Role of physical exercise, vagal nerve stimulation, and vagotomy in inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis, represents the two predominant clinical entities within this spectrum of gastrointestinal disorders. Current evidence indicates that the etiology of IBD is multifactorial, involving a complex interplay between host genetic susceptibility and environmental determinants. In recent years, non-pharmacological strategies such as physical exercise and vagus nerve stimulation have gained increasing attention as adjunctive therapeutic approaches. Vagus nerve stimulation has emerged as a promising therapeutic modality, particularly in conditions characterized by autonomic dysfunction and diminished vagal tone. Conversely, vagotomy, by disrupting vagal control, abolishes parasympathetic reflexes and may potentiate inflammatory responses and exacerbate IBD symptomatology under stress conditions. Physical exercise has likewise been investigated as a non-pharmacological intervention in Crohn’s disease and ulcerative colitis. Although the precise mechanisms remain to be fully elucidated, accumulating evidence suggests that skeletal muscle contractions promote the secretion of myokines, with recognized anti-inflammatory properties. These myokines act on the intestinal microenvironment, conferring protection against malignant transformation and modulating the composition and function of the gut microbiota. In this review, we critically examine the interplay between physical exercise, vagus nerve stimulation, and vagotomy in the pathophysiology and management of IBD, with particular emphasis on their immunomodulatory and therapeutic potential.

Key Words: Physical exercise; Vagus nerve stimulation; Subdiaphragmatic vagotomy; Inflammatory bowel disease; Crohn’s disease; Ulcerative colitis

Core Tip: The vagus nerve plays a central role in gut-brain communication and the modulation of gastrointestinal inflammation through the cholinergic anti-inflammatory pathway. In this review, we explore the distinct and complementary effects of physical exercise, vagal nerve stimulation, and vagotomy in inflammatory bowel disease. While physical exercise emerges as a non-pharmacological strategy capable of enhancing vagal tone and releasing anti-inflammatory myokines, vagal nerve stimulation offers direct neuromodulation of immune responses and mucosal integrity. In contrast, vagotomy disrupts parasympathetic signaling and exacerbates intestinal inflammation. Understanding how these interventions impact the vagus nerve and immune homeostasis provides insight into novel therapeutic approaches for inflammatory bowel disease management.

INTRODUCTION

The gastrointestinal tract (GIT) is composed of several organs that differ in structure, morphology, and function, acting sequentially to carry out the basic processes of food digestion and nutrient absorption[1]. In addition to these digestive functions, the GIT plays relevant roles in the endocrine and immunological systems, being essential for the maintenance of body homeostasis[2]. The autonomic nervous system (ANS) performs specific functions in regulating the body, such as cardiovascular activity, intestinal motility and metabolic control. It consists of a complex network of central and peripheral neurons, functionally organized into three main divisions: Sympathetic, parasympathetic and enteric, adjusting different physiological processes to the body’s needs[3]. Among these divisions, the enteric nervous system (ENS) stands out, known for its ability to act autonomously and for forming a complex network of neurons distributed along the GIT wall. In addition to directly controlling various gastrointestinal functions, the ENS maintains bidirectional communication with the central nervous system (CNS), constituting the so-called “gut-brain axis”[4-6]. Among the components that make up this axis, the vagus nerve acts as a cross-communication pathway between the gut and the brain[7]. This complex communication system involves, in addition to the vagus nerve, sympathetic connections, endocrine system, immunological changes, humoral and gut microbiota-related mechanisms[8]. There is a direct relationship between the vagus nerve and the immune system, allowing inflammation of the periphery to be detected by vagal afferent fibers and integrated into the brainstem, affecting the response in various pathological conditions[9]. As a result, an efferent vagal signal is generated, which modulates the immune response and plays a crucial role in the body’s homeostasis[10].

The interaction between the ANS and the intestinal immune system is of great importance in preserving tissue balance and regulating mucosal inflammatory responses, with the vagus nerve being a key component in this process, by directly modulating enteric neurons and, indirectly, immune cells[11]. Within this perspective, the pathophysiology of inflammatory bowel diseases (IBD) often involves complex brain-gut interactions, in which the vagus nerve can play a crucial role by innervating important parts of the gastrointestinal system[12]. Dysfunction of the brain-gut axis can exacerbate inflammation and intensify disease symptoms, and during this process, the vagus nerve performs a direct anti-inflammatory function through cholinergic inhibition of proinflammatory cytokines[13].

From this point of view, vagotomy is a surgical procedure that involves the removal of part of the vagus nerve. This procedure can be classified as truncal, when there is vagal denervation of the distal part of the esophagus and the region close to the stomach; or selective, when the nerve cut occurs only in the gastric portion, promoting the denervation of the parietal cells located in the upper portion of the stomach[14-16]. The vagotomy procedure has historically been used to study the physiological function of the vagus nerve in the face of pathological conditions in which the cholinergic pathway is involved, as well as to treat conditions such as peptic ulcer disease and gastroesophageal reflux, when conventional treatments fail to reduce symptoms[17]. However, the removal of this vagal control can significantly reduce parasympathetic reflexes, especially in stressful situations[18].

Vagus nerve stimulation (VNS) has been approved by the United States Food and Drug Administration (FDA) for the treatment of refractory epilepsy, chronic treatment-resistant depression, and chronic major depressive disorder unresponsive to conventional therapies[19]. The mechanisms underlying VNS involve the controlled activation of vagal fibers, resulting in afferent and efferent effects[20]. Afferent fibers, which constitute the majority of the vagus nerve, transmit visceral sensory information to the nucleus tractus solitarius (NTS) in the brainstem. From there, neural signals modulate autonomic, neuroendocrine, and behavioral circuits, with influence in regions such as the locus coeruleus, hypothalamus, and prefrontal cortex[21,22]. Efferent fibers mediate peripheral autonomic responses, including regulation of gastrointestinal motility, heart rate, and inflammatory cytokine release. This occurs primarily through activation of the cholinergic anti-inflammatory pathway, in which vagal stimulation inhibits the production of pro-inflammatory cytokines by interacting with α7 nicotinic acetylcholine (ACh) receptors on immune cells, a mechanism increasingly explored as a therapeutic target in IBDs and other immune-mediated conditions[23-25].

In IBDs, dysbiosis is commonly observed, characterized by an imbalance in the composition of intestinal microbial populations, which can accentuate inflammation and increase intestinal permeability[26]. Vagal stimulation can reverse these adverse effects, promoting a more balanced intestinal environment, helping to restore the integrity of the intestinal barrier and reducing the exacerbated immune response, making VNS a promising therapeutic approach for the treatment of IBDs[27,28]. In parallel with pharmacological approaches and direct neural interventions, physical exercise has gained prominence as an effective complementary strategy in the management of intestinal inflammation[29]. Regular aerobic exercise modulates the ANS, promoting an increase in parasympathetic tone and, consequently, in the anti-inflammatory cholinergic pathway[30]. In addition to directly influencing vagal tone, physical exercise reduces hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, often exacerbated in situations of chronic stress associated with IBD, promoting a reduction in circulating cortisol levels and systemic oxidative stress Exercise also induces the release of anti-inflammatory myokines, such as interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonist (IL-1ra), by skeletal muscle in response to muscle contraction, which can act autocrine, paracrine, and endocrine, directly influencing intestinal immune function[31]. It is also important to highlight that physical exercise increases the availability of neurotransmitters such as dopamine, serotonin (5-HT) and endorphins, which play central roles in regulating the gut-brain axis. These neurotransmitters are associated with improved mood, reduced perception of stress, and increased motility[32-34].

