural networks, which can project to structures such as acini, ducts and islets of Langerhans. The entry and distribution of nerve fibers are typically characterized by dual perivascular and periductal pathways	[12-15]
Neural components	It comprises both vagal afferents and efferents, and together with sympathetic nerves and spinal afferents, forms the neural input-output framework of the liver. Within the neural pathways of the liver-brain axis, vagal hepatic afferent signals represent a crucial component, which is responsible for transmitting interoceptive information to the brainstem and central nervous system for integration	Vagal efferents: Preganglionic neurons originate from the dorsal motor nucleus of the vagus nerve, project first to the intrapancreatic ganglia, and then cholinergic postganglionic fibers act on target structures such as pancreatic islets. Vagal afferents: The somata of sensory neurons are located in the nodose ganglion, with their fibers projecting back to the relevant brainstem nuclei; spinal afferents are also involved in this process	[8,13,15,16]
Functional characteristics	It further highlights the “perception-central integration-feedback regulation” axis of metabolic status: The liver transmits interoceptive signals including nutritional, metabolic and inflammatory cues to the brain, which contributes to the maintenance of metabolic homeostasis	It further emphasizes the rapid and precise regulation of secretory activities: The vagal pathway is involved in the secretion and regulation of pancreatic islet hormones during the preprandial and prandial phases; its parasympathetic cholinergic inputs can potentiate secretory responses such as insulin release	[16,17]
Innervation characteristics	It is characterized by lower density, weaker local synaptic networks, a higher proportion of afferent signals, and indirect regulation: Owing to the absence of intrinsic ganglia in the liver, the structural basis for local short reflexes is relatively weak, thus rendering the liver more reliant on integrated output regulation at the central level	It is featured by a higher degree of local organization, dense synaptic connections and direct regulatory effects: The hierarchical architecture consisting of preganglionic neurons, intrapancreatic ganglia and postganglionic cholinergic fibers provides the anatomical basis for rapid and highly plastic local regulation	[13,16]

ORGAN-SPECIFIC FUNCTIONAL DIVERSITIES IN VAGAL REGULATORY MECHANISMS

Regulation of hepatic glucose and bile acid metabolism by the vagus nerve

Maintenance of metabolic homeostasis necessitates bidirectional communication between visceral organs and the central nervous system. Vagal sensory neurons, residing in the vagal ganglia, are responsible for transmitting interoceptive signals from visceral tissues to the medulla oblongata[18]. These neurons display substantial heterogeneity in terms of molecular profiles, anatomical connections, and physiological functions[19]. Each subtype of vagal sensory neuron, characterized by unique molecular markers, exhibits selective innervation of specific target organs, including the larynx, stomach, intestines, pancreas, heart, and lungs[20]. Emerging studies have demonstrated that the highly specialized cellular, molecular, and anatomical organization of vagal sensory neurons is essential for the accurate sensing, integration, and transduction of interoceptive signals. This specialized configuration not only plays a crucial role in the regulation of metabolic homeostasis but also participates in the modulation of other vital physiological processes, such as respiratory control and reward-related signaling.

The enteroinsular axis, encompassing both hormonal and non-hormonal components, contributes to the precise regulation of glucose metabolism[21]. Neural mechanisms, most notably PNS activation, have been implicated in the modulation of glucose homeostasis during the postprandial period, primarily by potentiating the secretory capacity of pancreatic β-cells in response to nutrient ingestion[22]. Furthermore, bile acids (BAs) have emerged as critical regulators of gut hormone release-with glucagon-like peptide-1 representing the major effector-and are involved in the fine-tuning of postprandial glycemic control[23].

