Autonomic nervous system as a key modulator in stress-related inflammatory bowel disease: Mechanisms and therapeutic implications

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory intestinal disorder affecting more than 7 million people worldwide, with a growing global burden. Psychological stress may aggravate intestinal inflammation by disrupting autonomic nervous system (ANS) balance. This review considers the contribution of the ANS to stress-related IBD. Sympathetic and vagal pathways can exert distinct effects on intestinal barrier integrity, immune responses, and inflammatory activity through neurotransmitters and neuroimmune signaling. We also explore ANS-targeted therapies, such as β-blockers and vagus nerve stimulation, as potential precision interventions for IBD.

Key Words: Autonomic nervous system; Brain-gut axis; Stress; Inflammatory bowel disease; Mechanism; Therapy

Core Tip: This review provides a novel perspective on stress-associated inflammatory bowel disease by highlighting autonomic nervous system dysregulation as a key link between psychological stress and intestinal inflammation. We discuss the dual roles of sympathetic and vagal pathways, disease-specific autonomic responses in ulcerative colitis and Crohn’s disease, and emerging autonomic nervous system-targeted therapies. Current controversies and future directions toward personalized neuromodulation are also addressed.

INTRODUCTION

Inflammatory bowel disease (IBD) mainly comprises ulcerative colitis (UC) and Crohn’s disease (CD). It is a chronic gastrointestinal disorder characterized by recurrent intestinal inflammation. IBD affects more than 7 million people worldwide and remains a substantial global health burden[1]. Incidence and prevalence are projected to decline by 2050. However, the increasing proportion of older patients and the persistent disease burden will continue to strain healthcare systems worldwide[2,3].

Stress has emerged as a significant risk factor for IBD[4,5] and is independently associated with an increased risk of disease relapse and clinical deterioration[6,7]. The association between stress and IBD manifestations is bidirectional, which may create a self-perpetuating cycle[8]. Stress primarily influences IBD progression by modulating the brain-gut axis (BGA)[9]. The BGA comprises interconnected neural and endocrine systems, including the autonomic nervous system (ANS), central nervous system (CNS), enteric nervous system (ENS), and the hypothalamic-pituitary-adrenal (HPA) axis[10]. The ENS is an intrinsic reflex network within the intestinal wall that includes sensory neurons, interneurons, and motor neurons. The ANS mediates bidirectional communication between the ENS and CNS. The CNS regulates gastrointestinal function and neural responses to stress. Conventional IBD therapies, including 5-aminosalicylates (5-ASA) and corticosteroids, may cause adverse effects such as diabetes, infections, hepatorenal toxicity, and osteoporosis with long-term use[11]. In parallel with conventional pharmacotherapies, medicine-food homology resources have emerged as promising candidates for IBD management, with recent studies demonstrating their capacity to modulate gut microbiota and suppress intestinal inflammation[12]. Given that the ANS links central stress signals to intestinal regulatory processes, targeting autonomic pathways may represent a promising therapeutic strategy for stress-related IBD. Moreover, neuroprotective bioactive compounds derived from medicinal edible plants have emerged as potential modulators of the ANS, providing new perspectives for targeting neuroimmune pathways in stress-related IBD[13]. Therefore, this review summarizes the role of the ANS as a critical relay between psychological stress and intestinal inflammation, and further discusses the therapeutic potential of ANS modulation for IBD (Figure 1)[14,15].

Figure 1 Risk factors for inflammatory bowel disease. As a critical risk factor, stress interacts with genetic susceptibility and environmental triggers to promote disease via neuroendocrine-immune dysregulation, heightened gut inflammation, dysbiosis, and barrier dysfunction, collectively driving inflammatory bowel disease pathogenesis. IBD: Inflammatory bowel disease. The pattern was created with BioGDP.com[14,15].

STRUCTURE AND FUNCTION OF THE ANS

The ANS is composed of the sympathetic nervous system (SNS) and parasympathetic nervous system (PNS), which generally exert opposing regulatory effects. Through coordinated actions, these two branches maintain physiological homeostasis by modulating visceral and vascular smooth muscle activity, glandular secretion, and endocrine regulation of glucose, lipid, and electrolyte metabolism. In addition, the ANS contributes to the control of thermoregulation, sleep-wake cycles, and blood pressure. Sympathetic fibers travel along blood vessels to enter the intestinal wall and extend to the myenteric plexus, submucosal plexus, and mucosa. The SNS plays an essential role in regulating intestinal motility, secretion, and vascular tone. Through activation of α2-adrenergic receptors (α2-ARs), sympathetic signaling suppresses postsynaptic potentials in submucosal secretomotor neurons and myenteric motor neurons. Moreover, α1-adrenergic signaling counteracts vasodilation induced by neuroactive mediators, including substance P (SP), calcitonin gene-related peptide, and nitric oxide[16].

The PNS represents an important branch of the ANS and consists of cranial and sacral divisions. The cranial division primarily mediates parasympathetic regulation of the gastrointestinal tract through the vagus nerve (VN), while the sacral division modulates functions of the distal intestine via sacral parasympathetic pathways. The VN originates from the medulla oblongata and serves as the major cranial parasympathetic pathway that innervates the digestive system. Vagal efferent fibers arise mainly from the nucleus ambiguus and dorsal motor nucleus of the vagus (DMV). These projections provide distinct patterns of innervation to different regions of the gastrointestinal tract, particularly the proximal and mid-gastrointestinal tract. In contrast, sacral parasympathetic pathways mainly regulate the distal colon and associated pelvic organs[17] (Figure 2).

Figure 2 Bidirectional regulation of target organs by the autonomic nervous system. (1) Cervical nerves; (2) Thoracic nerves; (3) Lumbar nerves; and (4) Sacral nerves. The autonomic nervous system regulates bodily functions through the antagonistic actions of the sympathetic and parasympathetic nerves. Activation of the sympathetic nerve leads to increased energy expenditure and organ function enhancement, resulting in elevated heart rate, accelerated respiration, increased blood pressure, bronchodilation, and pupil dilation, while concurrently inhibiting gastrointestinal motility and digestive secretion. In contrast, parasympathetic nerve activation decreases energy consumption and promotes energy storage, leading to decreased heart rate, slowed respiration, reduced blood pressure, bronchoconstriction, and pupil constriction, while also enhancing gastrointestinal motility and digestive secretion. Furthermore, these systems interact synergistically in specific physiological processes, such as sexual function, where parasympathetic dominance occurs during arousal and sympathetic dominance during orgasm. This delicate balance between antagonism and synergy allows the body to adapt efficiently to various physiological demands, including stress, digestion, and reproduction. The pattern was created with BioGDP.com[14].

Approximately 80% of VN fibers are afferent and 20% efferent. Afferent fibers transmit gastrointestinal sensory information to the nucleus tractus solitarius, which relays signals to the DMV to regulate efferent activity via vagovagal reflexes. The dorsal vagal complex, comprising the nucleus tractus solitarius, DMV, and area postrema, serves as the primary autonomic reflex center[18]. Sensory inputs are further conveyed to higher CNS regions, including the amygdala, paraventricular nucleus of the hypothalamus, and locus coeruleus. Following central integration, VN efferent fibers regulate cardiac, pulmonary, and gastrointestinal motility. Rather than directly innervating intestinal lamina propria, efferent VN fibers primarily interact with enteric neurons, which subsequently release neurotransmitters such as acetylcholine (ACh) to influence intestinal epithelial, neural, and immune functions[19] (Figure 3).

Figure 3 Bidirectional communication between vagus nerve and gastrointestinal tract. The digestive system transmits signals through mechanoreceptors (e.g., food-related mucosal stroking, distension, and contraction) and chemoreceptors (detecting nutrients, hormones, pH, and immune stimuli). These signals travel through vagal afferent fibers to the nucleus tractus solitarius (NTS) and then to the central nervous system. The NTS processes visceral sensory information and transmits it to higher brain regions, including the paraventricular nucleus, the dorsal motor nucleus of the vagus, and the rostral ventromedial medulla. γ-aminobutyric acid, glutamate, and norepinephrine act as primary neurotransmitters in this process. The paraventricular nucleus of hypothalamus, upon the integration of signals, activates corticotropin-releasing hormone neurons to stimulate the hypothalamic-pituitary-adrenal axis, leading to the release of glucocorticoids that regulate gastrointestinal function. The rostral ventromedial medulla, influenced by NTS projections, modulates visceral pain perception through μ-opioid receptors. Simultaneously, the dorsal motor nucleus of the vagus, following signal integration, activates excitatory pathways via vagal efferent fibers to release acetylcholine or inhibitory pathways to release non-adrenergic non-cholinergic neurotransmitters like nitric oxide or vasoactive intestinal peptide in the digestive tract. Ach: Acetylcholine; NANC: Non-adrenergic non-cholinergic; GC: Glucocorticoid; HPA: Hypothalamic-pituitary-adrenal axis; PVN: Paraventricular nucleus of hypothalamus; RVM: Rostral ventromedial medulla; DMV: Dorsal motor nucleus of vagus; LC: Locus coeruleus; NTS: Nucleus tractus solitarius. The pattern was created with BioGDP.com[14].

MECHANISMS OF STRESS-INDUCED IBD

Psychological stress triggers physiological responses that include neuroendocrine activation, immune modulation, and changes in gastrointestinal function[20]. Studies have linked stress to IBD progression[21,22]. Clinical studies, however, have reported inconsistent associations between stress and IBD outcomes. This variation may reflect differences in stress-assessment methods, disease phenotype, including UC and CD, and patient characteristics[23,24]. Current evidence suggests that psychological stress perception is closely associated with disease activity and relapse risk in IBD[25,26]. The stress response is mediated mainly through the BGA. Within this network, the ANS links central stress signals to intestinal inflammatory responses.