Based on this, the vagus nerve plays a central role in regulating gut inflammation through complex neuroimmune mechanisms, especially via activation of the cholinergic anti-inflammatory pathway[35,37]. Indeed, the anti-inflammatory effects of both physical exercise and VNS involve common pathways mediated by increased vagal tone and activation of the anti-inflammatory cholinergic reflex, both of which depend on the functional integrity of the vagus nerve[24]. In an animal model, it was shown that light exercise increased gastric motility only in animals with preserved vagal innervation, while vagotomy suppressed this effect, resulting in greater gastric retention and less weight gain[38]. Similarly, Silva et al[39] showed that both exercise and pyridostigmine attenuated delayed gastric emptying and cisplatin-induced hypotension, in addition to restoring baroreflex sensitivity, effects associated with cholinergic modulation. On the other hand, vagotomy can negatively impact the balance of pro- and anti-inflammatory cytokines under conditions of physiological stress, indicating a more complex and even antagonistic role in the beneficial effects of exercise and VNS[40]. This gap justifies the need for comparative studies, and it is proposed that an integrated investigation of the effects of physical exercise, VNS and vagotomy could elucidate the distinct and complementary mechanisms of these approaches in autonomic modulation and intestinal inflammation.

PATHOPHYSIOLOGY OF IBD

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic immune-mediated inflammatory disorders of the GIT, collectively referred to as IBD. Although it is not as common as diabetes or irritable bowel syndrome and has relatively low incidence rates, IBD is not considered a rare disease. There are currently almost 7 million people diagnosed worldwide, reflecting an increase in global prevalence of 85% since 1990[41]. IBD results from a complex interaction between genetic, immunological, microbial and environmental factors. It is suggested that it is the result of an uncontrolled immune response to stimuli from the microbiota and the environment in genetically susceptible individuals. In summary, its pathophysiology involves several mechanisms, including dysregulated immune responses, environmental factors, alterations in intestinal microorganisms (dysbiosis) and genetic alterations related to the disease. Some evidence shows associations between genotypes and the manifestation of these diseases, such as susceptibility to mycobacterial infection, dysfunctions in the ubiquitination system (translational modifications and protein degradation), dysregulation of nuclear factor κB (NF-κB), exacerbation of the inflammatory response mediated by the T helper cell (Th) 1/Th17 axis, with impairment of regulatory T cells (Tregs) functions. The role of environmental factors, whether as a stimulus or cause of the uncontrolled immune response, continues to be debated[42-44].

Speaking specifically of the two main phenotypes of IBD, UC is clinically defined as a chronic, nonspecific, recurrent IBD involving the rectum and mucosa of the colon. Its typical pathological feature involves inflammation of the mucosa and submucosa, ulcerations, and crypt abscesses, which can cause perforation, fistula, cancerous changes, pseudopolyp formation, toxic megacolon, and stenosis[45]. CD, on the other hand, initially described by Crohn BB[46] in 1932 (which justifies its name), is characterized by an inflammatory process that can affect any segment of the GIT, from the mouth to the anus, with the terminal ileum and colon being the most affected areas. This inflammation also occurs transmurally and may have greater intensity of symptoms than UC[47]. The chronic inflammation characteristic of CD has important symptoms including bleeding, abdominal pain, fecal urgency, and diarrhea, compromising the absorption of nutrients and contributing to the low quality of life of patients who are affected by this disease[48].

Changes in the gut microbiota in patients with CD are related to a reduction in the diversity and abundance of bacteria, more specifically of Firmicutes and Bacteroides, and an increase in Actinobacteria and Proteobacteria. There is also a lower abundance of butyrate-producing bacteria such as Faecalibacterium prausnitzii and Roseburia spp., while invasive and pathogenic bacteria such as Escherichia coli are more abundant[49]. In a predictive study of the manifestation of CD in individuals with a family history related to first-degree relatives based on the microbiota, important alterations related to Ruminococcus torques, Blautia, Colidextribacter, and in the genus Oscillospiraceae and Roseburia were observed[50]. These changes in the gut microbiota contribute to the activation of the immune system, as the presence of pathogenic microorganisms is associated with the release of pathogen-associated molecular patterns and activation of Toll-like receptor 4 (TLR4) through lipopolysaccharides (LPS) present in the membranes of gram-negative bacteria. The activation of these receptors allows the translocation of NF-κB, a factor that induces the transcription of pro-inflammatory cytokines and increased oxidative stress, triggering a cascade of inflammatory reactions in the GIT and activation of the immune system[51].

The progression of CD is marked by exacerbation of the inflammatory response, with dysfunctions in innate immunity of the intestinal mucosal barrier and remodeling of the extracellular matrix through the expression of matrix metalloproteinases and the increase of adhesion molecules, such as mucosal addressin cell adhesion molecule-1. This modified microenvironment facilitates the migration of leukocytes to the inflamed sites, promoting a Th1 response through cytokines such as IL-12 and tumor necrosis factor α (TNF-α). This imbalance contributes to transmural inflammation and granuloma formation, leading to complications such as stenosis, fistulas, and abscesses. Another important point is the increase in IL-23, which promotes chronic inflammation and contributes to the differentiation and maintenance of Th17 cells, a subtype of CD4+ T cells associated with autoimmune and inflammatory responses. Its main function is to amplify the inflammatory response by sustaining the proliferation of Th17 cells and the production of pro-inflammatory cytokines, such as IL-17, IL-22, and TNF-α, which exacerbate tissue damage and perpetuate intestinal inflammation, as well as suppressing the activity of Tregs, promoting a pro-inflammatory environment[51].

The typical pathological feature of UC especially involves inflammation of the mucosa and submucosa, ulcerations, and abscesses in the crypts[42]. Dysbiosis is seen in patients, although to a lesser extent than in patients with CD, and it is unclear whether it is a cause or effect of mucosal inflammation. Patients show decreased biodiversity, seen in the lower proportion of Firmicutes and increased gamma-proteobacteria, Enterobacteriaceae and Deltaproteobacteria, a sulfite-reducing bacterium in the colon[52]. Current evidence characterizes innate and adaptive cellular immunity as key to the pathogenesis of the disease, where antigens activate innate immunity through the action of antigen-presenting cells and T lymphocytes, triggering a series of inflammatory events that also stimulate the adaptive immune system The interaction between innate and adaptive immune responses is highly affected by several cytokines. Any interruption in this communication can lead to the initiation and propagation of an inflammatory response in the mucosal tissue[53].

Dendritic cells, which present antigens in the innate immune system and have high expression of TLRs, become more sensitive and activate several transcription factors, such as NF-κB, promoting inflammatory responses and consequently releasing pro-inflammatory cytokines, such as TNF-α, IL-1 and IL-6. The destruction of intestinal crypts in colitis results from the infiltration of inflammatory cells, such as T lymphocytes and neutrophils, which injure epithelial cells. The significant increase in neutrophils in the crypts, driven by IL-8, a cytokine with potent chemotactic action on these cells, contributes to the severity of the disease. In addition, cytokines such as TNF-α, IL-12, and IL-23 can also stimulate the production of IL-8, reinforcing its role in the defense of the intestinal mucosa and in the recruitment of neutrophils[54].