The vagus nerve, via its cholinergic signaling axis, orchestrates profound reprogramming of hepatic metabolic flux-favoring glycolysis and de novo fatty acid biosynthesis at the expense of β-oxidation and gluconeogenesis-with this regulatory effect supported by both surgical and genetic experimental evidence[24]. Specifically, our analysis of topologically enriched metabolic modules (glycolysis/gluconeogenesis and lipid metabolism) identified that vagotomy (VNX) induces a coordinated shift in the transcriptional profiles of key metabolic enzymes: Upregulating those pivotal to glycolytic flux, de novo fatty acid synthesis initiation/elongation, endoplasmic reticulum-localized fatty acid elongation, and ω-oxidation, while concurrently downregulating core enzymes governing β-oxidation, acyl-CoA oxidase 1 and acetyl-CoA acyltransferase 1A, and gluconeogenesis (fructose-1,6-bisphosphatase 1 and phosphoenolpyruvate carboxykinase 1) following VNX. Complementary genetic evidence from VAChT-KDhom (homozygous vesicular acetylcholine transporter knockdown mice)-an experimental model where acetylcholine release is diminished owing to a 60%-70% reduction in VAChT expression[25]-further corroborates this cholinergic-dependent regulation: Quantitative analysis of hepatic tissues isolated from VAChT-KDhom mice revealed marked upregulation of glucokinase and fatty acid synthase. Collectively, these findings delineate that the vagus nerve executes a pan-regulatory role in fine-tuning the homeostatic balance of the hepatic metabolic interactome, underscoring that the vagus nerve and vagal cholinergic system mediate a substantial reprogramming of hepatic metabolic flux toward glycolysis and fatty acid biosynthesis[24].

BAs are endogenously synthesized and conjugated in hepatocytes, subsequently stored in the gallbladder, and secreted into the intestinal lumen in response to nutrient ingestion[25]. Following microbial-mediated modifications-including deconjugation and biotransformation of primary BAs to secondary Bas-the resultant BA fractions are sequestered within the semi-liquid chyme of the distal intestine[26]. Approximately 95% or more of the total BA pool is reabsorbed at the terminal ileum and retrogradely transported to the liver through the enterohepatic circulation[27]. Beyond their canonical function in facilitating lipid digestion and absorption, BAs have been increasingly recognized as pleiotropic metabolic modulators that contribute to the regulation of energy expenditure and glucose homeostasis[28,29].

As a key mediator of the brain-liver axis, the vagus nerve orchestrates hepatic glucose and BAs metabolism through a “two-pronged” regulatory mechanism. On one hand, it directly regulates hepatic glucose production by modulating the activity of key gluconeogenic enzymes and the expression of glucose metabolism-related genes via cholinergic signaling pathways. On the other hand, the vagus nerve indirectly affects glucose metabolism by shaping the composition and signaling functions of BAs in the liver and enterohepatic circulation. Specifically, vagal activation alters the profile of hepatic BAs (e.g., the ratio of conjugated to unconjugated BAs), which in turn modulates the activation of BAs-activated nuclear and membrane receptors, specifically Farnesoid X receptor and G Protein-Coupled BAs receptor 1[25] in hepatocytes and intestinal epithelial cells, thereby regulating glucose homeostasis at the systemic level. This dual regulatory effect of the vagus nerve underscores its central role in hepatic metabolic regulation and provides a potential therapeutic target for metabolic disorders such as T2DM and non-alcoholic fatty liver disease.

Regulation of the pancreatic insulin-glucagon axis by the vagus nerve

The direct innervation of pancreatic islets by vagal efferent fibers constitutes the anatomical prerequisite for vagal modulation of the pancreatic insulin-glucagon axis, and this innervation pattern exhibits prominent interspecies and regional heterogeneity. For instance, the density of vagal innervation to pancreatic islets is comparatively higher in rodents than in humans; within the pancreas, innervation density is greater in the central region relative to the peripheral parenchyma. For greater functional relevance, cholinergic receptors (predominantly muscarinic 3 muscarinic subtypes) are widely expressed on the plasma membranes of both pancreatic β-cells (insulin-secreting) and α-cells (glucagon-secreting). This ubiquitous receptor distribution enables vagal nerve fibers to transduce cholinergic signals directly to islet endocrine cells, thereby establishing a structural framework that underpins the precise, cell-type-specific regulation of the insulin-glucagon axis.