Causes disorders of intestinal nerve information

The ENS is a downstream target of autonomic regulation and contributes to intestinal function and immune homeostasis[27]. Under psychological stress, neuroendocrine responses are largely coordinated by the HPA axis and ANS, which together influence intestinal neural activity and immune homeostasis. Corticotropin-releasing hormone (CRH) signaling induced by stress can activate intestinal neural circuits through CRH receptors expressed in the gut. This process disrupts epithelial barrier integrity and facilitates inflammatory responses by promoting mast cell (MC) activation and the release of pro-inflammatory mediators[28,29]. Stress may also promote IBD relapse and symptom exacerbation through hypothalamic-ANS activation of the ENS and increased production of pro-inflammatory cytokines[30].

The ENS participates in the regulation of intestinal inflammation by releasing various neurotransmitters and neuropeptides, including SP, vasoactive intestinal peptide (VIP), and neuropeptide Y (NPY)[31]. Increased SP and VIP signaling can activate MC and promote inflammatory mediator release. Mediators released from MCs can further stimulate enteric neurons, establishing a bidirectional neuroimmune interaction that contributes to the persistence of intestinal inflammation[32]. Under stress conditions, increased SP release activates neurokinin-1 receptors expressed on mesenteric adipocytes. This interaction activates nuclear factor-κB (NF-κB) signaling, increases interleukin-8 (IL-8) secretion, and promotes inflammation[33]. In colitis models, disruption of VIP signaling reduces IL-22 production by ILC3s, impairing mucosal protection and increasing susceptibility to inflammation[34]. Increased NPY expression and enteric nerve proliferation are associated with enhanced inflammation in colitis models. Inhibition of NPY reduces inflammatory responses and tumor necrosis factor-alpha (TNF-α) production[35]. In patients with IBD, elevated TNF-α and IL-6 levels are associated with activation of the hypothalamic-ANS and HPA axes, while plasma NPY levels may reflect autonomic stress responses[36] (Figure 4).

Figure 4 Stress-induced enteric nervous system signaling regulating intestinal immune responses. Stress activates the hypothalamic-pituitary-adrenal axis and autonomic nervous system, which modulate enteric nervous system activity and neuropeptide release. Enteric nervous system-derived substance P, vasoactive intestinal peptide, and neuropeptide Y regulate immune cell activation, mast cell responses, group 3 innate lymphoid cells-mediated mucosal protection, and inflammatory signaling in mesenteric adipocytes. These neuroimmune interactions establish a bidirectional feedback loop that influences intestinal inflammation and disease progression. HPA: Hypothalamic-pituitary-adrenal axis; CRH: Corticotropin-releasing hormone; ANS: Autonomic nervous system; ENS: Enteric nervous system; MC: Mast cell; VIP: Vasoactive intestinal peptide; NPY: Neuropeptide Y; ILC3: Group 3 innate lymphoid cells; TNF-α: Tumor necrosis factor-α; SP: Substance P; IL: Interleukin. The pattern was created with BioGDP.com[14].

Enteric glial cells (EGCs) are important components of the ENS that participate in neuroimmune regulation and intestinal barrier maintenance[37,38]. In early IBD, pro-inflammatory stimuli can induce reactive EGC proliferation and hypertrophy. These changes may help maintain mucosal integrity and limit inflammation. In chronic disease, EGC depletion and disruption of the glial network may instead aggravate intestinal inflammation[39]. These findings suggest that stress-related autonomic dysregulation may affect EGC-mediated neuroimmune responses and thereby contribute to intestinal inflammation.

Disrupts intestinal immune homeostasis

Psychological stress can disrupt immune regulation through neuroendocrine and autonomic pathways, contributing to intestinal inflammation in IBD. Stress-related autonomic activation alters immune cell function, including T-cell differentiation, macrophage polarization, and MC activation, thereby disrupting intestinal immune homeostasis[40,41]. Chronic stress is associated with Th17/Treg imbalance, characterized by increased Th17 differentiation and reduced regulatory T-cell responses. This imbalance can increase pro-inflammatory cytokine production and impair mucosal immune tolerance[42-44]. In addition, stress activates MCs through neuroimmune interactions, resulting in the release of inflammatory mediators, including histamine, proteases, and cytokines, which contribute to epithelial dysfunction and intestinal inflammation[45-47].

Sympathetic activation represents an important pathway linking stress responses to immune alterations. Stress-induced norepinephrine (NE) release activates β-adrenergic signaling, which can affect immune cell survival and inflammatory activity[48]. These findings indicate that ANS imbalance serves as a key mechanism connecting psychological stress with intestinal immune dysregulation and IBD progression.

Affects the expression of neurotransmitters

The gastrointestinal tract contains an extensive neuroendocrine network that produces various neurotransmitters and neuropeptides involved in brain-gut communication and intestinal homeostasis. Psychological stress can disrupt autonomic balance, leading to alterations in neurotransmitter signaling and impaired regulation of gastrointestinal functions. Dysregulation of neurotransmitters, including 5-hydroxytryptamine, dopamine, SP, and VIP, affects intestinal motility, visceral sensitivity, immune activation, and inflammatory responses, thereby contributing to IBD pathophysiology and symptom severity[49].

Impairs the intestinal mucosal barrier

The intestinal mucosal barrier maintains immune homeostasis, and its dysfunction is a critical feature of IBD pathogenesis. Stress-induced CRH activation can promote MC degranulation and the release of inflammatory mediators, including proteases and TNF-α. This process increases epithelial permeability and impairs barrier function[29,50]. Clinical and experimental studies indicate that acute and chronic stress can alter tight junction protein expression, increase intestinal permeability, and disrupt epithelial homeostasis[44,51,52]. Psychological stress can also impair mitochondrial function and induce oxidative stress in intestinal epithelial cells, resulting in disruption of epithelial integrity and barrier function[45,53,54]. Chronic stress further affects epithelial cell turnover and barrier repair, which may increase mucosal permeability and visceral sensitivity[55,56].

Disrupts gut microbial homeostasis

Gut microbiota dysbiosis is a common feature of IBD and is associated with psychological stress. Stress-related autonomic activation, particularly increased catecholamine release, can alter microbial composition and function. This may involve disrupted microbial signaling and expansion of opportunistic pathogens[57]. Dysbiosis is associated with reduced anaerobes, including Firmicutes, and a lower abundance of short-chain fatty acid (SCFA)-producing bacteria. It is also associated with increased Proteobacteria and facultative anaerobes, such as Escherichia coli, which may promote intestinal inflammation[58]. Stress can further impair mucosal barrier function and innate immunity, favoring microbial imbalance and bacterial translocation[40,59,60]. In germ-free mouse models, colitis severity is often attenuated, supporting the essential role of the microbiota in IBD pathogenesis[61]. These findings support bidirectional interactions between the gut microbiota and host neuroimmune responses that may amplify intestinal inflammation.

In addition, microbial metabolites, particularly SCFAs, play important roles in maintaining intestinal homeostasis. Reduced SCFA production under stress conditions may impair immune regulation and barrier integrity, as well as disrupt BGA communication, thereby exacerbating IBD progression[62-64]. SCFA supplementation has been shown to attenuate cortisol responses to stress[65] and promote mucosal integrity in IBD[66]. Collectively, these findings suggest that stress-induced autonomic dysregulation contributes to gut microbiota imbalance and its downstream inflammatory effects in IBD (Figure 5).

Figure 5 The impact of stress on intestinal inflammation. Stress can lead to inflammatory bowel disease through various pathways, such as affecting the transmission of intestinal nerve information, affecting the release of neurotransmitters and gastrointestinal hormones, disrupting intestinal barrier function, causing dysmotility, participating in immune inflammatory responses, affecting intestinal microbiota balance, and the release of microbial metabolites, ultimately participating in systemic inflammatory responses. HPA: Hypothalamic-pituitary-adrenal axis; CRH: Corticotropin-releasing hormone; GC: Glucocorticoid; CSF1: Colony-stimulating factor 1; Ach: Acetylcholine; TNF-α: Tumor necrosis factor-alpha; MPO: Myeloperoxidase; IL: Interleukin; CRP: C reactive protein. The pattern was created with BioGDP.com[14].

THE ROLE OF ANS IN STRESS-RELATED IBD

Psychological stress disrupts ANS function, impairing sympathetic-parasympathetic balance. In CD, ANS dysfunction correlates with symptom severity and inflammatory biomarkers. Sympathetic hyperactivity is frequently associated with increased systemic and intestinal inflammation, reflected by elevated erythrocyte sedimentation rate, C reactive protein (CRP), TNF-α, and mucosal cytokines [IL-8, interferon (IFN)-γ][67]. In contrast, enhanced parasympathetic activity is linked to reduced systemic inflammation, including lower erythrocyte sedimentation rate and TNF-α levels. Longitudinal studies in UC demonstrate that increased parasympathetic tone predicts reduced systemic inflammation over three years, although it does not predict mucosal disease severity[68]. These findings identify the ANS as a key regulator in stress-related IBD pathogenesis and a potential therapeutic target.

The role of SNS in stress-related IBD

Heart rate variability is widely used as a noninvasive index of autonomic regulation. Patients with IBD show altered ANS activity, characterized by increased sympathetic activity and reduced parasympathetic activity. These changes are associated with intestinal inflammation severity and clinical status[69]. Autonomic abnormalities occur in both CD and UC. CD has been associated mainly with sympathetic dysregulation, whereas UC is more often associated with impaired vagal function[67,70]. Emotional states may also influence autonomic balance. In CD, positive emotions are associated with adaptive sympathetic activation. In UC, positive emotional states are associated with balanced sympathetic and vagal activity, whereas negative emotional states are associated with reduced parasympathetic activity[71].