In UC, CD4+ T cells can secrete many inflammatory factors related to the Th2 profile (such as IL-4, IL-13) and Th17-related proinflammatory cytokines (IL-17A). These T-cell-derived cytokines not only directly damage intestinal tissue but also stimulate macrophage polarization. Despite the predominance of M1 macrophages in colitis, M2 macrophages play important roles in antagonism of inflammation and in promoting healing, which contributes to the resolution of the inflammatory condition. Modulation of the M1/M2 polarization state can alter the process of colonic local inflammatory responses, so macrophage-targeted therapies are increasingly recognized as novel therapeutic approaches for gut inflammation[55].

It is important to highlight that maintaining a balance between pro- and anti-inflammatory cytokines is crucial for gut homeostasis, since these cellular communicators provide trophic stimuli and defenses against pathogens, among other essential functions. In CD, there is a disturbance of this harmony mediated by changes in the gut microbiota and a combination of factors. In particular, the presence of single nucleotide polymorphisms in cytokine genes such as IL-10, important in the maintenance of tissue integrity and anti-inflammatory activity, as well as in cytokine receptors (IL-10 receptor A, IL-10 receptor A, IL-23 receptor and type I interferon receptor), cytokine-induced transcription factors (signal transducer and activators of transcription (STAT) 1, STAT3, STAT4) and associated signaling cascade (such as Janus kinase 2)[56]. Given the complexity of microbiome-metabolite interactions and their critical role in gastrointestinal disorders, it is clear that a one-size-fits-all approach is inadequate. Personalized research and medicine, guided by genetic, immunological and microbiome profiles, is the key to identifying specific dysregulated pathways in individual patients and in the pathophysiology of IBDs. Importantly, cytokine interaction can be disease- and tissue-specific, and can change over time in the same patient. Therefore, identifying predictors of response to specific therapies should be the main point of future therapeutic interventions to determine the best personalized approach[57,58].

THE VAGUS NERVE IN THE CONTEXT OF THE GUT-BRAIN AXIS

The GIT is a highly complex system that is sensitive to environmental responses, responsible for integrating essential functions such as digestion, nutrient absorption, intestinal motility, and body defense[59]. Such complexity is supported by the gut-brain axis, which allows the gut not only to receive information from the CNS but also to respond to it, influencing homeostatic balance and gut inflammation mechanisms[6]. It is important to understand the neural networks that innervate the GIT, organized in the extensive and complex ENS. This system has the function of establishing an efficient communication link between the CNS and the gastrointestinal responses, so that it can also be integrated with other physiological and behavioral responses of the organism[60].

The ENS, often referred to as the “second brain”, is an intrinsic neural network that covers the entire GIT, composed of neurons and glial cells organized into two main plexuses: The myenteric plexus or Auerbach’s plexus, located between the longitudinal and circular muscle layers, and the submucosal or Meissner’s plexus, located below the mucosa, near the intestinal lumen. The myenteric plexus controls muscle movements that displace food along the GIT, while the submucosal plexus regulates the secretion of digestive enzymes, mucus, and the absorption of nutrients and electrolytes[60,61].

It is essential to understand the neuroimmune interactions that develop in the intestinal region[62]. The ENS includes a variety of intrinsic neurons, located within the intestinal wall, such as intrinsic primary afferent neurons, interneurons, and motor neurons. Intrinsic primary afferent neurons are activated by mechanical stimuli such as distension in the mucosa or indirectly via 5-HT, and chemical stimuli such as the presence of amino acids, fatty acids, pH variations present in the intestinal lumen and can express substances such as choline acetyltransferase (ChAT), neuromedin U and calcitonin gene-related peptide. The interneurons, which express ChAT, substance P and 5-HT, connect to other neurons and are involved in the generation and propagation of migratory motor complexes, essential for digestion and absorption of nutrients[63,64]. Motor neurons, on the other hand, can be excitatory, which express ChAT and substance P, or inhibitory, which express vasoactive intestinal peptide (VIP) and nitric oxide, acting in the contraction or relaxation of smooth muscle to promote the coordinated movement of intestinal contents. In addition, a subset of secretory/vasodilator neurons, which express VIP, regulate epithelial secretion and intestinal blood flow[64,65].

The neural network is also made up of extrinsic neurons that present their cell bodies located outside the intestine, either in sensory or autonomic ganglia and brainstem, and connect to the GIT through projections[66]. These are divided into extrinsic sensory afferent, sympathetic efferent, and parasympathetic afferent neurons. Extrinsic neurons modulate intestinal motility, secretion, and immune response to pathogens. While sympathetic neurons release adrenaline to inhibit intestinal motility, parasympathetic neurons release ACh to stimulate motility and secretion. This modulation is crucial for the GIT response to different stimuli, including stressful situations[67]. Cajal interstitial cells are also part of the intestinal peristaltic communication, producing slow and spontaneous electrical responses, generating rhythmic contractions of the intestinal muscles and modulating the transmission of signals between enteric neurons and gastrointestinal smooth muscle cells, ensuring coordinated motor communication[68]. All this neuroimmune communication plays an essential role in maintaining intestinal homeostasis and in responding to inflammatory and infectious diseases[69]. Neuronal and immunological cells have receptors and molecular signals that allow reciprocal communication with each other[70,71].

In this context, the vagus nerve stands out as the central axis of this signalling network, being the main component of the parasympathetic, acting as a crucial conductor of signals between the brain and the intestine and directly influencing gastrointestinal function[14,72]. Vagal fibers are composed of 80%-90% afferent fibers, which are responsible for transmitting sensory information of visceral origin to the CNS, as well as somatic and gustatory sensations. The remaining 10%-20% correspond to efferent fibers, which release ACh in various locations, such as the neuromuscular junction, intrinsic nerve fibers, or secretory cells, modulating autonomic and visceral functions[8].

In the gastrointestinal system, the activation of parasympathetic fibers promotes increased intestinal motility and glandular secretions, an important function for GIT homeostasis[73]. In contrast, stimulation of the sympathetic system reduces intestinal activity and blood flow to the intestine, redirecting blood to the heart and muscles in stressful situations[74]. The vagus nerve is the tenth pair of cranial nerves, running a long way in the human body, presenting its origin in the region of the dorsal motor nucleus of the medulla oblongata (medulla oblongata), the lower region of the brainstem, and extends from the neck to the abdomen. In the neck, it innervates muscles of the pharynx and larynx, responsible for swallowing and vocalization. In the heart, in turn, it has parasympathetic vagal fibers that act to reduce heart rate and control cardiovascular function[75].

Upon arrival at the GIT, the vagal celiac branch extends from the duodenum to the distal region of the descending colon, containing sensory afferent fibers that include mucosal mechanoreceptors, chemoreceptors, tension receptors in the esophagus, stomach, and proximal small intestine, and sensory endings in the liver and pancreas[76]. These receptors are also associated with gut hormones and regulatory peptides released by enteroendocrine cells that use neuronal signals from the gut to the NTS and distribute them to various regions of the CNS, such as the locus coeruleus, the rostral ventrolateral medulla, the amygdala, and the thalamus. The most important function of the vagus nevus is afferent, allowing the bidirectional connection between the internal organs and the brain[8].