The vagus nerve plays a pivotal role in the regulation of energy metabolism, food intake, and glycemic homeostasis, which is attributed to its dominant regulatory control over pancreatic endocrine hormone secretion[18]. Early preclinical investigations in rat models demonstrated that electrical stimulation of the vagus nerve modulates the secretory profiles of insulin and glucagon from pancreatic islet cells[30,31]. However, prior preclinical and clinical investigations focusing on the regulatory modalities through which vagus nerve stimulation (VNS) modulates glycemic dynamics and glucose metabolism-associated hormones have reported discrepant outcomes.

Low-frequency electrical stimulation of the VNS (5-30 Hz) elicits concurrent activation of vagal afferent fibers-responsible for conveying interoceptive signals to the central nervous system-and efferent fibers that provide innervation to the pancreas and other critical visceral organs[32]. Studies that strictly control confounding variables (including pulse width, current intensity, and stimulation duration) while only adjusting the stimulation frequency or target site have clearly defined the specific glycemic regulatory effects and differences in the underlying mechanisms mediated by these two types of fibers. Specifically, 5 Hz VNS delivered to the cervical vagus nerve of rats significantly increases fasting blood glucose levels[32,33]. In contrast, maintaining the 5 Hz frequency but shifting the stimulation to the peripheral end of the cervical vagus nerve (efferent fiber-dominated) in type 2 diabetic rats reduces blood glucose responses during the oral glucose tolerance test. This diametrically opposite effect is essentially due to the different regulatory pathways mediated by afferent and efferent fibers[34]. Consistently, 30 Hz VNS targeted at the abdominal vagus nerve of obese rats effectively decreases fasting blood glucose and improves insulin resistance, whereas 10 Hz stimulation exerts no significant metabolic effects, further confirming the obvious frequency dependence of low-frequency VNS in glycemic regulation.

Browning et al[35] further clarified the differential regulatory roles of vagal afferent and efferent signals through an experimental design in rats where the 5 Hz stimulation frequency and other parameters were fixed, with only the stimulation site of the cervical vagus nerve altered[32]. Stimulation of the central end of the transected cervical vagus nerve (afferent fiber-dominated) increased blood glucose by activating the hypothalamic-sympathetic pathway; conversely, stimulation of the peripheral end (efferent fiber-dominated) reduced blood glucose by regulating pancreatic insulin secretion. These findings provide direct experimental evidence for the bidirectional glycemic regulatory mechanism mediated by vagal afferent and efferent fibers. In contrast, high-frequency VNS (including optogenetic high-frequency stimulation) regulates blood glucose by targeting specific nerve branches. For example, confining stimulation to the pancreatic branch of the vagus nerve reduces blood glucose by promoting β-cell proliferation and insulin secretion, which reflects the site-specific regulatory feature of high-frequency VNS. In addition, high-frequency stimulation or selective fiber stimulation at a fixed site can further help alleviate glucose metabolic disorders by regulating the gut-brain axis pathway[35].

A pivotal distinction between the functional contributions of vagal afferent and efferent signaling was delineated via targeted stimulation of the proximal or distal transected segments of the cervical vagus nerve in rats at 5 Hz. This experimental maneuver elicited two distinct glycemic responses: An afferent-mediated elevation in glycemia, or an efferent-dependent reduction in glycemia, with both outcomes attributed to concomitant modulations in pancreatic endocrine hormone secretory profiles[36]. In a contrasting experimental paradigm, high-frequency vagal stimulation in the kilohertz range is postulated to exert a nerve conduction-blocking effect, thereby abrogating both afferent and efferent signaling to the pancreas and liver. High-frequency electrical stimulation at 5 kHz is postulated to interrupt the transduction of vagal afferent “hunger” signals to the central nervous system, a therapeutic approach clinically implemented for the management of obesity[37,38]. Of note, this neuromodulatory intervention also confers a hypoglycemic benefit in patients with diabetes mellitus by lowering fasting plasma glucose concentrations and HbA1c levels[39].