The SNS exhibits bidirectional immunomodulatory effects, with its proinflammatory or anti-inflammatory actions determined by multiple factors, including disease stage, adrenergic receptor subtype expression, neurotransmitter concentration, and immune cell context[72]. NE-mediated β2-AR activation generally suppresses macrophage-derived proinflammatory cytokine production, whereas α-adrenergic signaling may promote inflammatory responses under certain conditions. Such differential effects are influenced by local NE gradients and receptor expression patterns, as lower levels of NE may preferentially activate high-affinity α-AR, whereas higher local concentrations may increasingly engage β-AR[72]. For example, low concentrations of NE may enhance macrophage TNF-α production via α2-AR signaling[73]. Willemze et al[74] further demonstrated that β2-AR activation suppresses lipopolysaccharide (LPS)-induced cytokine production in macrophages in a dose-dependent manner, whereas sympathectomy in Rag1-/- mice significantly reduced NE levels and aggravated colonic edema, goblet cell depletion, and mucosal injury. During early inflammation, sympathetic activation promotes neurotransmitter release, enhancing immune cell recruitment and inflammatory mediator production. These mediators subsequently inhibit sympathetic signaling, leading to sympathetic nerve degeneration and dysfunction, which may explain stage-dependent variations in sympathetic fiber density[16,73]. Straub et al[75] demonstrated that the SNS exerts anti-inflammatory effects when sympathetic innervation is preserved. Sympathectomy reduced inflammation in acute DSS-induced colitis but aggravated inflammation in IL10-/- and chronic DSS colitis models.

Stress-induced sympathetic activation increases NE release, which activates α-AR in intestinal vasculature, resulting in splanchnic vasoconstriction and reduced mucosal perfusion[76]. Prolonged intestinal hypoperfusion causes epithelial damage and compromises mucosal integrity. Noradrenergic β2-AR activation also impairs intestinal barrier integrity, increasing antigen permeability and immune activation[77]. At the same time, stress-induced neuroimmune activation promotes MC degranulation, leading to the release of histamine, tryptase, and inflammatory mediators that disrupt epithelial tight junctions and increase intestinal permeability[78]. Stress-induced sympathetic activation also contributes to gut microbiota dysbiosis. Elevated NE can affect bacterial growth and virulence, favoring the expansion of potentially pathogenic bacteria and increasing microbe-derived inflammatory signals[79]. Barrier dysfunction permits the translocation of bacteria and toxins. It can also disrupt microbial balance and activate immune responses, thereby worsening intestinal inflammation[80]. Catecholamines can directly regulate intestinal immune responses through adrenergic receptors expressed on immune cells. Noradrenergic signaling may enhance macrophage activation and increase the production of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6[16]. In addition, catecholamine-mediated adrenergic signaling can also activate NF-κB. This promotes NF-κB nuclear translocation and inflammatory gene transcription, which may sustain mucosal inflammation[81]. Clinically, circulating catecholamine levels correlate with IBD severity, supporting the therapeutic potential of targeting stress-related adrenergic signaling[82].

The role of VN in stress-related IBD

The VN exerts dual anti-inflammatory effects via afferent and efferent mechanisms. Afferent vagal fibers activate the HPA axis, promoting glucocorticoid release. Efferent vagal activity enhances cholinergic signaling through the release of ACh. ACh activates α7 nicotinic ACh receptors (α7nAChRs) expressed on immune cells, thereby suppressing NF-κB activation and reducing pro-inflammatory cytokine production through the cholinergic anti-inflammatory pathway (CAIP)[83]. Activation of α7nAChR by ACh induces downstream JAK2-STAT3 signaling in macrophages, contributing to suppression of inflammatory gene expression[84]. α7nAChR activation can also suppress inflammasome activation and oxidative stress responses, thereby attenuating inflammatory responses[85]. Collectively, these findings indicate that α7nAChR serves as a critical downstream mediator through which the VN regulates immune responses. Vagotomy attenuates this protective effect, impairing inhibition of MC degranulation and promoting colitis development[86,87]. Although direct anatomical connections between vagal efferent fibers and intestinal macrophages have not been established, the VN may regulate intestinal immune homeostasis indirectly through enteric neural circuits[88]. This mechanism has been supported by studies in a mouse model of postoperative ileus, in which cholinergic interneurons within the myenteric plexus mediated vagal-dependent inhibition of intestinal macrophage activation[89]. Furthermore, stress suppresses VN-mediated anti-inflammatory activity by activating autonomic projection neurons of the paraventricular hypothalamic nucleus, which stimulate both the DMV and spinal sympathetic preganglionic neurons[90].

The VN exerts anti-inflammatory effects in coordination with the spleen via a neuroimmune reflex. Previous studies have proposed that efferent vagal signals act on the celiac-mesenteric ganglia, where ACh is released to activate postsynaptic α7nAChR on the splenic nerve, thereby promoting NE release in the spleen[91]. NE subsequently activates β2-AR on splenic lymphocytes, inducing ACh release, which then binds α7nAChR on splenic macrophages, inhibiting TNF-α production and promoting anti-inflammatory effects[92]. However, the classical VN-spleen anti-inflammatory pathway remains controversial, as evidence supporting direct functional and anatomical connectivity between the VN and splenic nerve is insufficient[93]. Furthermore, Simon et al[94] reported that NE released from splenic nerve terminals directly targets β2-AR-expressing splenic myeloid cells, independent of T-cell-mediated cholinergic signaling. These findings suggest that the precise mechanisms underlying VN-mediated anti-inflammatory effects require further clarification (Figure 6).

Figure 6 The role of autonomic nervous system in stress-related inflammatory bowel disease. Stress-induced sympathetic nervous system activation increases norepinephrine (NE) release and signals through α-adrenergic receptor (AR) and β-AR. Excessive sympathetic nervous system activity can slow intestinal motility, impair the mucosal barrier, and promote inflammation. Vagus nerve stimulation may suppress inflammation through hypothalamic-pituitary-adrenal axis-dependent glucocorticoid release. The vagus nerve engages abdominal ganglia and the splenic nerve, promoting NE release from splenic nerve terminals. NE activates β2-AR on cholinergic T lymphocytes, inducing acetylcholine (ACh) release. ACh activates α 7 nicotinic ACh receptor on macrophages and inhibits tumor necrosis factor-α production. Vagal fibers also regulate the enteric nervous system through the myenteric plexus. ACh signaling can activate α 7 nicotinic ACh receptor on intestinal macrophages and reduce pro-inflammatory cytokine release. HRV: Heart rate variability; AR: Adrenergic receptor; NE: Norepinephrine; TNF-α: Tumor necrosis factor-α; HPA: Hypothalamic-pituitary-adrenal axis; GC: Glucocorticoid; ACh: Acetylcholine; α7nAChR: Α 7 nicotinic acetylcholine receptor. The pattern was created with BioGDP.com[14].

IBD patients have been reported to exhibit reduced vagal tone. In CD, low resting VN activity is associated with elevated circulating TNF-α levels, even during remission[95]. The prevalence of IBD is higher after vagotomy than in non-vagotomized individuals (0.8% vs 0.5%), and incidence increases over time after vagotomy. CD shows a stronger association with vagotomy than UC[96], underscoring the critical role of VN in IBD pathophysiology. Vagal signaling has anti-inflammatory effects, and stress may compromise this immunomodulatory pathway and aggravate IBD. ANS dysfunction has also been reported in IBD, with severity that may vary according to individual stress resilience and emotional state[71]. Further studies should define the mechanisms of ANS dysfunction and its relationship with inflammation to identify therapeutic targets for IBD.

TREATMENT OF IBD

Current treatment methods

Psychotherapy: Psychological comorbidities, including anxiety, depression, and chronic stress, are common in patients with IBD. They are associated with poorer quality of life and less favorable illness experiences[97]. Psychological interventions, including cognitive-behavioral therapy, stress management, mindfulness-based interventions, and hypnotherapy, have been explored as adjunctive approaches to IBD management. Among these interventions, cognitive-behavioral therapy has shown benefits in reducing psychological symptoms and improving health-related quality of life[98,99]. However, its long-term psychological benefits remain uncertain, and evidence is insufficient to confirm sustained anti-inflammatory or disease-modifying effects[100]. Stress management similarly improves quality of life without altering disease progression or recurrence[101]. Mindfulness-based interventions provide additional benefits, including reductions in inflammatory markers (IL-6, CRP, fecal calprotectin) and improvements in psychological outcomes, with greatest efficacy observed in CD patients with severe psychological symptoms[44,102,103]. Overall, psychological interventions appear to improve patient-reported outcomes, whereas evidence for direct disease-modifying effects remains limited[104,105].

Drug therapy: Pharmacological therapy remains central to IBD management. Conventional anti-inflammatory agents, including 5-ASA and corticosteroids, are commonly used to induce remission. 5-ASA exerts anti-inflammatory effects by inhibiting cyclooxygenase and lipoxygenase activity, suppressing NF-κB activation, and regulating inflammatory mediator production[106,107]. Corticosteroids provide rapid symptom relief by regulating glucocorticoid receptor-mediated transcription and suppressing pro-inflammatory cytokines[108,109]. Their long-term use is limited because they do not maintain sustained remission and can cause substantial adverse effects, including metabolic complications and neuropsychiatric disturbances[110-113].

Biologic therapies have expanded treatment options for IBD by targeting specific inflammatory pathways. Anti-TNF agents[114], IL-12/23 inhibitors[115], and anti-integrin therapies[116,117] can induce and maintain remission, promote mucosal healing, and improve outcomes in moderate to severe IBD. However, some patients experience primary nonresponse, secondary loss of response, or treatment intolerance. High cost and the need for long-term treatment also limit their use and support the search for complementary approaches[118,119].