Within this perspective, the participation of cholecystokinin peptide (CCK) and hormones such as ghrelin and leptin regulates feelings of temporary hunger and satiety, since these agents are sensitive to the presence of food in the intestine[77]. CCK is a hormone secreted by cells I of the proximal small intestine (duodenum and jejunum), and plays a role in controlling food intake and reducing gastric emptying speed. By activating CCK-1 receptors in enteric vagal afferent fibers, CCK promotes a longer food residence time in the GIT, which contributes to satiety effects. It acts via vagal innervation and coordinates nerve impulses that regulate gastric motility. CCK also acts as a neurotransmitter and is present in regions such as the cerebral cortex, thalamus, hypothalamus, and basal ganglia, where it activates vagal afferent nerve endings in the NTS[78,79].

Leptin acts in synergy with CCK to inhibit food intake in the short term and promote long-term body weight reduction, also through vagal afferent fibers. On the other hand, ghrelin, produced mainly by the cells of the stomach, has an opposite role, acting as a hunger signal. This hormone regulates energy intake by inhibiting the vagal afferent stimulus, stimulating appetite and the search for nutrients. Thus, the interaction between CCK, leptin and ghrelin forms a complex mechanism of regulation that affects food intake[4,80,81]. In addition to these mechanisms, there are parasympathetic efferent fibers that act in intestinal peristalsis, secretion of digestive enzymes, the digestive process, nutrient absorption and reflex actions (coughing, sneezing, swallowing and emesis) with active commands coming from the brain. When activated, they release ACh, which can bind to muscarinic and nicotinic receptors, modulating various gastrointestinal functions[82].

MECHANISMS OF ACTION OF THE CHOLINERGIC VAGAL PATHWAY IN GASTROINTESTINAL INFLAMMATION

CNS controls several functions of the digestive system, sending neural signals that help regulate and coordinate its activities. Activation of the parasympathetic nervous system results in the release of the neurotransmitter ACh, which can bind to muscarinic and nicotinic receptors[35]. In the GIT, the activation of these receptors contributes to the recognition of motor and sensory signals related to the presence of nutrients, satiety stimuli, and appetite control. The vagus nerve regulates essential functions in the GIT by connecting the CNS to the immune system[8]. Peripheral inflammation is detected by vagal afferent fibers and integrated into the brainstem, which influences appetite, mood, and the behavior of various pathologies. These signals generate efferent responses that modulate the immune response, playing a central role in the body’s homeostasis and, because of this, it is being explored as a therapeutic target in several inflammatory diseases[10,83]. In the last decade, studies have tried to demonstrate the properties of the vagal anti-inflammatory pathway, in an attempt to elucidate the pathways through which this signalling occurs[24,84].

The concept of the cholinergic anti-inflammatory pathway emerged in a pioneering way in the year 2000 in studies carried out by Borovikova et al[85]. The result of the cell culture showed that in response to LPS-induced endotoxin produced by bacteria, ACh was essential to reduce pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-18. This mechanism led to the development of the term “inflammatory reflex”, and demonstrated therapeutic potential for the control of chronic and acute inflammation through neuromodulation. These authors reported that the vagus nerve was able to activate the splenic sympathetic nerve through a vagosympathetic synergistic effect[85]. The vagus nerve-mediated inflammatory physiological neural reflex is necessary for the control of inflammation in situations of tissue injury or exposure to pathogens (Figure 1). The removal of this reflex in genetic conditions or chronic pathologies can cause excessive inflammatory responses and expression of pro-inflammatory cytokines.

Figure 1 This illustration shows activation of the vagal cholinergic anti-inflammatory pathway in response to intestinal inflammation, as observed in inflammatory bowel diseases such as Crohn’s disease. On the left, the anatomical connection between the brain, vagus nerve, and gastrointestinal tract is shown. The enlarged section on the right illustrates an inflamed intestinal mucosa, characterized by microbiota dysbiosis (1), disruption of the epithelial barrier, and immune cell infiltration (2). Vagal efferent fibers release acetylcholine, which binds to the alpha-7 nicotinic acetylcholine receptor expressed on macrophages and dendritic cells (3). This binding suppresses the differentiation of T helper 17 cells (pro-inflammatory helper T lymphocytes) that produce interleukin (IL)-17 and IL-22 (4), inhibits the release of pro-inflammatory cytokines (tumor necrosis factor α, IL-1, IL-8, high mobility group box 1) (5), while promoting the expansion of forkhead box protein 3+ regulatory T cells (6), contributing to immune homeostasis. α7nAChR: Alpha-7 nicotinic acetylcholine receptor; Th17: T helper 17 cells; FoxP3+ Treg: Regulatory T cells expressing the transcription factor forkhead box protein 3; TNF-α: Tumor necrosis factor α; IL-1: Interleukin-1; IL-8: Interleukin-8; HMGB-1: High mobility group box 1; IL-17: Interleukin-17; IL-22: Interleukin-22.

Gastrointestinal vagal afferents are composed mainly of unmyelinated C-type fibers and finely myelinated Aδ fibers, which act in the transmission of sensory information. These fibers are classified based on four main aspects: The location of the receptive field (mucosa, muscle, or serous-mesenteric), which defines where the stimulus is detected; the innervated GIT region, which indicates the specific part of the GIT monitored by the fiber; the modality of the primary stimulus (chemical, osmotic, or mechanical), which describes the type of signal to which the fiber responds; and the response to distension or pressure, which characterizes how the fiber reacts to mechanical changes in the GIT[10,86]. Afferent fibers of the vagus nerve recognize inflammatory components of the peripheral region, such as pro-inflammatory cytokines (TNF-α, IL-6), a result of the activation of macrophages and other cells of the immune system from the moment that TLRs, nucleotide-binding oligomerization domain receptors, and other molecular pattern recognition receptors are associated with pathogens[87].

The dorsal vagal complex, which comprises the sensory nuclei of the NTS, the area postrema, and the dorsal motor nucleus of the vagus, responds to systemic changes such as increased circulating levels of TNF-α, altering motor activity in the vagus nerve[24]. The central terminals of vagal afferents enter the brainstem and synapse with neurons in the NTS, using glutamate as their main neurotransmitter[10,73]. In addition, some vagal afferents form monosynaptic connections between the NTS and the dorsal motor nucleus of the vagus, allowing for rapid and direct communication between these structures[88]. This synapse utilizes neurotransmitters such as glutamate and γ-aminobutyric acid[10,89]. The dorsal vagal complex integrates these signals and transmits the information through vagal flow to the enteric network[89].

Vagal afferents respond to cytokines and inflammatory mediators by regulating channels such as potential transient receptor V1, transient receptor A1, and purinergic P2X receptors, which suggests that inflammation may modulate the signalling and sensitivity of these afferents[10]. The vagus nerve afferent vagal pathway is involved in neuroendocrine activation and regulation of the HPA axis in response to stress by detecting pro-inflammatory cytokines in the circulation. This activates the pathway with the release of corticotropin-releasing hormone by the hypothalamus, which stimulates the production of adrenocorticotropic hormone by the adenohypophysis and subsequent release of cortisol by the adrenal glands. Cortisol has essential functions in metabolism, immunity, and stress response, among others[8]. Stimulation of the vagus nerve, through efferent fibers, releases ACh, which binds to alpha-7 nicotinic ACh receptors (α7nAChR) in macrophages, inhibiting the production of pro-inflammatory cytokines, being crucial in the regulation of inflammation in IBDs[90,91]. α7nAChR is the best characterized nicotinic receptor subtype in the immune system and is primarily involved in inhibiting inflammation by modulating the production of anti-inflammatory cytokines, suppressing dendritic cell and macrophage activity, and T cell differentiation (Figure 1)[92,93].