As such, elucidating the innervation-specific regulatory pattern of the vagyus nerve-which govern the distinct modulation of pancreatic hormone secretion (insulin/glucagon dynamics) and hepatic glucose metabolism via organ-specific vagal fiber subsets-represents a foundational prerequisite for advancing the mechanistic understanding of the coordinated vagal control over pancreatic-hepatic glucose homeostasis[32].

COMPLICATIONS OF VAGAL NERVE INJURY AND ITS REGULATORY DURING HEPATIC AND PANCREATIC TRANSPLANATION

Causes of intraoperative vagal nerve injury

Vagal nerve injury in hepatopancreatic transplantation is mostly iatrogenic and closely related to specific surgical steps and operative techniques. The main reason is the traditional belief that nerve transection is an unavoidable consequence of adequate exposure. Direct injury caused by anatomical separation and necessary ligation: To free the organ and complete vascular anastomosis, the surgeon must sever the ligaments, mesenteries and connective tissues around the target organ. The hepatic and abdominal branches of the vagus nerve often pass through these structures. For example, in liver transplantation, amputation of the hepatogastric ligament and the hepatoduodenal ligament is a routine step, while the hepatic branch of the vagus nerve (HBVN) runs within the hepatogastric ligament and enters the hepatic portal along with the hepatic artery[40]. Similarly, during pancreatic transplantation or related complex surgeries (such as donor pancreas acquisition), it is very easy to damage the vagus nerve fibers that innervate the pancreas when separating the tissues around the pancreatic head and neck. A clinical study has confirmed that in laparoscopic pancreaticoduodenectomy, preserving HBVN can significantly reduce the incidence of delayed postoperative gastric emptying[41]. This indirectly suggests that in the liver-pancreas transplantation area with similar anatomical structures, the risk of nerve injury and its clinical consequences are equally alarming. Mechanical traction and compression caused by exposure of the surgical field: To obtain a sufficient surgical field of view, hepatopancreatic transplantation often requires the use of wide retractable hooks to forcefully pull apart organs such as the costal arch, liver or stomach. This prolonged and extensive mechanical traction can directly act on the vagus nerve trunks or their branches that run around the esophageal hiatus and within the abdominal cavity, causing traction or compression injuries to the nerves. The occurrence of various peripheral neuropathy after liver transplantation suggests that surgery-related factors may affect neurological function[42]. Thermal diffusion damage caused by the use of energy equipment: Thermal energy from electrosurgical and ultrasonic devices can damage vagal nerve branches, impairing conduction function. This kind of damage is often concealed and irreversible. The inherent “functional denervation” of transplant surgery: The nature of organ transplantation determines that all external neural connections of the donor organ are completely cut off during the acquisition process. Therefore, the transplanted liver or pancreas is in a “denervation” state in the initial stage. Although there is evidence suggesting that there may be limited neural regeneration after transplantation[43], this process is slow, incomplete, and the degree of functional recovery is highly uncertain. Therefore, it is of great physiological significance to protect the residual vagus nerve structure and function on the receptor side to the greatest extent and create conditions for potential neural regeneration and functional connectivity.