Because psychological symptoms and intestinal inflammation are closely related, antidepressants have also been investigated in IBD. Selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and the metal polyphenol antidepressant CSMTC may improve psychological symptoms. In experimental models, these agents have also shown anti-inflammatory effects involving immune regulation, oxidative stress modulation, and the microbiota-gut-brain axis[120-123]. Clinical studies suggest that antidepressants may improve psychological symptoms and may be associated with lower healthcare utilization and better disease-related outcomes in selected patients with IBD and psychological comorbidities[124,125]. Their role in IBD treatment remains uncertain because clinical evidence is limited and potential confounding factors remain.

Most current IBD therapies target immune and inflammatory pathways rather than neural mechanisms involved in intestinal immune homeostasis. Emerging evidence indicates that the ANS plays a critical role in regulating inflammation through neuroimmune interactions. Therefore, ANS-targeted interventions represent a promising therapeutic direction that may complement existing immune-based treatments. These emerging approaches will be discussed in the following section.

ANS-targeted therapy in IBD

Regulate the SNS: α2-ARs are potential therapeutic targets in IBD. These receptors are expressed at presynaptic and postsynaptic sites in enteric neurons, as well as in non-neuronal cells, including intestinal epithelial and smooth muscle cells. They regulate enteric neurotransmission, gastrointestinal motility, and visceral sensation[126]. In patients with active UC, the α2-AR agonist clonidine reduces sympathetic overactivity and restores sympathovagal balance. An 8-week course of transdermal clonidine reduced muscle sympathetic nerve activity, plasma epinephrine concentrations, and the low-frequency/high-frequency ratio, while increasing high-frequency power. These autonomic improvements were accompanied by lower disease activity, symptom relief, and less endoscopic inflammation, although histologic improvement was limited during this early treatment period[127]. The selective α2-AR agonist dexmedetomidine attenuates TNBS-induced colitis by suppressing IL-23-driven Th17 responses. This finding implicates α2-AR-mediated sympathetic signaling in adaptive immune activation during intestinal inflammation[128]. In DSS-induced colitis, dexmedetomidine inhibits TLR4/MyD88/NF-κB signaling and reduces IL-1β, IL-6, and TNF-α expression. It also restores tight-junction integrity and limits intestinal epithelial apoptosis[129]. However, the effects of α2-AR signaling are not uniformly protective. Bai et al[130] showed that psychological stress aggravated TNBS-induced colitis by increasing dopamine β-hydroxylase expression. The α2-AR antagonist RX821002 reduced histopathologic injury and lowered TNF-α and IL-1β expression. Meanwhile, Zádori et al[126] found that clonidine aggravated DSS-induced colitis. Genetic deletion of α2A-AR abolished this effect, identifying α2A-AR as the principal subtype responsible for clonidine-induced inflammation. The selective α2A-AR antagonist BRL 44408 reduced DAI scores, MPO infiltration, and the expression of CCL3, CXCL2, CXCL13, and G-CSF. Clonidine reversed these effects, further supporting a role for α2A-AR signaling in intestinal inflammation. Thus, the effects of α2-adrenergic signaling appear to vary depending on receptor subtype, experimental model, and inflammatory status.

Stress-induced catecholamine release promotes IL-17A-mediated neutrophil infiltration through activation of STAT3 signaling. The β1/β2-AR antagonist propranolol inhibits STAT3 phosphorylation and suppresses the expression of CXCL1 and CXCL2. It also reduces the stress-induced expansion of circulating CD11b⁺Ly6C⁺Ly6G⁺ cells and decreases IL-6 and IL-1β levels, while exerting no significant effect on IL-17A expression[131]. Moreover, propranolol reverses the neutrophil recruitment and colonic injury induced by isoproterenol, a β-AR agonist that mimics stress-induced β-AR activation[131]. NE promotes visceral hypersensitivity by increasing nerve growth factor expression and sensitizing colon-specific neurons in the thoracolumbar dorsal root ganglion. Combined administration of phentolamine (an α1/α2-AR antagonist) and propranolol (a β1/β2-AR antagonist) alleviates nerve growth factor upregulation and visceral hypersensitivity, independently of inflammatory responses[132]. In UC rats, the β1/β2-AR antagonist carvedilol and the β3-AR agonist mirabegron inhibit GSK-3β/NF-κB, Notch, and PS1/BACE-1/Aβ signaling in the colon. These agents reduce inflammatory and oxidative responses, limit β-amyloid deposition, and modulate fibrosis by decreasing transforming growth factor-β1 and α-smooth muscle actin while increasing Smad7. They also restore goblet-cell numbers and improve mucosal barrier function[133]. Similarly, the β3-AR agonist SR58611A reduces colonic MPO activity, downregulates the expression of inflammatory cytokines, and ameliorates mucosal structural damage. However, it fails to restore the decreased β3-AR mRNA expression in the distal colonic mucosa/submucosa. This finding suggests that its therapeutic effects may not rely on transcriptional upregulation of the receptor but may instead involve post-transcriptional regulation, modulation of receptor function, or receptor-independent mechanisms[134]. The β2-AR agonist (R)-salbutamol is also protective in experimental colitis. It suppresses p-NF-κB expression, lowers TNF-α and IFN-γ concentrations in serum and colonic tissue, reduces colonic CD4+ leukocyte infiltration, and activates the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 antioxidant pathway. In addition, (R)-salbutamol modulates gut microbiota by increasing beneficial bacteria, such as Akkermansia, and reducing potentially pathogenic bacteria, including Bacteroides and Proteobacteria[135]. Together, these findings show that the effects of β-adrenergic modulation may depend on receptor subtype, ligand properties, and the pattern of receptor activation.

Besides pharmacological manipulation of α- and β-ARs, interventions aimed at sympathetic neural pathways may provide an alternative approach for modifying intestinal inflammatory responses. The superior mesenteric nerve (SMN), which arises from the superior mesenteric ganglion, supplies sympathetic innervation to the gastrointestinal tract. SMN sympathectomy exacerbates DSS-induced colitis in mice. In contrast, SMN stimulation alleviates disease severity, as indicated by reduced DAI scores, although its effects on inflammatory mediators, including IL-1β and CCL3, remain limited[136]. Selective activation of superior mesenteric ganglion sympathetic postganglionic neurons inhibits macrophage activation and LPS-induced TNF-α production in the spleen and mesenteric lymph nodes[137]. Splenic nerve stimulation activates sympathetic splenic nerve fibers, promoting NE release and subsequent activation of β2-ARs on splenic cells. This signaling pathway suppresses the mRNA expression of TNF-α, S100A8, and S100A9, downregulates the hypoxia-inducible factor-1α pathway, and alleviates colonic edema[137]. Furthermore, transrectal insertion of an optical fiber followed by blue LED illumination (460 nm) of the colon activates local sympathetic nerves. Through the β-AR-CREB signaling pathway, this intervention reduces MAdCAM-1 mRNA and protein expression in colonic vascular endothelial cells, thereby inhibiting immune cell extravasation from the circulation into colonic tissues. Consequently, it decreases the number of CD45+ cells in the lamina propria and intraepithelial lymphocyte compartments and downregulates the mRNA expression of IL-12, IL-21, and IL-17[138]. These findings indicate that circuit-specific sympathetic interventions may represent a more precise therapeutic strategy for IBD than systemic manipulation of sympathetic activity.

Regulate the VN: VN is the main component of PNS, and measures to treat IBD with VN include medication, diet, exercise, acupuncture, and VN stimulation (VNS). Galantamine is an acetylcholinesterase inhibitor and an allosteric modulator of nicotinic receptors. It crosses the blood-brain barrier, enhances central cholinergic activity and vagal output, and is approved for the treatment of Alzheimer’s disease. Galantamine was shown to restore plasma ACh levels and activate peripheral α7nAChR signaling, resulting in a dose-dependent reduction in ulcer area. These protective effects were mediated by the regulation of the JAK2/STAT3, NF-κB, and p-Akt/Bcl-2 pathways, along with reduced MPO and malondialdehyde levels and improved cell survival[139]. The α7nAChR agonist GTS-21 strengthens the intestinal barrier, limits bacterial translocation, and suppresses colonic IL-6 production through the VN-spleen-macrophage axis[140]. The α7nAChR agonist nicotine and the acetylcholinesterase inhibitor huperzine A also exhibit anti-inflammatory effects in experimental colitis models. These agents reduce MPO activity, malondialdehyde levels, and the expression of pro-inflammatory cytokines (IL-1β and TNF-α), while also inhibiting NF-κB activation and restoring Visfatin levels[141]. In patients with mild-to-moderately active UC, adding a transdermal nicotine patch to standard therapy for 6 weeks increases clinical remission and improves endoscopic, histologic, and quality-of-life outcomes[142]. A 6-mg nicotine enema likewise relieves symptoms, improves endoscopic and histologic indices, and reduces serum CRP in patients with UC[143]. However, its clinical use is limited by tolerability, addiction risk, and safety concerns. Notably, despite therapeutic benefits in UC, nicotine paradoxically increases CD risk and progression. Smoking is one of the major environmental risk factors for CD and exhibits a dose-dependent impact on disease progression. Compared with non-smokers, CD patients who smoke have a twofold increased risk of disease relapse, a higher prevalence of ileal involvement, and poorer outcomes, particularly among women[144]. In macrophages infected with the CD-associated Mycobacterium avium subspecies paratuberculosis (MAP) UCF4 strain, nicotine activates α7nAChR and promotes M1 polarization. This response increases iNOS, IL-6, and TNF-α expression while reducing the M2 marker CD206 and the anti-inflammatory cytokine IL-10. Nicotine also inhibits caspase-3-dependent apoptosis, increases intracellular MAP survival, and thereby amplifies bacterial burden and inflammation. The α7nAChR antagonist mecamylamine abolishes these effects[145]. The opposing effects observed in UC and CD may reflect disease-specific immune environments and cellular targets. In UC, α7nAChR activation appears to restrain excessive innate inflammation. In CD, particularly in the presence of microbial triggers such as MAP, nicotine may instead promote pathogenic macrophage activation and bacterial persistence.