Intestinal lymphoid cells appear to be important in the pathogenesis of IBDs because they have the ability to produce Th1 cell-derived cytokines, particularly interferon γ, modelled on natural killer cells produced by type 1 intestinal lymphoid cells, and Th2 cell-derived cytokines, such as IL-5 and IL-13, modeled on nuocytes. There are also type 3 intestinal lymphoid cells, which can secrete Th17 cell-derived cytokines, such as IL-17 and IL-22[94]. Wang et al[95] identified the α7nAChR as the main receptor by which splenic macrophages are modulated. Defects of the underlying vagal reflex circuit can be replaced by direct electrical stimulation of the vagus nerve to achieve a therapeutic effect[96]. The anti-inflammatory effect of VNS is lost in α7nAChR knockout mice and can be blocked by specific α7nAChR antagonists. However, this effect can be mimicked both in vivo and in vitro by a pharmacological approach using α7nAChR agonists with similar results[95,97]. The cholinergic anti-inflammatory reflex is a mechanism capable of responding to pathogen invasion or tissue damage. This process involves signalling endotoxins or pro-inflammatory cytokines through afferent fibers of the vagus nerve, which transmit the information to the brain. Soon after, an anti-inflammatory signal is sent back through efferent fibers from the vagus nerve to the celiac plexus. The splenic nerve activates CD4+ T cells in the spleen that express ChAT+ T cells. These cells migrate to macrophages and release ACh (Figure 1)[12,98,99]. ACh interacts with α7nAChR receptors expressed on macrophages, reducing the release of inflammatory mediators such as TNF, IL-1, IL-18, high mobility group box 1, and other pro-inflammatory cytokines (Figure 1)[100].

In addition to macrophages, Tregs, a specialized subset of CD4+ T cells characterized by the expression of the transcription factor forkhead box protein 3, play an essential role in modulating the immune response. Tregs exert a suppressive function on immune effector cells and contribute to the maintenance of immune homeostasis. Evidence suggests that the interaction between cholinergic signalling and Tregs may enhance the anti-inflammatory effects mediated by the vagus nerve, expanding the relevance of this neuroimmune axis in the control of inflammatory diseases[101,102]. From a molecular point of view, activation of α7 receptors causes inhibition of NF-κB, preventing its activation by interfering with the phosphorylation of the inhibitory protein-κB and the transcriptional activity of NF-κB. In addition, activation of the α7 receptor can inhibit the phosphorylation of STAT3, resulting in the formation of non-phosphorylated STAT3, which binds to the p50 and p65 subunits of NF-κB, preventing its translocation to the nucleus[103,104].

A second proposed mechanism for the anti-inflammatory effect of α7 receptor activation involves activation of the Janus kinase 2/STAT3 signalling pathway. Activated STAT3 can induce the production of tristetraproline, a protein that plays a role in the degradation of pro-inflammatory cytokine mRNAs, thereby contributing to the reduction of inflammation. A third additional mechanism that can regulate these cholinergic responses is related to the activation of the phosphatidylinositol 3-kinase/protein kinase B/nuclear factor erythroid-2-related factor 2 pathway, which promotes the expression of the enzyme heme oxygenase-1. Heme oxygenase-1 has anti-inflammatory and antioxidant properties, reinforcing the control of inflammation[105,106]. Communication between vagal fibers and neurons in the myenteric plexus results in the release of ACh, which regulates the inflammatory reflex and contributes to the recovery of immune balance in the gut. The rapid signal conductance promoted by these fibers highlights the vagus nerve as a promising target in pathologies related to intestinal inflammation[8,35].

PHYSICAL EXERCISE AND ITS RELATIONSHIP TO IBD

Physical exercise is recognised for promoting a general feeling of well-being and has been proposed as an anti-inflammatory adjuvant in the treatment of chronic inflammatory diseases, both in humans and in animal models[107]. Several pieces of evidence indicate that regular exercise positively modulates physiological functions relevant to gastrointestinal homeostasis, including motility, intestinal permeability, immune response, and microbiota composition[108]. Regular physical exercise induces systemic physiological adaptations, affecting the neuromuscular[109], cardiovascular[110], respiratory[111], autonomic[112], endocrine[113] and gastrointestinal[114]. However, these adaptations do not occur in a linear manner, being modulated by the intensity, duration, load and volume of training, as well as by the predominance of the metabolic pathways involved[115]. Parameters such as intensity and frequency directly impact muscle, hormonal, and neural signalling, including increased catecholamine signalling, release of sarcoplasmic calcium, changes in mechanical strength, metabolic disorders, acid-base imbalance, elevation of muscle temperature and an increase in circulating concentrations of adrenaline[116-119].

The answers vary according to the intensity and duration of the exercise. Strenuous training and states of dehydration are associated with gastrointestinal adverse effects, with symptoms such as nausea, vomiting, abdominal pain and diarrhea, mainly attributed to intestinal ischemia, a condition reported by up to 70% of athletes[120,121]. On the other hand, in the study by Ordille and Phadtare[122], it was shown that both low- and high-intensity exercise can reduce pro-inflammatory cytokines, promote beneficial changes in the gut microbiota, and improve health-related quality of life in IBD patients.

Scientific evidence has shown an important contribution of physical exercise in improving the inflammatory condition present in CD and UC (Figure 2)[29,123,124]. Klare et al[123] showed that the regular practice of moderate-intensity physical exercise, three times a week, for ten weeks, resulted in improved quality of life and well-being in CD patients with light to moderate activity. Similarly, Chan et al[125], in a study conducted in the United Kingdom, observed that, despite the limitations reported by patients with post-inflammatory ileitis and UC for exercising, those who engaged in physical activities had a reduction in gastrointestinal symptoms.

Figure 2 Schematic representation of the modulatory effects on intestinal inflammation by three different interventions: Physical exercise (left), vagus nerve stimulation (lower right), and subdiaphragmatic vagotomy (upper right). Physical exercise and vagus nerve stimulation promote protective effects through increased vagal tone and activation of the cholinergic anti-inflammatory pathway. In contrast, vagotomy disrupts this pathway, leading to reduced protective effects and potential exacerbation of intestinal inflammation. IBD: Inflammatory bowel disease; GI: Gastrointestinal.

In this sense, some training protocols have been carried out in experimental models. Among them, the swimming exercise protocol in rats has stood out for its low cost of applicability, ease of handling and possibility of developing both aerobic and anaerobic skills[98]. de Oliveira Santos et al[126], for example, used aerobic swimming and strength training as a treatment in animals with acetic acid-induced UC. The results showed that the training was able to attenuate the increase in gastric emptying rate through the activation of the vagal cholinergic pathway, which increases the tone and release of nitric oxide, thus promoting gastric accommodation and reducing emptying time.

During physical activity, skeletal muscle secretes myokines such as irisin, myostatin, IL-15, brain-derived neurotrophic factor (BDNF), myonectin, and decorin, mediators with autocrine, paracrine, and endocrine actions, which influence the composition of the microbiota and intestinal function. Among the mechanisms involved, the activation of AMP-activated protein kinase, the reduction of fecal bile acids, the increase in the production of short-chain fatty acids (SCFAs), the elevation of luminal immunoglobulin A, the acceleration of intestinal transit, and the activation of the HPA axis stand out[127]. In a mouse model, an aerobic training protocol performed for 16 weeks was associated with improved memory and increased abundance of bacteria from the Lachnospiraceae family, negatively correlated with anxiety-like behaviors, and produced butyrate, a SCFA capable of upregulating the expression of BDNF in the hippocampus and frontal cortex, promoting neuronal survival, neurogenesis, and synaptogenesis[128]. Overall, exercise appears to regulate the levels of BDNF, hormones (e.g., cortisol), and neurotransmitters such as norepinephrine, dopamine, and 5-HT. However, this regulation is dependent on exercise intensity[129].