Impact of vagal nerve integrity on postoperative period

Protecting the integrity of the vagus nerve has multiple positive implications for early graft protection after transplantation and the stable recovery of multiple system functions. Reducing ischemia-reperfusion injury: Ischemia-reperfusion injury is an important inducement for early graft dysfunction and rejection after transplantation. The “cholinergic anti-inflammatory pathway” activated by the vagus nerve is a key physiological anti-inflammatory mechanism[44]. Studies have shown that neural regulation may affect the repair process of transplantation-related injuries[45]. The mechanism by which the vagus nerve regulates inflammatory responses through α 7nAChR provides a theoretical basis for its role in transplant protection[46]. Promoting the recovery of gastrointestinal motility and reducing related complications: The vagus nerve is the “master switch” for regulating the motility of the upper digestive tract, and its integrity is crucial for the early recovery of gastrointestinal function after surgery. Studies have confirmed that preserving HBVN during pancreaticoduodenectomy is an independent protective factor for reducing the incidence of delayed postoperative gastric emptying[41]. Preservation of the vagus nerve may also have a positive impact on postoperative metabolic regulation[47]. In liver transplantation, delayed gastric emptying can affect the implementation of early enteral nutrition and prolong the hospital stay. Therefore, protecting the vagus nerve has direct clinical benefits. Regulating metabolism and potentially supporting regeneration: In addition to anti-inflammation and regulating gastrointestinal motility, the vagus nerve is also deeply involved in the regulation of metabolic homeostasis. Metabolic disorders after transplantation are associated with multiple factors[48], among which the metabolic impact of immunosuppressants deserves attention[49]. Neural regulation may affect metabolic balance through multiple pathways[50]. Clinical studies have shown that metabolic abnormalities are associated with changes in specific biochemical indicators[51]. In the context of liver transplantation, the graft needs to quickly adapt to the metabolic environment within the host and restore its function. Any intrinsic mechanism that can support its metabolic adaptation and repair and regeneration is of great value. Neurological function recovery after pancreatic transplantation may improve metabolic regulation[52]. Protecting the vagus nerve may be a potential favorable factor in supporting this process.

Recovery of endocrine function after liver and pancreas transplantation

The reconstruction of endocrine function after transplantation, especially the homeostasis of glucose metabolism, is the core factor determining the long-term quality of life and prognosis of patients. Vagal nerve injury can interfere with this precise process through multiple pathways. New-onset diabetes after liver transplantation: The incidence of new-onset diabetes after liver transplantation in recipients remains high, seriously affecting their quality of life[48]. The etiology is complex. Classic factors include the direct toxicity of immunosuppressants (such as tacrolimus and glucocorticoids, which can damage the function of pancreatic β cells and aggravate insulin resistance)[49]. In this context, vagal nerve injury may act as an additional, non-exclusive factor that could further weakens the anti-inflammatory effect, and might also reduces hepatic insulin sensitivity by down-regulating the α7nAChR-STAT3 (signal transducer and activator of transcription 3) signal, constituting a potential second blow of deteriorating glucose metabolism[50]. Aggravating insulin resistance: The vagus nerve, through its anti-inflammatory effect, helps improve insulin sensitivity throughout the body and in the liver[45]. The subclinical low-grade inflammatory state resulting from nerve injury may amplify insulin resistance caused by surgical trauma and immunosuppressants. Interfering with BAs metabolic signals: The vagus nerve is involved in regulating the hepatointestinal circulation of BAs. BAs are not only components of digestive juices but also important metabolic signaling molecules. Clinical studies have shown that the level of 12α-hydroxylated BAs in the plasma of patients with insulin resistance is elevated[51]. The denervation state of the liver after transplantation may disrupt the normal BAs signal feedback loop, thereby having an adverse effect on glucose metabolism. The neuroendocrine reconstitution challenge of pancreatic transplantation: Pancreatic transplantation is an effective method for treating insulin-dependent diabetes, aiming to restore physiological insulin secretion. Successful transplantation can free patients from exogenous insulin and stabilize or even reverse some diabetic complications[52]. However, transplanted pancreas also faces the inherent defect of “denervation”, losing the fine regulation of the central nervous system (including the vagus nerve). This means: First-phase insulin secretion deficiency: The transplanted pancreas fails to respond to vagus nerve signals triggered by vision, smell or chewing food, resulting in weakened insulin secretion in the “first phase” of postprandial blood sugar and a decline in the early control ability of blood sugar. Impaired reverse regulation of hypoglycemia: The vagus nerve plays a key role in perceiving and responding to hypoglycemia and coordinating the secretion of glucagon. Interruption of this pathway may lead to changes in the hypoglycemic perception threshold, sluggish responses to reverse regulatory hormones, and an increased risk of severe hypoglycemic events. Uncertainty of neural regeneration: Despite the evidence of neural regeneration[41], this process is influenced by multiple factors, such as surgical techniques, the potential neurotoxicity of immunosuppressants, and the severity of pre-existing diabetic neuropathy in patients before surgery. The degree and quality of neural re-innervation are directly related to whether the transplanted pancreas can reconstruct neuroendocrine regulation close to physiological conditions.