Enteral nutrition may benefit IBD through vagal pathways. High-fat feeding stimulates cholecystokinin (CCK) release and activates CCK1 receptors on vagal afferents. This response engages a nicotinic receptor-dependent cholinergic pathway that suppresses TNF-α and IL-6 production. It also limits bacterial translocation and endotoxin leakage, thereby protecting the intestinal barrier. Vagotomy and pharmacologic blockade of either CCK or nicotinic receptors abolish these effects, confirming the requirement for vagal signaling[146]. MCs are effectors of this diet-vagus reflex. Lipid-rich nutrition inhibits MC degranulation and improves barrier dysfunction[147]. In children with moderate-to-severe CD, exclusive enteral nutrition with an oral polymeric formula containing 14% protein, 44% carbohydrate, and 42% fat produced higher rates of mucosal healing than oral methylprednisolone. It also reduced endoscopic and histologic scores and led to greater weight gain. The intervention improved growth and had a favorable safety profile[148]. Consistent with these findings, clinical guidelines recommend enteral nutrition to induce remission in CD[149].

Psychosocial stress can exacerbate UC, and yoga has been evaluated as an adjunctive stress-management strategy. Compared with standard self-care interventions, regular yoga practice (90 minutes per week for 12 weeks) significantly reduced perceived stress among patients with UC in clinical remission, accompanied by improvements in clinical symptoms and quality of life. Reduced disease activity persisted during the 24-week follow-up period[150]. These effects may partly reflect increased vagal tone and improved autonomic balance[151], with downstream effects on intestinal immunity. Inspired by yoga practices, Werner et al[15] compared abdominally targeted physical exercises with general exercise. The targeted program stabilized fecal calprotectin concentrations in patients with IBD and increased clinical remission in CD, but not in UC. The different responses may reflect the anatomical and pathological distinctions between these diseases. Because UC commonly involves the rectum, abdominal exercise may have limited direct mechanical effects on rectal inflammation. By contrast, the transmural and segmental lesions of CD may be more responsive to exercise-induced changes in local blood flow and intestinal motility.

Electroacupuncture (EA) at ST36 activates the vagus-adrenal axis and enhances noradrenergic signaling, resulting in increased serum NE levels and reduced EGC activation. EA also suppresses the S100β/RAGE/MyD88/NF-κB cascade, decreases TNF-α expression, and limits MC activation and degranulation, ultimately alleviating visceral hypersensitivity in UC during the remission phase[152]. EA at ST37 activates ChAT-positive neurons in the DMV, thereby increasing vagal efferent activity and ACh release. ACh then acts on α7nAChR-expressing colonic immune cells and activates the CAIP. This response reduces CXCL1 and IL-5 expression and attenuates intestinal inflammation[153]. These studies provide a mechanistic basis for evaluating EA as a vagally mediated neuromodulatory intervention in IBD.

Invasive VNS requires surgical placement of an electrode around the cervical VN and connection to a chest-wall pulse generator under general anesthesia. VNS exerted both preventive and therapeutic effects in DSS-induced colitis. Preventive stimulation promotes epithelial proliferation, limits apoptosis, and preserves barrier integrity. Therapeutic VNS reduced systemic and intestinal inflammatory responses by decreasing splenic CD11b+ cell and monocyte populations, limiting leukocyte recruitment, suppressing lamina propria infiltration of eosinophils, neutrophils, monocytes, immature macrophages, and CD169- mature macrophages, and attenuating the production of pro-inflammatory cytokines and chemokines such as TNF-α and CXCL1[154]. VNS restores vagal activity and improves disease severity, epithelial integrity, and histopathologic injury. These effects did not rely on the canonical IL-10/α7nAChR-dependent CAIP. Instead, VNS exerted its protective effects by inhibiting colonic protein SUMOylation, particularly SUMO2/3 conjugation, thereby reducing IL-6 and TNF-α production[155]. In clinical settings, VNS (10 Hz) has been shown to restore vagal tone in patients with mild-to-moderate CD, resulting in reduced disease activity, decreased levels of inflammatory biomarkers, including CRP and fecal calprotectin, and the achievement of endoscopic remission[156]. In patients with moderately active CD, VNS (10 Hz) has also shown promising therapeutic effects. VNS treatment induced clinical and endoscopic remission and was associated with marked reductions in intestinal expression of pro-inflammatory mediators[157]. In biologic-refractory CD, VNS improved endoscopic and histopathologic outcomes and reduced systemic and intestinal inflammation. CRP, TNF-α, and IFN-γ concentrations declined, while patient-reported quality of life improved[158]. However, VNS requires at least 3 months to achieve therapeutic effects and is unsuitable as a monotherapy for patients with severe IBD[157]. Clinical application of VNS in IBD remains limited by surgical risks (e.g., bleeding, infection, cough, and hoarseness), sparse colonic VN innervation, uncertain efficacy in proctitis, and potential cardiovascular off-target effects. Distal abdominal stimulation may reduce cardiac off-target effects. Subdiaphragmatic abdominal VNS (10 Hz) significantly improved stool consistency, reduced plasma CRP levels, attenuated CD3+ T-cell infiltration in the mucosal and muscular layers, and exerted no detectable cardiovascular effects in rats[159]. Zhang et al[160] identified intermittent bipolar sacral nerve stimulation (SNS) as a potentially safer alternative. Daily SNS at 5 Hz for 1 hour increased vagal tone and reduced sympathetic activity, as indicated by altered pancreatic polypeptide concentrations and lower NE release. SNS also downregulated the Th1/Th17 mediators TNF-α, IL-6, and IL-17A while increasing IL-10 and IL-4. This response may involve vagal efferent pathways through the nucleus tractus solitarius and DMV. In patients with mild-to-moderate UC, 2 weeks of SNS targeting the S3 and S4 sacral foramina limited deterioration of autonomic balance, increased clinical response, reduced Mayo scores, lowered plasma CRP and serum TNF-α, and altered gut microbial composition[161].

Transcutaneous VNS (taVNS) is a noninvasive alternative to implanted VNS and has a more favorable safety profile. By activating vagal pathways, taVNS inhibits IL-6/JAK2/STAT3 signaling and reduces IL-12p70, IL-17A, and macrophage-colony stimulating factor production, which supports mucosal repair[162]. In preclinical studies, taVNS attenuates DSS-induced colitis by reducing colonic inflammation, tissue injury, matrix metalloproteinase-2 and matrix metalloproteinase-9 expression, and the apoptosis-related proteins Bax, Bak1, and caspase-8. However, the beneficial effects of taVNS appear to be model-dependent, as its efficacy is limited in DNBS-induced colitis. This difference may reflect the predominantly superficial epithelial injury and mucosal inflammation caused by DSS, compared with the deeper, transmural inflammation and extensive immune activation induced by DNBS[163]. Clinical studies in pediatric IBD indicate that taVNS increases vagal tone and reduces disease activity. It also lowers fecal calprotectin in UC, whereas the reduction in CD is not statistically significant[164]. The response to taVNS may therefore depend on disease phenotype, inflammatory pattern, and severity. The differential responses observed across experimental models and clinical subtypes highlight the importance of considering disease heterogeneity when optimizing vagal neuromodulation strategies for IBD. However, despite encouraging preclinical evidence, the limited clinical data on taVNS in IBD represent a key research gap that needs to be addressed. Large-scale randomized controlled trials, long-term clinical evaluations, and mechanistic studies are therefore important priorities for future research to establish its therapeutic efficacy, optimize stimulation parameters, and define its clinical applicability in different IBD phenotypes (Figure 7; Table 1).

Figure 7 Treatment of inflammatory bowel disease various methods such as lifestyle changes, psychotherapy, drug therapy, and neural regulation can help treat inflammatory bowel disease by restoring the intestinal mucosal barrier, regulating the intestinal immune response, reducing the release of inflammatory factors, restoring the balance of the intestinal microbiota, and regulating the bidirectional communication between the brain and the gastrointestinal tract. IBD: Inflammatory bowel disease. The pattern was created with BioGDP.com[14].

Table 1 Autonomic nervous system-targeted interventions for inflammatory bowel disease.