Another substance secreted by skeletal muscle that deserves to be highlighted is IL-6, since despite being considered a pro-inflammatory factor, it induces anti-inflammatory responses such as the increase of IL-10 and IL-1ra and stimulates the secretion of glucagon-like peptide 1 (GLP-1), which can act in the repair of the intestinal mucosa after damage related to the pathogenesis of IBDs[130,131]. Physical exercise can be considered an alternative therapy in IBDs, due to the role of skeletal muscle in the secretion of these myokines such as IL-6, IL-15, IL-1ra and irisin, which is an exercise-induced hormone and has an important relationship in the regulation of metabolic functions in adipose tissue and nervous system, altered responses in the presence of CD and UC[131].

In addition, changes in the diversity of metabolites in the gut that are induced by aerobic exercise are associated with increased parasympathetic activity, via vagal communication in the brain-gut axis[75]. Changes in neurotransmitters caused by physical exercise also alter gastrointestinal functioning[132]. Severo et al[108] highlight exercise recommendations, emphasizing that exercise can benefit gastrointestinal diseases with appropriate intensity and modality. In patients with IBD, including CD and UC, light to moderate walking or running (60% of maximum heart rate), three times a week, for ten weeks, improves quality of life without worsening the inflammatory condition, while moderate-intensity aerobic and resistance training can help reduce markers related to inflammation.

In patients with IBD, there is a significant correlation between vagal tone and emotional adjustment, and profiles with lower expression of negative emotions tend to have greater autonomic balance. It is observed that, in CD, a positive coping profile is associated with a lower vagal tone, while in UC, this profile is related to a higher vagal tone[133]. In addition, patients with CD who have low vagal tone at rest demonstrate higher levels of TNF-α in the blood and salivary cortisol, when compared to those with higher vagal tone[134], showing that reduced vagal tone is associated with a pro-inflammatory state. In this context, vagal tone monitoring can be a useful strategy to identify states of greater inflammatory vulnerability and guide adapted therapeutic interventions. These interventions may include pharmacological strategies, enteral nutrition, VNS, and regular physical exercise, aiming to explore the anti-inflammatory potential of the vagus nerve[133].

The importance of physical exercise in the bidirectionality between the intestine and the CNS can also be evidenced by the regulation of serotonergic neurotransmission. Experimental data have shown that moderate exercise leads to a diversification of the gut microbiota, characterized by an increase in bacteria that are responsible for the synthesis of 5-HT and that protect individuals against symptoms of anxiety and depression[135] that may be associated with IBD[136]. The function of the GIT is altered in IBD since there is dysregulation of the structures of the ENS, and it is responsible for coordinating and regulating almost all aspects of intestinal function, such as intestinal motility, fluid and electrolyte transport, mucin secretion, cytokine production and regulation of epithelial barrier function[137].

In recent years, physical exercise has gained prominence as a promising therapeutic strategy in the context of IBD, driven by the advancement of new research methodologies and the discovery of multiple interconnected physiological pathways. The improvement of techniques in molecular biology, as well as the study of receptors distributed throughout the GIT and specific hormones, has allowed a deeper understanding of the mechanisms involved in exercise-induced gastrointestinal changes at different intensities[114]. Cronin et al[138] conducted a randomized, crossover clinical trial with eight weeks of combined aerobic and resistance training in physically inactive IBD patients in clinical remission. Body composition was assessed by dual-energy X-ray absorptiometry. Adherence to the prescribed exercise program was 87.5%. Participants in the exercise group showed favorable changes, with a median reduction of 2.1% in total body fat percentage and a median increase of 1.59 kg in total lean mass. Regarding disease activity, there was no significant worsening or improvement in disease activity scores in the intervention group. There were also no significant changes in quality of life scores or mood and anxiety scores between the control and intervention groups. The levels of pro-inflammatory cytokines (IL-8, IL-10, IL-6, and TNF-α) and C-reactive protein (CRP) were similar between the groups at baseline, indicating low disease activity, and remained unchanged after the intervention, suggesting disease stabilization with exercise.

In another study involving quiescent or mildly active patients with CD, a total of 45 individuals were randomly allocated to a control, endurance or muscle training group. The dropout rate was significantly higher in the resistance group (47%) compared to the resistance group (13%). In both exercise groups, maximum and average strength in the upper and lower limbs increased significantly. Emotional function improved significantly in the resistance group. The CD activity index did not show significant changes between the groups, but decreased in the resistance group (from 95 to 88), remained stable in the resistance group (84 to 85), and increased in the control group (from 64 to 73). Inflammatory parameters remained unchanged in all groups[139]. Klare et al[123] conducted a randomized clinical trial involving thirty patients with mild to moderate IBD. The intervention consisted of moderate-intensity supervised jogging three times a week for ten weeks, compared to a control group without exercise prescription. Health-related quality of life improved by 19% in the intervention group and 8% in the control group. Scores on the social subscale of the IBD questionnaire improved significantly in the intervention group compared to the control group.

Exercise-induced increases in central 5-HT and dopamine levels may influence gut motility, secretion, and immune function through descending pathways, potentially involving vagal afferents, while endorphins released during physical activity may alleviate the perception of abdominal pain and modulate stress responses through central and/or peripheral mechanisms[132]. Exercise may also modulate enteroendocrine cells, which can interact directly with vagal afferents by releasing 5-HT[140]. This interaction occurs through the activation of 5-HT₃ receptors located on vagal afferent fibers. Moreover, gut hormones such as CCK, GLP-1, and peptide YY (PYY) can signal to the brain via vagal afferents expressing specific receptors for these hormones[141]. Studies in rodents have shown that aerobic exercise modulates the synthesis and metabolism of 5-HT, leading to increased concentrations in both the brainstem and hippocampus in response to physical activity. This elevation in 5-HT levels has been associated with reductions in depressive and anxiety-like behaviors[142]. Various behaviors regulated by the gut microbiota are dependent on intact serotonergic neurotransmission. Notably, approximately 90% of the body’s 5-HT is synthesized by enterochromaffin cells in the gut and can be modulated by SCFAs produced by spore-forming bacteria[143]. High-intensity exercise has been shown to decrease circulating levels of ghrelin, potentially due to the concurrent release of anorexigenic hormones such as PYY and GLP-1, which act to suppress appetite[144]. The possibility of enhancing exercise-induced benefits through targeting gut metabolism is supported by findings demonstrating elevated levels of anorexigenic hormones (PYY and GLP-1) and reductions in orexigenic hormones (ghrelin and leptin) in normal-weight individuals following aerobic exercise training[141,144].

VNS AS A THERAPY FOR IBD

The gut-brain axis allows a modulation of intestinal inflammation and, via the anti-inflammatory cholinergic axis, the reduction of the exacerbated inflammatory response, showing efficacy in diseases such as UC and CD, since these pathologies affect the function of the intestinal barrier and promote exacerbated inflammation[145,146]. VNS is recognized as a neuromodulator technique that can be applied invasively or non-invasively to treat various clinical conditions. The therapeutic response to VNS varies according to the application method, and both forms are widely studied and used in clinical practice[27,75]. VNS was first cleared by the United States FDA in 1997 for the treatment of refractory epilepsy and in 2005 for cases of treatment-resistant chronic depression[147]. After 2005, it was also recognized for the use of motor rehabilitation of the upper limbs after ischemic stroke and the treatment of cluster headache and migraine. These approvals are based on clinical evidence of efficacy and safety, and official records can be consulted in the FDA’s database[148].