CUTTING-EDGE INTERVENTION STRATEGIES: NEUROPROTECTION AND NEUROMODULATION-DECIPHERING MECHANISMS TO OPTIMIZE PRECISION TRANSPLANTATION PROTOCOLS

In the field of hepatopancreatic transplantation, the focus is gradually shifting from merely pursuing surgical success to ensuring the long-term stability of the endocrine and metabolic functions of grafts. As the core pathway connecting the central nervous system to metabolic organs, the loss of vagus nerve innervation is a key factor leading to post-transplant dysfunction. Therefore, exploring perioperative neuroprotective strategies and postoperative neural function regulation or regeneration therapies represents a cutting-edge direction for achieving precision transplantation and improving patients’ long-term prognosis.

Vagus nerve protection techniques in hepatopancreatic transplantation

Currently, liver transplantation features several of the most challenging procedural steps, namely manual end-to-end anastomosis of the suprahepatic vena cava, cuff-type anastomosis of the portal vein, and strict control of the anhepatic phase to a duration of less than 20 minutes[53]. At present, most pancreatic transplantation surgeries adopt enteric drainage and systemic venous drainage[54]. The procurement process of donor livers and pancreata inevitably severs the nerve plexuses surrounding the hepatic artery and splenic artery. Therefore, current research focuses more on functional protection or improving transplant outcomes by regulating neural pathways. Preclinical studies have shown that VNS, as a neuromodulatory approach, exhibits protective potential against transplant-related injuries. Research has confirmed that in a rat model of hepatic ischemia-reperfusion injury, VNS can inhibit cardiomyocyte ferroptosis by activating the SLC7A11-GPX4 axis thereby alleviating remote cardiac injury[55]. This suggests that mitigating ischemia-reperfusion injury during transplantation by regulating neural activity may serve as an indirect neurofunctional protection strategy. However, there is no available literature supporting clinical studies on direct vagus nerve anastomosis or specific preservation techniques during hepatopancreatic transplantation.

Vagus nerve-targeted neuromodulation

When the anatomical integrity of nerves cannot be preserved, targeted functional regulation emerges as a highly promising alternative strategy. VNS can regulate systemic and local inflammation through the powerful cholinergic anti-inflammatory pathway, holding dual value in the field of transplantation. Studies have found that the modulation of glucose-sensitive neuronal activity in the lateral hypothalamic area by gastric vagal afferents may play an important role in the short-term regulation of feeding[21]. As an emerging neuromodulation technology, VNS has demonstrated remarkable potential in the treatment of disorders of consciousness in recent years due to its ability to remotely regulate key brain network activities, inhibit neuroinflammation, and enhance neuroplasticity[56]. Multiple studies have applied low-level VNS to suppress atrial fibrillation induction. Low-level VNS denotes electrical modulation of the vagus nerve that does not induce sinus bradycardia or impair atrioventricular conduction; as a promising therapeutic strategy for atrial fibrillation, it can suppress autonomic nervous system remodeling and abrogate the formation of vicious pathological cycles[57]. These findings provide a theoretical basis for using VNS as an adjuvant therapy to improve graft survival rate and function.