Intervention	Molecular mechanism/signaling pathway	Therapeutic effects	Model/population	Limitation	Ref.
Clonidine	Activate α2-AR	↓ muscle sympathetic nerve activity; ↓ plasma epinephrine; restores sympathovagal balance (↓ low-frequency/high-frequency); improves DAI, clinical symptoms, endoscopy	Patients with active UC (n = 9, clonidine group; n = 7, placebo group)	Small sample size; unclear whether sympathetic overactivity is UC-specific or a generic feature of inflammatory states	[127]
Dexmedetomidine	Activate α2-AR	↓ weight loss, ↓ mortality; ↓ histologic damage score; ↓ IL-23, ↑ IL-10/IL-4	TNBS-induced colitis in BALB/c mice (in vivo + in vitro)	Ip. route not clinical iv.; mechanism (Tr1 cells) not fully validated; short observation (6 days)	[128]
Dexmedetomidine	Activate α2-AR; TLR4/MyD88/NF-κB	↓ DAI score, ↓ weight loss, ↑ colon length; ↓ intestinal permeability (↓ FITC-D); ↑ ZO-1, occludin, claudin-1; ↓ serum and colonic IL-1β/IL-6/TNF-α; ↓ intestinal epithelial cell apoptosis (↑ Bcl-2, ↓ Bax and cleaved caspase-3)	DSS-induced colitis in female C57BL/6J mice	Prophylactic administration only	[129]
RX821002	Inhibit α2-AR	↓ body weight loss; ↓ histological damage and inflammatory cell infiltration in lamina propria; ↓ TNF-α, ↓ IL-1β	Restraint stress + TNBS-induced colitis in BALB/c mice	No direct catecholamine level measurement (dopamine β-hydroxylase used as surrogate marker); specific immune cell subtypes not identified	[130]
Clonidine; BRL 44408	Activate α2a-AR and inhibit α2a-AR	Clonidine: ↑ DAI elevation, ↑ weight loss; BRL 44408: ↓ weight loss, ↓ colonic MPO levels; ↓ CCL3, CXCL2, CXCL13, G-CSF, ↑ TIMP-1	DSS-induced colitis in wild-type, α2A/α2B/α2C-AR KO C57BL/6 mice	Specific downstream signaling mechanism of α2A-AR in colitis remains unclear	[126]
Propranolol	Inhibit β1/β2-AR; STAT3 signaling	↓ stress-aggravated body weight loss, ↑ colon length; ↓ histological damage; ↓ peripheral blood neutrophils (CD11b+Ly6C+Ly6G+) and colonic neutrophil infiltration; ↓ IL-6, IL-1β, CXCL1, CXCL2 mRNA levels; ↓ phosphorylation of STAT3	DSS-induced colitis in male C57BL/6 mice under chronic unpredictable stress or chronic restraint stress	Propranolol did not attenuate DSS-induced colitis without stress; other stress-related signaling pathways may also be involved	[131]
Phentolamine + propranolol	Inhibit α1/α2-AR and β1/β2-AR; nerve growth factor/Trka signaling	↓ visceromotor response to graded CRD (visceral hypersensitivity); ↓ nerve growth factor expression in muscularis externa and mucosa/submucosa	Heterotypic chronic stress-induced visceral hypersensitivity in male Wistar rats	Does not distinguish α- vs β-AR contribution individually	[132]
Carvedilol and/or Mirabegron	Inhibit β1/β2-AR; activate β3-AR; GSK-3β/NF-κB, Notch, PS1/BACE-1/Aβ signaling	↓ colon edema index; ↑ body weight; ↓ histological damage score (inflammatory infiltration, edema, hemorrhage, fibrosis); ↓ PS1, BACE-1, Aβ; ↓ Notch1, NICD, HES1; ↑ goblet cells; ↑ PPAR-γ, p(S9)-GSK3-β; ↓ TNF-α, malondialdehyde, NF-κB; ↓ Transforming growth factor-β1, α-smooth muscle actin; ↑ SMAD-7; ↓ collagen deposition (MTC); ↓ p(Y654)-β-catenin; ↑ E-cadherin (mirabegron-specific effect)	Iodoacetamide-induced UC in male Wistar rats	Only validated in single iodoacetamide model; carvedilol also possesses α1-AR blocking activity that may contribute partially; mirabegron off-target effects not fully excluded	[133]
SR58611A	Activate β3-AR	↓ colonic MPO activity; ↓ tissue TNF-α, IL-1β, IL-6 levels; restored c-kit-positive ICC network in myenteric plexus	DNBS-induced colitis in male Sprague-Dawley rats	Preventive administration only; no β3-AR antagonist or KO validation	[134]
(R)-salbutamol	Activate β2-AR; nuclear factor erythroid 2-related factor 2/heme oxygenase-1; NF-κB	↓ body weight loss, ↓ DAI score, ↑ colon length, ↓ splenomegaly; ↓ histological damage score (inflammatory infiltration, crypt destruction); ↓ serum and colonic TNF-α, IL-1β, IL-6, IFN-γ; ↓ colonic CD4+ leukocyte infiltration; ↓ p-NF-κB p65; ↑ Nrf-2, heme oxygenase-1; ↑ ZO-1, occludin; ↓ transforming growth factor-β1, α-smooth muscle actin expression; ↓ collagen deposition (picrosirius red staining); restores intestinal microbiome structure	Repeated DSS-induced chronic colitis in male C57BL/6 mice	β2-AR-specific downstream signaling mechanism not fully elucidated; mechanism of microbiome regulation by β2-AR unclear	[135]
Superior mesenteric nerve electrical stimulation		↓ DAI; no significant change in body weight, endoscopy score, histology score; no significant change in colonic IL-1β, IL-6, TNF-α, CXCL3, CCL3, CXCL2, CXCL1	DSS-induced acute colitis in male SD rats	SMN does not completely innervate the colon; stimulation parameters not optimized (optimal frequency/amplitude)	[136]
Splenic nerve stimulation	β2-AR; hypoxia-inducible factor-1α signaling	↓ colon weight/length ratio; ↓ DAI; ↓ colonic TNF-α, S100A8, S100A9 mRNA; trends toward ↓ colonic MCP-1, IL-6, TNF-α, IFN-γ protein; spleen weight; no significant change in body weight, endoscopy score, histology score	DSS-induced acute colitis in female C57BL/6N mice	Mechanism of spleen-to-colon communication unclear; stimulation parameters not optimized for colitis (adopted from arthritis model)	[137]
Optogenetic activation of local colonic sympathetic innervations; intra-rectal optic fiber insertion; blue LED (460 nm)	β-AR-CREB	↓ weight loss, ↓ colon shortening, ↓ histology score; ↓ CD45+ immune cell abundance in lamina propria and intraepithelial lymphocyte; ↓ colonic IL-6, TNF-α, IL-12, IL-21, IL-1β, IL-17 mRNA; ↓ endothelial MAdCAM-1 and ICAM-1 (mRNA and protein)	DSS-induced acute colitis in male/female chr2/TH transgenic mice (C57BL/6 background)	Optogenetic manipulation not limited to blood vessel-surrounding fibers; translatability of optogenetic approach to human IBD	[138]
Galantamine	Activate α7nAChR; JAK2/STAT3, NF-κB, and p-Akt/Bcl-2 pathways	↓ ulcerative area; ↓ colon mass index; ↓ colonic malondialdehyde; neutrophil infiltration: ↓ ICAM-1; ↓ MPO activity; ↓ NF-κB; ↓ TNF-α; ↓ HMGB1; ↓ RAGE; ↑ p-JAK2; ↓ SOCS3; ↑ p-Akt; ↑ Bcl-2; ↑ IL-10	TNBS-induced colitis in male Wistar rats	No assessment of central vs peripheral contribution	[139]
GST-21	Activate α7nAChR	↓ serum IL-6, IL-2; ↑ serum IL-10; ↓ colonic IL-6; ↓ colonic permeability; ↑ claudin-1 mRNA; restored GI motility; ↓ bacterial translocation to blood and mesenteric lymph nodes	CLP-induced polymicrobial abdominal sepsis in OF-1 mice; Chrna7-/- mice	Polymicrobial sepsis model, not IBD	[140]
Nicotine; Huperzine A	Activate α7nAChR; inhibit ACh esterase; NF-κB signaling	Nicotine: ↓ macroscopic lesion score; ↓ colonic MPO activity; ↓ NF-κB expression; ↓ serum IL-1β; restored serum visfatin levels. Huperzine A: ↓ macroscopic and microscopic lesion scores; ↓ colonic MPO activity; ↓ NF-κB expression; ↓ serum IL-1β and TNF-α; ↓ colonic malondialdehyde	Acetic acid-induced colitis in Sprague-Dawley rats	Muscarinic receptor involvement not excluded	[141]
Nicotine	Activate α7nAChR	Nicotine patch therapy combined with standard treatment: ↑ complete remission rate; ↑ quality of life scores; ↓ clinical symptom scores; ↓ endoscopic and histologic inflammation scores. Nicotine carbomer enema combined with standard treatment: ↓ St Mark’s score; ↓ stool frequency; ↓ sigmoidoscopic and histologic score; 3/17 achieved complete remission; 10/17 improved; 5/6 partial responders further improved with extended treatment	Active UC in human patients (n = 72, mild-to-moderate); active ulcerative colitis in human patients (n = 22, all non-smokers)	Small sample size; single-center; combined with standard therapy (nicotine efficacy alone not established)	[142,143]
Nicotine; mecamylamine	Activate/inhibit α7nAChR; macrophage polarization; caspase-3-dependent apoptosis	Nicotine: Pro-inflammatory effect (m1 polarization, ↑ iNOS, ↑ IL-6, ↑ TNF-α, ↓ CD206, ↓ IL-10; ↑ intracellular bacterial viability/survival; ↓ caspase-3-dependent apoptosis. Mecamylamine abrogates all nicotine effects	Thp-1-derived macrophages infected with mycobacterium avium subspecies paratuberculosis UCF4 (CD-associated pathogen), MTB, or lipopolysaccharide	Immortalized cell line (THP-1) may not fully recapitulate primary human macrophages; no in vivo validation; no primary cells from CD/UC patients	[145]
High-fat feeding	Activate CCK1 receptors; activate peripheral nicotinic receptors	↓ TNF-α; ↓ IL-6; ↓ intestinal permeability; ↓ plasma endotoxin; ↓ bacterial translocation to distant organs; protective effects abrogated by vagotomy, CCK-A/B receptor antagonists, and peripheral nicotinic receptor antagonist (chlorisondamine)	Hemorrhagic shock model in male Sprague-Dawley rats	No direct measurement of vagal ACh release or α7nAChR activation; not directly tested in IBD models	[146]
Polymeric diet		↑ mucosal healing (endoscopic + histologic); ↑ weight; ↓ endoscopic score (CDEIS); ↓ histologic score; ↓ ileal and colonic ulcer	Children with active, newly diagnosed CD (n = 37)	Open-label; single-center; small sample size; short-term; no long-term relapse data	[148]
Yoga		↑ quality of life (IBDQ); ↓ disease activity; no effect on social function	Adult patients with UC in clinical remission but impaired quality of life (n = 77)	Single-center; open-label; low compliance; no measurement of ANS function; self-reported outcomes may be affected by lack of blinding	[150]
Routine physical exercises targeted to the abdomen		↑ clinical remission rates in CD; ↓ disease activity; stabilization of fecal calprotectin; ↑ quality of life	Patients with mild-to-moderate IBD (15 CD, 11 UC)	Small sample size; short duration (4 weeks); single-center; no endoscopic assessment	[15]
Electroacupuncture at ST36	Vagus-adrenal axis; S100β/RAGE/MyD88/NF-κb signaling	↓ visceral hypersensitivity; ↓ disease activity (DAI scores); ↑ colon length; ↓ histologic score; ↓ TNF-α, IL-6, IL-1β; ↓ mast cell counts and tryptase expression; ↓ enteric glial cells activation; ↑ serum NE levels	Male Sprague-Dawley rats with DSS-induced colitis in remission stage	No receptor blocker validation; potential interference from skin mechanoreceptors	[152]
Electroacupuncture at ST37	Activate α7nAChR	↓ weight loss; ↓ DAI scores; ↑ colon length; ↓ histologic score; ↓ TNF-α, IL-6, CXCL1, IL-1β, IL-5; ↑ activation of chat+ neurons in dorsal motor nucleus of the vagus; ↑ vagal efferent fiber discharge frequency; ↑ α7nAChR content in proximal colon. Effects blocked by α7nAChR antagonist methyllycaconitine citrate	Male C57BL/6J mice with DSS-induced colitis	No exclusion of vagal-adrenal anti-inflammatory pathway; precise identity of α7nAChR+ immune cells unclear	[153]
Right cervical vagus nerve stimulation	VN	Prophylactic: ↑ epithelial proliferation; ↓ apoptosis. Therapeutic: ↓ infiltration of eosinophils, neutrophils, monocytes, immature macrophages, and mature CD169- macrophages; ↓ pro-inflammatory cytokine (TNF-α, CXCL1); ↓ splenic CD11b+	Wild-type female C57BL/6J mice with DSS-induced colitis	Transient body weight loss after prophylactic VNS masks true benefit; exact molecular mechanisms of anti-inflammatory effect remain unclear; DSS model is T cell-independent, limiting assessment of adaptive immunity	[154]
Right cervical vagus nerve stimulation	Sumoylation	Restores vagal tone (↓ low-frequency/high-frequency); improves DAI, body weight, intestinal bleeding, survival; preserves colon length/histological integrity and ↓ intestinal permeability; ↓ colon IL-6 and TNF-α; ↑ IL-10; inhibits sumoylation (↓ SUMO1, ↓ SUMO2/3)	Male C57BL/6 mice with DSS-induced colitis	Use of global SUMO KO models limits cell-specific mechanism delineation	[155]
Left cervical vagus nerve stimulation	VN	↓ CDAI (clinical remission); ↓ CDEIS (endoscopic remission); ↓ CRP and fecal calprotectin; restores vagal tone (HFNU) and sympatho-vagal balance (low-frequency/high-frequency); ↓ perceived digestive pain (VAS); improves anxiety and depression (HAD); ↓ plasma and gut pro-inflammatory cytokines; ↑ anti-inflammatory transforming growth factor-β1	Mild-to-moderately active CD patients (n = 7); moderately active CD patients (n = 9)	Small sample size; open-label pilot study without control group; cannot exclude placebo effect	[156,157]
Left cervical vagus nerve stimulation	VN	↓ CDAI (clinical remission); ↓ fecal calprotectin; ↓ serum TNF and IFN-γ; tendency of ↓ SES-CD; ↓ ileal histopathology (Geboes score); improved quality of life (IBDQ, SHS)	Biologic-refractory patients with moderately to severely active CD (n = 16)	Small sample size; open-label design without control group; cannot exclude placebo effect	[158]
Subdiaphragmatic abdominal vagus nerve stimulation	VN	Improved stool quality; no blood in feces. ↓ histological damage (mucosal architecture, leukocyte infiltration); ↓ plasma CRP; ↓ infiltration of eosinophils, neutrophils (MPO+), and CD3+ T cells in mucosal, submucosal, and muscle layers	TNBS-induced intestinal inflammation in Sprague-Dawley rats	Small sample size; exact anti-inflammatory molecular mechanisms not elucidated	[159]
Sacral nerve stimulation	VN	↓ DAI; ↑ colon length; ↓ histological damage and MPO activity; increases vagal activity (↑ HF, ↑ plasma pancreatic polypeptide) and decreases sympathetic activity (↓ plasma norepinephrine); ↓ serum IL-2, IL-5, IL-12p70, IL-13, EGF; ↓ tissue IL-1α, IL-6, IL-17A, TNF-α; ↑ serum IL-4; ↑ tissue IL-10	TNBS-induced colitis in Sprague-Dawley rats	Exact anti-inflammatory molecular mechanisms not fully elucidated	[160]
Sacral nerve stimulation targeting the S3 and S4 sacral foramina	VN	↑ clinical response rate; ↓ Mayo score; ↓ plasma CRP; ↓ serum TNF-α; restores autonomic activity (HRV: Vagal/sympathetic balance); changes absolute abundance of fecal microbiota (↑ Bacteroidetes-related species, ↓ Firmicutes/Proteobacteria/Actinobacteria)	Patients with mild and moderate UC (n = 26)	Small sample size; short duration (2 weeks); single-center study; clinicians not blinded; baseline imbalance in Mayo score and microbiota abundance	[161]
Transcutaneous vagus nerve stimulation	VN; IL-6/JAK2/STAT3 signaling	↓ DAI and ameliorates histopathological damage (reduced inflammatory infiltration, restored crypt architecture and goblet cells); ↓ IL-6, p-JAK2, p-STAT3; ↑ occludin, ↑ ZO-1; suppresses systemic inflammatory cytokines (↓ IL-2, IL-4, IL-5, IL-6, IL-12p70, IL-17A, macrophage-colony stimulating factor, IFN-γ, TNF-α)	DSS-induced acute UC in male Sprague-Dawley rats	Mechanistic focus limited to IL-6/JAK2/STAT3 without exploring α7nAChR-mediated cholinergic anti-inflammatory pathway or other signaling cascades	[162]
Transcutaneous vagus nerve stimulation	VN	In DSS colitis: ↓ DAI, macroscopic and histological scores; ↓ weight loss, colon bleeding, fecal consistency loss; ↑ colon length; ↓ colonic pro-inflammatory markers (IL-1β, TNF-α, Mip1β, metalloproteinases 9, Nos2); ↓ (Bax, Bak1, Casp8); in DNBS colitis: Only partially mitigates weight loss and DAI; no significant effects on macroscopic/histological scores, colonic pro-inflammatory markers, or apoptotic markers	DSS- and DNBS-induced acute colitis in male C57BL/6 mice	Possible non-vagal innervation of auricular stimulation site; lack of mechanistic validation	[163]
Transcutaneous vagus nerve stimulation	VN	↑ clinical remission; ↓ fecal calprotectin; improves anxiety scores (PROMIS); modulates HRV (recalibration of vagal tone based on baseline HFNU)	Pediatric and young adult patients with mild to moderate CD or UC (n = 22; 10 CD, 12 UC)	Small sample size; single-center; not double-blind; no endoscopic disease assessments; heterogeneity in baseline disease activity; HRV analysis not standardized	[164]