Invasive VNS involves implanting a device consisting of: (1) A pulse generator implanted subcutaneously into the patient’s chest wall; (2) An electrode cuff wrapped around the cervical bundle of the left vagus nerve; and (3) A wire connecting the pulse generator and electrode cuff. This device is implanted by a qualified surgeon and activated two weeks after the surgery protocol. In the following weeks, the device is programmed and adjusted according to the patient’s case, to reduce possible adverse effects[149,150]. Although cervical VNS is effective for several diseases, it is an invasive procedure that can involve risks such as infection, pain at the implant site, vocal changes, dysphagia, and injury to adjacent structures[151].

Invasive VNS acts directly on the cervical region of the left vagus nerve, promoting activation of central autonomic pathways, including the nucleus of the solitary tract and the dorsal motor nucleus of the vagus, which results in efficient activation of the anti-inflammatory cholinergic pathway (α7nAChR), systemic reduction of inflammatory cytokines, and improvement of intestinal mucosal integrity[152,153]. The pilot study by Bonaz et al[24] is the result of the first investigation of VNS implanted in seven patients with active CD. Patients treated by vagal electrical stimulation had decreased abdominal pain, improved CRP and fecal calprotectin, in addition to endoscopic remission of the disease within a six-month follow-up, managing to restore vagal tone by a mechanism of regulation of the intrinsic anti-inflammatory pathway, signalling that this slow-acting treatment appears effective in mild to moderate CD. Bonaz et al[24] demonstrated that chronic vagal electrical stimulation improved colitis induced by intracolonic instillation of trinitrobenzene sulfonic acid in rats, reducing body weight loss and levels of inflammatory markers. These effects were observed both in the damaged colon region and in the immediately adjacent segment, through histological analysis and quantification of myeloperoxidase activity[154].

More recently, non-invasive techniques have emerged in scientific research and therapeutic purposes, such as transcutaneous cervical VNS (tcVNS) and transcutaneous auricular VNS (taVNS). These approaches have been studied for the treatment of epilepsy, depression, chronic headaches, pain-related disorders, obesity, inflammatory and cardiovascular diseases, and autonomic dysfunctions[7,155,156]. TaVNS targets the auricular branch of the vagus nerve, with electrodes positioned in the outer ear, especially in the auricular concha. TcVNS, on the other hand, applies the electrodes to the cervical region of the neck to activate the vagal fibers. Both techniques are non-invasive, easy to use, and lower cost[157,158]. VNS, both invasive and non-invasive, shares similar mechanisms, although its effects are not entirely understood. As with invasive stimulation, taVNS and tcVNS reach the NTS, influencing central and ANS-mediated responses. As previously mentioned, invasive VNS is associated with reducing pro-inflammatory cytokines through activating the cholinergic anti-inflammatory pathway[159]. Evidence indicates that taVNS may also reduce sympathetic activity[160]. Although the response to non-invasive stimulation is more indirect, it tends to be better tolerated and presents fewer risks[161].

Preliminary clinical trials with vagal, invasive or transcutaneous stimulation have shown reduced inflammatory markers, such as fecal calprotectin and CRP, and decreased disease activity[35,37,162]. This suggests that vagal stimulation is a practical therapeutic approach for IBD, reducing inflammation and lowering the side effects of pharmacological treatments. The vagus nerve can also influence intestinal permeability by modulating the ENS and enteric glial cells, which are essential for the integrity of the intestinal barrier[163]. Specifically, the gastrointestinal effects of vagal electrical stimulation work in close agreement with the cholinergic anti-inflammatory pathway (Figure 2)[83].

VNS can restore compromised gut barrier function in IBDs by preserving the integrity of occlusion junctions by activating enteric glial cells and expressing proteins such as occludin and zonula occludens-1[13,35,164]. In addition, it regulates the translocation of NF-κB, a crucial mediator of inflammation, helping to control the local and systemic inflammatory response[35]. These effects are essential to prevent the translocation of microorganisms and toxins, reduce inflammation and oxidative stress, and make vagal stimulation a promising strategy in treating gastrointestinal inflammatory diseases. Reduced vagal tone determined by heart rate variability has been described in patients with CD[165]. Vagal neuromodulation, which upregulates the cholinergic anti-inflammatory pathway, has been shown to have protective effects on intestinal inflammation. Patients with low vagal tone have higher serum concentrations of TNF-α, suggesting that strengthening this pathway may be a relevant therapeutic approach[134]. Thus, vagus nerve modulation has potential therapeutic applications for patients with IBDs, with the need to individualize therapy according to the type and severity of IBD.

VAGOTOMY AND ITS EFFECTS ON IBD

A vagotomy is a surgical procedure that consists of the section or removal of part of the vagus nerve, one of the main components of the parasympathetic nervous system. This nerve is key in regulating gastrointestinal functions, including controlling gastric emptying and releasing digestive enzymes[166,167]. Until the end of the 70s, vagotomy was widely used as the first line of treatment for gastroduodenal ulcers, especially in cases of gastric hyperacidity. The procedure’s objective was to reduce acid production in the stomach, promoting ulcer healing and preventing recurrences[168,169].

There are three main types of vagotomy: Truncal or subdiaphragmatic, selective, and highly selective. Truncal vagotomy involves the complete sectioning of the anterior and posterior vagal trunks above the diaphragm, significantly reducing acid secretion[170]. Truncal vagotomy, by completely disrupting the parasympathetic innervation of the stomach, results in a drastic reduction in acid secretion, which has long been effective for treating peptic ulcers[171]. However, this technique was associated with significant adverse effects, such as gastric atony, gastric retention, and post-vagotomy diarrhea. These symptoms occurred due to the loss of parasympathetic regulation of gastrointestinal motility and sphincter function. To mitigate these effects, it was often necessary to perform a drainage procedure, such as pyloroplasty[172]. With the advancement of more effective and less invasive drug therapies, such as proton pump inhibitors, histamine type 2 receptor antagonists, and antibiotics for the treatment of infection by Helicobacter pylori, a bacterium closely associated with the development of ulcers, vagotomy has fallen into disuse. It has been reserved only for specific and complicated cases. In rare situations of refractory ulcers, when other therapeutic approaches have not been successful, vagotomy can still be considered, after a careful evaluation of the patient[173,174].

The second type of vagotomy is selective vagotomy, which preserves the hepatic and celiac branches of the vagus nerve, reducing acid secretion, with less impact on motility. On the other hand, highly selective (or parietal) vagotomy is considered the most advanced technique it sections only the fibers that innervate the gastric wall, maintaining the innervation of the antrum and pylorus, which preserves gastric motor function, reducing the risk of complications such as diarrhea and gastric retention[16,175]. In the context of IBDs, such as UC and CD, vagotomy has shown potential to aggravate the condition in animal models (Figure 2)[176]. In agreement, the study by Giovangiulio et al[177] showed that mice submitted to vagotomy had more severe dextran sulfate sodium-induced colitis compared to the control group.