Stem cell-derived neurotrophic factor delivery therapy

With the development of biomedicine, neurotrophic factors, as therapeutic agents for neural repair, play an irreplaceable role in restoring and maintaining the functions of neurons in the peripheral and central nervous systems[58]. Promoting vagus nerve-specific regeneration within grafts is the core goal for restoring their complete neural regulation. Stem and progenitor cells exert a multifaceted role in kidney diseases, as they possess the capacity to facilitate tissue regeneration, mediate immune modulation and preserve renal homeostasis[59]. Promoting neural regeneration within grafts is an ideal goal for restoring their complete neural regulation. Mesenchymal stem cells (MSCs) are a group of multifunctional pluripotent precursor cells with excellent self-renewal and differentiation capabilities[60], can serve as efficient vehicles for delivering neurotrophic factors that specifically promote vagus nerve regeneration. Exosomes derived from MSCs are rich in various bioactive molecules and can regulate the immune microenvironment, thereby creating a favorable niche for vagus nerve-specific regeneration. Studies have shown that insulin-like growth factor 1 receptor (IGF1R) is capable of interacting with checkpoint kinase 2 (CHK2) to mediate DNA damage, while human umbilical cord MSCs (HUcMSCs) exert a protective effect on renal injury in diabetic rats. HUcMSCs mediate the IGF1R-CHK2-p53 (tumor protein p53) signaling pathway, which is a potential mechanism for the treatment of diabetes[61]. Although MSCs have yielded certain therapeutic efficacy in the early phase of clinical application, their application potential is enormous and has not yet been fully exploited due to various reasons. One key underlying cause is that oxidative damage triggered by oxidative stress (OS) impairs the in vivo engraftment and functional performance of MSCs. Ferroptosis, a form of regulated cell death triggered by OS, is characterized by iron-dependent overaccumulation of cytotoxic reactive oxygen species and lipid peroxides, accompanied by plasma membrane disruption that ultimately culminates in cell demise. Therefore, inhibiting MSC ferroptosis is essential to ensure the sustained delivery of neurotrophic factors for vagus nerve-specific regeneration, thereby enhancing the regenerative efficiency and realizing the therapeutic potential. Therefore, targeted strategies for inhibiting ferroptosis in MSCs should be developed to enhance their proliferation and regeneration capabilities and realize their therapeutic potential. Iron chelators and free radical-scavenging antioxidants may be new approaches to achieve this goal, which are worthy of further research in MSCs[62].

CONCLUSION

As a critical pathway connecting the central nervous system and metabolic organs, the vagus nerve exhibits remarkable organ-specific differentiation in innervation between the liver and pancreas. The hepatic vagus nerve is predominantly composed of a low-density network accompanying the portal region/biliary tract and blood vessels, which is more characterized by sensory input and indirect regulation, thereby influencing hepatic glucose metabolic flux, BAs signaling, and the threshold of inflammatory responses. In contrast, the pancreatic vagus nerve features a high-density, strongly cholinergic efferent innervation centered on the islets of Langerhans, enabling rapid and precise spatiotemporal regulation of α/β/δ cells. These anatomical and functional disparities provide a structural and mechanistic basis for explaining the divergent trajectories of endocrine recovery following liver and pancreas transplantation.

In the future, neural integrity should be incorporated into the concept of precision transplantation. On the one hand, high-resolution three-dimensional neural anatomy and intraoperative nerve preservation/monitoring should be employed to minimize iatrogenic injury as much as possible. On the other hand, clinical translational studies on parameter-controllable and precisely targeted vagus nerve modulation (e.g., VNS) should be carried out, which can be combined with regenerative strategies (e.g., stem cell-derived neurotrophic factors to improve the graft microenvironment and promote reinnervation) to form combined interventions. By systematically exploring the differences in vagal innervation between the liver and pancreas, this review provides an important breakthrough for optimizing transplantation protocols and restoring post-transplant endocrine function.