AR: Adrenergic receptor; TLR4: Toll-like receptor 4; NF-κB: Nuclear factor-κB; GSK-3β: Glycogen synthase kinase-3β; CREB: CAMP-response-element-binding protein; JAK: Janus kinase; STAT: Signal transducer and activator of transcription; Akt: Protein kinase B; Bcl-2: B-cell lymphoma-2; α7nAChR: Α7 nicotinic acetylcholine receptor; ACh: Acetylcholine; CCK1: Cholecystokinin-1 receptor; VN: Vagus nerve; IL: Interleukin; FITC-D: Fluorescein isothiocyanate-dextran; ZO-1: Zonula occludens-1; TNF-α: Tumor necrosis factor-α; MPO: Myeloperoxidase; CCL3: C-C motif chemokine ligand 3; CXCL2: C-X-C motif chemokine ligand 2; G-CSF: Granulocyte-colony-stimulating factor; TIMP-1: Tissue inhibitor of metalloproteinase-1; CRD: Colorectal distension; PS1: Presenilin-1; BACE-1: Beta-site amyloid precursor protein-cleaving enzyme-1; Aβ: Amyloid-beta; PPAR-γ: Peroxisome proliferator-activated receptor-γ; SMAD-7: SMAD family member 7; MTC: Masson’s trichrome staining; ICC: Interstitial cells of Cajal; IFN-γ: Interferon-γ; MCP-1: Monocyte chemoattractant protein-1; SOCS3: Suppressor of cytokine signaling 3; GI: Gastrointestinal; iNOS: Inducible nitric oxide synthase; IBDQ: Inflammatory Bowel Disease Questionnaire; CD: Crohn’s disease; NE: Norepinephrine; CDAI: Crohn’s Disease Activity Index; CDEIS: Crohn’s Disease Endoscopic Index of Severity; CRP: C-reactive protein; HFNU: High-frequency normalized units; VAS: Visual analogue scale; HAD: Hospital Anxiety and Depression scale; SES-CD: Simple Endoscopic Score for Crohn’s Disease; SHS: Short Health Scale; HF: High-frequency power; EGF: Epidermal growth factor; HRV: Heart rate variability; Mip1β: Macrophage inflammatory protein-1β; Nos2: Nitric oxide synthase 2; PROMIS: Patient-Reported Outcomes Measurement Information System; UC: Ulcerative colitis; MTB: Mycobacterium tuberculosis; IBD: Inflammatory bowel disease; ANS: Autonomic nervous system; VNS: Vagus nerve stimulation.