The effect of vagotomy significantly reduces the biosynthesis of pro-resolutive mediators, such as lipoxins, resolvins, protectins, and maresins. These mediators are essential for the resolution of inflammation, and their decrease leads to a delay in this process, which has been observed in experimental models, such as peritonitis in mice[178]. In addition, vagotomy is associated with an increase in exudate leukocyte count and the production of pro-inflammatory cytokines and chemokines. In vagotomized mice, an increase in leukocytosis and expression of inflammatory markers was observed, indicating that vagotomy may exacerbate the inflammatory response[25]. A recent study by Liu and Forsythe[179] showed that vagotomy delays the resolution of inflammation and compromises the immune response to infections, as demonstrated in models of Escherichia coli infection. Research has indicated that VNS is crucial for regulating the immune response and resolving infections. Serhan et al[180] evaluated the possible link between vagotomy and the development of IBDs, including CD and UC. Based on data from the Swedish Patient Registry, the researchers followed more than 15000 individuals who had undergone vagotomy between 1964 and 2010, comparing them with a corresponding cohort of non-vagotomized individuals. Their analysis revealed an increased risk of IBD after vagotomy, particularly in the first decade after the procedure. This elevated risk was more significant for CD, especially in patients undergoing truncal vagotomy compared to those who had selective vagotomy. These findings support the idea that vagus nerve activity plays a protective and anti-inflammatory role in gut health and may help regulate immune responses involved in IBD. The vagus nerve’s role in intestinal homeostasis goes beyond its direct regulation of inflammation, also involving an intrinsic interaction with the microbial environment. In this context, the complex communication between commensal bacteria and the host nervous system, already well established, consists of the production of several neurotransmitters by bacteria in the GIT, including 5-HT, gamma-aminobutyric acid, dopamine, and norepinephrine, capable of directly influencing vagal afferent terminals located in the intestine[78].

Disruption of this vagal pathway, as observed after vagotomy, significantly impacts the diversity and composition of the gut microbiota. This disruption leads to intestinal dysbiosis, affecting enteric neurons, particularly VIPergic innervation, and altering mucin fucosylation, crucial for maintaining gut microbiota homeostasis[181]. Research by He et al[182] demonstrated that vagotomized mice exhibited notable alterations in both the composition and function of their gut microbiota, specifically showing a significant reduction in 5-hydroxyindoleacetic acid-producing bacteria, involved in tryptophan metabolism. Microbial metabolites play a crucial role in gut-brain communication. SCFAs such as acetate, butyrate, propionate, and other signalling molecules such as LPS, 5-HT, and gamma-aminobutyric acid, produced by the gut microbiota, influence the activity of enteroendocrine neurons. This modulation, in turn, affects the afferent neural pathway that transmits signals to the brain[183]. Vagotomy alters this signalling, interrupting eating behaviour and eliminating the anorectic effects associated with dietary fiber and SCFAs resulting from microbial fermentation. Although the specific molecular mechanisms of SCFA-mediated vagal signalling are still being elucidated, these acids are known to interact with several G-protein-coupled receptors[184].

Altered gut microbiota contributes to the activation of the immune system, since the presence of pathogenic microorganisms is associated with the release of pathogen-associated molecular patterns and the activation of TLR4 through LPS present in the membranes of gram-negative bacteria, whose activation allows the translocation of the transcription factor NF-κB, responsible for inducing the expression of pro-inflammatory cytokines and increased oxidative stress, thus triggering a cascade of inflammatory reactions in the GIT and the subsequent activation of the immune system. Therefore, these results suggest that the vagus nerve plays a crucial role in modulating the immune response, acting through the anti-inflammatory cholinergic pathway, which relies on the integrity of the vagus nerve and spleen to control inflammation[185]. Table 1 summarizes the main findings described in this article, providing a comparative overview of the discussed results.

Table 1 Comparative effects of physical exercise, vagal nerve stimulation, and vagotomy on inflammatory bowel disease.

Evaluated aspect	Physical exercise	Vagal nerve stimulation	Vagotomy
Vagal tone	Increases vagal tone	Directly stimulates the vagus nerve	Interrupts vagal modulation
Inflammatory cytokines	Reduces TNF-α, IL-6, IL-1β via myokines	Inhibits TNF-α, IL-6, IL-1β through cholinergic anti-inflammatory pathway	Increases TNF-α, IL-6, and other pro-inflammatory cytokines
Myokines/protective mediators	Increases IL-6 (anti-inflammatory action), IL-10, IL-1ra, irisin
Intestinal barrier integrity	Improves the mucosal barrier	Enhances tight junction proteins (occludin, ZO-1), protects the barrier	Reduces barrier integrity
Gut microbiota	Increases diversity, short-chain fatty acid production	Positively modulates microbiota	May worsen dysbiosis
Neurotransmitters/gut-brain axis	Increases serotonin, dopamine, endorphins, improves mood and brain-gut communication	Modulates the brain-gut axis via central vagal projections	Disrupts autonomic and central regulation
Overall inflammation in IBD	Decreases inflammation and symptoms	Reduces inflammation, may promote remission	Exacerbates intestinal inflammation
Stress response/HPA axis	Reduces cortisol and oxidative stress	Regulates HPA axis through vagal signaling	Impairs HPA axis regulation
Immune modulation	Improves intestinal immune function	Modulates immune cells via α7nAChR (e.g., macrophages, Tregs)	Weakens immune response
Application method	Non-invasive, safe	Invasive (implant) or non-invasive (auricular/cervical transcutaneous)	Surgical, irreversible
Risks/side effects	Gastrointestinal symptoms with excessive intensity (nausea, cramps)	Invasive vagal nerve stimulation may cause dysphonia, pain, infection; non-invasive is well tolerated	Increases IBD risk; worsens inflammation in animal models
Current clinical use in IBD	Complementary (recommended: Light/moderate aerobic activity)	Emerging therapy with promising results in Crohn’s disease and ulcerative colitis	Not recommended; associated with worsened outcomes

IBD: Inflammatory bowel disease; HPA: Hypothalamic-pituitary-adrenal; TNF-α: Tumor necrosis factor α; IL-6: Interleukin-6; IL-1β: Interleukin-1β; IL-10: Interleukin-10; IL-1ra: Interleukin-1 receptor antagonist; ZO-1: Zonula occludens-1; Tregs: Regulatory T cells; α7nAChR: Alpha-7 nicotinic acetylcholine receptor.

CONCLUSION

The evidence presented in this study reinforces the importance of non-pharmacological strategies in modulating intestinal inflammation in patients with IBDs. Physical exercise, by releasing anti-inflammatory myokines and promoting balance between the sympathetic and parasympathetic systems, has been shown to modulate the intestinal microbiota, reduce oxidative stress, and improve the integrity of the gastrointestinal mucosa. In parallel, the vagus nerve emerges as a promising line of research in treating conditions. Vagal electrical stimulation may present an innovative therapeutic approach in disorders related to autonomic dysfunction and reduced vagus nerve tone. Its anti-inflammatory effects related to modulation of the intestinal neuroimmune response suggest a significant potential to improve these pathologies’ symptoms and clinical course. Vagotomy, in this context, reaffirms the protective role of this nerve in intestinal homeostasis, since its interruption tends to aggravate intestinal inflammatory conditions. Thus, both physical exercise and vagal stimulation have the potential to complement the clinical management of IBD. Well-designed, controlled preclinical and clinical studies are essential to consolidate these approaches as effective and safe therapies.