Controversies and unresolved issues

Dual roles of sympathetic signaling in IBD: Sympathetic activation has traditionally been viewed as a driver of intestinal inflammation. Current evidence, however, indicates that sympathetic signaling is context dependent and can be either proinflammatory or immunoregulatory. Its effects vary with disease stage, inflammatory setting, AR subtype, target cell, and experimental model.

Excessive or sustained sympathetic activation, particularly under chronic psychological stress, has been associated with intestinal inflammation. Increased NE release activates adrenergic signaling in intestinal vascular, epithelial, and immune cells, leading to impaired mucosal perfusion, disruption of epithelial barrier integrity, MC activation, and microbial dysbiosis[76-79]. Catecholamine-dependent signaling can also activate immune cells and increase TNF-α, IL-1β, and IL-6 production, thereby amplifying intestinal inflammation[16]. These findings support a pathogenic role for chronic sympathetic overactivity in IBD. Other studies indicate that intact sympathetic innervation can restrain inflammation and maintain intestinal immune homeostasis. Straub et al[75] reported that sympathectomy reduced inflammation in acute DSS-induced colitis but worsened disease in IL10-/- mice and in chronic DSS colitis. Similarly, Willemze et al[74] showed that β2-AR activation suppressed LPS-induced cytokine production in macrophages, whereas the loss of NE after sympathectomy aggravated mucosal injury. These findings challenge the conventional view that sympathetic activity is uniformly proinflammatory.

Pharmacologic studies further illustrate this complexity because α- and β-adrenergic modulation has produced opposing outcomes. The α2-AR agonist clonidine improves autonomic balance and reduces disease activity in active UC by limiting sympathetic overactivity[127]. In contrast, α2A-AR activation can promote intestinal inflammation. Pharmacologic blockade or genetic deletion of α2A-AR attenuates DSS-induced colitis and reduces inflammatory chemokine expression[126]. Similarly, β-adrenergic signaling exhibits dual effects. The β2-AR agonist (R)-salbutamol suppresses NF-κB activation and increases nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling. Conversely, β1/β2-AR blockade with propranolol attenuates stress-induced colitis by inhibiting STAT3 activation, neutrophil recruitment, and inflammatory cytokine production[131,135].

Several mechanisms may explain these discrepancies. First, AR signaling is highly cell- and subtype-specific. Distinct ARs are expressed by immune, epithelial, vascular, and neural cells and engage different downstream pathways. Presynaptic α2-AR activation, for example, inhibits NE release through an autoregulatory feedback mechanism and reduces sympathetic neurotransmission, whereas α2A-AR signaling in immune cells may exert context-dependent effects, including the promotion of inflammatory responses under certain conditions. β2-AR activation can suppress macrophage inflammatory responses, yet excessive or sustained β-adrenergic stimulation during stress may damage epithelial integrity and activate immune pathways. Second, the function of sympathetic signaling may change over the course of inflammation. Early activation can promote immune-cell recruitment and mediator production. Persistent inflammation may subsequently induce sympathetic remodeling and dysfunction, thereby impairing neuroimmune regulation and resolution. Third, the models used to study adrenergic signaling represent different pathological processes. Acute chemically induced colitis, chronic immune-mediated colitis, and stress-associated inflammation may respond differently to the same intervention. NE concentration, receptor abundance, and the local immune environment may further determine whether sympathetic signaling is protective or harmful. Despite increasing evidence, the precise conditions determining beneficial vs detrimental sympathetic responses in human IBD remain unclear. Future studies should focus on identifying disease-specific adrenergic signatures, defining the contribution of individual AR subtypes in specific cell populations, and developing targeted interventions that restore appropriate sympathetic regulation rather than globally suppressing or enhancing SNS activity.

Controversies in the pathways underlying vagal immunomodulation: Although the anti-inflammatory role of the VN has been extensively demonstrated, the precise mechanisms by which vagal signaling regulates intestinal immunity remain controversial. The CAIP model proposes that vagal efferent activity increases cholinergic signaling and activates α7nAChR on immune cells, particularly macrophages. This response inhibits NF-κB activation and reduces proinflammatory cytokine production[83]. Direct synaptic connections between vagal efferents and intestinal macrophages have not been demonstrated, however. It remains unclear whether vagally released ACh reaches α7nAChR-expressing immune cells directly or acts through intermediate neural circuits.

One alternative explanation proposes that vagal fibers signal through enteric neurons in the myenteric plexus. ACh released by cholinergic interneurons could then regulate local immune homeostasis, as suggested by studies of postoperative ileus in mice[89]. In addition, the VN has been proposed to regulate inflammation through a spleen-dependent pathway, in which vagal signals promote NE release from splenic sympathetic nerves and subsequent ACh production by cholinergic T cells, leading to α7nAChR activation on splenic macrophages and suppression of TNF-α production[91,92]. This pathway remains controversial because direct anatomical and functional links between the VN and splenic sympathetic nerves are incompletely defined. Simon et al[94] further showed that splenic nerve-derived NE can act directly on β2-AR-expressing splenic myeloid cells without T-cell-derived cholinergic signaling. Thus, vagal signaling clearly restrains inflammation, but the relevant neural circuits have not been resolved. Advanced neural tracing and cell-specific perturbation will be required to distinguish direct cholinergic regulation from indirect pathways involving the spleen or ENS.

Disease-specific differences in ANS regulation between UC and CD: Responses to ANS-targeted therapy differ between UC and CD. Nicotine provides a clear example. It reduces inflammation in experimental colitis and improves clinical, endoscopic, and histologic outcomes in UC[141-143]. By contrast, smoking increases the risk of CD relapse and ileal involvement and is associated with worse clinical outcomes[144]. Other autonomic interventions show similar disease-specific patterns. taVNS reduces inflammatory activity and fecal calprotectin in UC, but its effects in CD are limited[164]. In experimental models, VNS shows stronger protective effects in DSS-induced mucosal inflammation than in DNBS-induced transmural colitis, suggesting that the efficacy of vagal modulation may depend on inflammatory characteristics and disease context[162,163]. Abdominally targeted exercise also increases clinical remission in CD but not in UC[15]. The same ANS-directed intervention may therefore have distinct or even opposing effects across IBD subtypes.

Several mechanisms may underlie these disease-specific responses. First, UC and CD differ in their predominant pathological features and immune landscapes. UC is primarily characterized by superficial mucosal inflammation, epithelial barrier disruption, and prominent infiltration of innate immune cells, including neutrophils, whereas CD is associated with transmural inflammation, granulomatous responses, macrophage activation, and fibrosis. Therefore, vagal or cholinergic stimulation may exert different therapeutic effects depending on disease phenotype, inflammatory context, and the dominant pathogenic pathways involved. Second, the immune and microbial environments may alter the consequences of autonomic signaling. Nicotine activates α7nAChR-dependent pathways and suppresses inflammation in UC. In a CD-associated MAP infection model, however, nicotine promotes M1 macrophage polarization, bacterial persistence, and inflammation[145]. Third, variations in anatomical involvement and neuroimmune interactions may influence therapeutic responses. UC is largely confined to the colonic mucosa, whereas CD affects multiple intestinal segments and deeper tissue layers, which may result in different accessibility and responsiveness of neural circuits, immune cells, and enteric nervous pathways to ANS modulation. Integrated neuroanatomical mapping, immune profiling, and microbiome analysis will be needed to identify subtype-specific autonomic signatures and match ANS-directed therapies to the appropriate IBD phenotype.

Limitations and future research directions

Evidence linking the ANS to IBD pathogenesis remains subject to several limitations. Many studies report associations among autonomic dysfunction, psychological stress, and intestinal inflammation, but do not establish the molecular pathways that connect sympathetic or parasympathetic activity to immune regulation. In particular, the distinct effects of chronic stress-induced sympathetic activation and vagal withdrawal on cytokine production, immune-cell trafficking, and epithelial barrier integrity require clarification. Most mechanistic evidence also comes from animal models, which do not fully reproduce the neuroimmune complexity of human IBD. Human translational studies that combine neurophysiological measurements, immune profiling, stress-related disease activity, and longitudinal clinical outcomes remain scarce. This evidence gap limits the clinical interpretation of experimental findings.

Future research should define how sympathetic and vagal pathways regulate immune-cell function, inflammatory mediators, and disease progression in stress-associated IBD. VNS requires further technical refinement before routine clinical use. Priorities include standardizing stimulation parameters, determining the optimal anatomical target and treatment duration, and evaluating combinations with established therapies such as biologics. A multimodal strategy that integrates neuromodulation with precision pharmacotherapy may improve the management of chronic intestinal inflammation and other immune-mediated diseases[165].

CONCLUSION

Psychological stress contributes to IBD progression, and the ANS links central neural activity to intestinal immune responses. Imbalance between sympathetic and parasympathetic signaling can aggravate disease, whereas restoration of autonomic regulation may have therapeutic value. Preclinical and early clinical studies support several ANS-directed interventions, but the evidence is not yet sufficient for broad clinical adoption. Future studies should focus on elucidating precise regulatory mechanisms, optimizing neuromodulation approaches, and developing personalized strategies for precise management of IBD.