Authors: Wenhui Tang (1Physiology and Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China.), Jiarui Wang (1Physiology and Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China.), Wenlei Wang (2Department of gastroenterology, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, Shandong, China.), Jiamiao Xue (1Physiology and Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China.), Yuyan Wang (1Physiology and Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China.), Fuhao Jiang (1Physiology and Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China.), Dimkpa Christabel Kechiyerunda (1Physiology and Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China.), Shengli Gao (3Special Medicine Department, School of Basic Medicine, Qingdao University, Qingdao 266071, China.), Tao Yuan (4Department of cardiology, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, Shandong, China.), Feifei Guo (1Physiology and Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China.)
Categories: Review, visceral hypersensitivity, dorsal root ganglion, nociceptor, gut microbiota
Source: International Journal of Medical Sciences
Doi: 10.7150/ijms.126361
Authors: Wenhui Tang, Jiarui Wang, Wenlei Wang, Jiamiao Xue, Yuyan Wang, Fuhao Jiang, Dimkpa Christabel Kechiyerunda, Shengli Gao, Tao Yuan, Feifei Guo
Visceral hypersensitivity (VH) is a condition where the internal organs have an enhanced sensitization to normal physiological stimuli or mild pathological stimuli, leading to chronic visceral pain or other discomforts, which is a typical characteristic of some intestinal disorders, such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). VH might be caused by gene, psychological disorders, social stress factors, gut microbiota, and some other factors, but the exact mechanisms are not yet clear. This review focuses on recent developments in the effect of intestinal cells on sensitization of nociceptors, high excitability of brain nuclei regulating visceral pain, and the novel roles of gut microbiota in VH. It is hoped to synthesize research advancements to demonstrate the possible peripheral and intracerebral processes of hypersensitization. Additionally, more animal experiments and clinical studies are still needed to improve our understanding about VH to reduce the suffering of patients with IBS and IBD.
Visceral hypersensitivity (VH) denotes a heightened responsiveness and sensitivity of internal organs to different mechanical, chemical, and thermal stimuli, and often leads to typical symptoms including abdominal pain, bloating, altered bowel habits, and general discomfort in the abdominal region 1. Until now, this type of abdominal pain is difficult to manage, posing a challenge for patients and clinicians. The symptoms of VH can negatively impact daily activities, work performance, emotional well-being, and overall life satisfaction. VH is now recognized as a major pathophysiological mechanism contributing to abdominal pain in patients with functional or inflammatory bowel diseases, such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) 2. As known, IBD, including ulcerative colitis (UC) and Crohn's disease (CD), is characterized by marked mucosal inflammation, whereas IBS mainly demonstrates altered gastrointestinal environment, persistent low-grade inflammation, abnormal neuro-immune interactions, and dysbiosis 3, 4. Although IBS and IBD are two different diseases, IBD patients usually manifest IBS-like symptoms during remission, which is termed “irritable inflammatory bowel syndrome” for persistent hypersensitivity 5. Moreover, studies exhibited many overlapping influencing factors of IBS-like symptoms in IBS and IBD, such as sensitized sensory nervous system, enhanced immune responses, and impaired intestinal barrier 2.
It is known that VH might be caused by the sensitization of the afferent neural pathways located at different levels. Visceral nociceptors are mostly present at the nerve terminals of dorsal root ganglia (DRG) neurons, and can be directly activated by a wide variety of stimuli 6. For example, the transient receptor potential (TRP) can sense thermal, chemical, and mechanical stimuli. The voltage-gated sodium channels (Nav1.7, Nav1.8, and Nav1.9), Piezo1, Piezo2 can sense mechanical stimuli 7, 8. The purinergic receptors (P2X and P2Y), toll-like receptor 4 (TLR4), protease-activated receptor 2 (PAR2) and 5- hydroxytryptamine (5-HT) receptor can sense chemical stimuli 8, 9. The activated nociceptors potentiated action potential firing of DRG neurons, which project axons to the dorsal horn of the spinal cord. Then, the major nociceptive signals are sent to the contralateral ventral posterolateral nucleus of the thalamus via the spinothalamic tract. Neurons in thalamus relay the sensory information (pain) to the primary somatosensory cortex, posterior parietal cortex, and the limbic system for perceiving the pain signaling, processing emotional response, and making responding decisions 10. Based on the pathway for the transmission of visceral pain signals, VH arises primarily in the following 1) sensitization of sensory neurons (predominantly involving changes in nociceptor function), 2) alterations in the excitability of spinal afferent pathways (with a focus on spinal dorsal horn neurons), and 3) sensitization of central pain-processing neurons. The exact causes of neural sensitization are not fully clear, but a complex interplay of intestinal cell function, gut microbiota, genetics, psychological factors, and environmental triggers might be involved.
Current narrative reviews on VH mainly focus on IBS. These reviews discuss advances in physiological mechanisms, covering potential drug targets like TRPV1, ASICs, voltage-gated sodium channels, ATP, PAR-2, cannabinoid, prostaglandin, tachykinin, and 5HT3 receptors 11. Research also shows that increased excitatory synaptic plasticity and changes in brain neural circuits contribute to VH 12, 13. Furthermore, the dynamic "microbiome shifts," characterized by the enrichment or depletion of specific bacterial taxa in IBS, and their significant impact on disease progression and pathology are explained 14. Recently, some articles have examined IBS-type symptoms in IBD, including low-grade residual inflammation, altered intestinal permeability, and VH, among others 15. The causes of VH in IBD are briefly outlined, such as highly sensitive or overexpressed TRPs, low-grade inflammation, alterations in the brain-gut axis, and post-inflammatory microbiota and metabolites 16-18. Thus, previous reviews primarily address pathophysiological mechanisms of VH, like abnormal nociceptors, dysbiosis, and enhanced sensory centers. However, few articles simultaneously discuss both IBS and IBD.
Based on the studies of VH in IBS and IBD, it is found that the peripheral nociceptors and central sensory neurons were strongly affected by molecules or transmitters from surrounding or functionally related cells, even the gut microbiota. For better understanding VH, this review presents the mechanism from three tightly interlinked (1) the active roles of intestinal cells (e.g., epithelial, enteroendocrine, immune cells) as translators of luminal stimuli into signals that prime peripheral nociceptor sensitization; (2) the specific circuits underlying the heightened excitability of defined brain nuclei, particularly those within the limbic and hypothalamic areas, which are responsible for maintaining the visceral pain state; and (3) the effects of gut microbiota dynamically influencing both peripheral intestinal afferent nerve and central sensory signals processing via the "microbiota-gut-brain" axis. This review integrates these components into a continuous narrative, tracing the pathogenic process from initial peripheral signal transduction in the gut to advanced central pain processing. We aim to provide a refined and coherent framework for understanding VH. Such an integrated perspective not only advances our mechanistic insight into the pathology of disorders like IBS and IBD but also illuminates novel potential targets for future therapeutic strategies.
This narrative review designed to synthesize and critically evaluate current knowledge on the mechanisms of VH. To ensure methodological transparency and quality, the review was conducted and reported following the recommendations of the Scale for the Assessment of Narrative Review Articles (SANRA) 19.
A structured, broad literature search was performed to identify relevant studies. The search strategy was informed by key concepts related to our review's aim, loosely guided by a PICO
Population/Problem: Patients with VH disorders (e.g., IBS, IBD with persistent pain) and relevant animal models.
Intervention/Exposure/Mechanism: Various biological mechanisms involve the interactions of intestinal epithelial cells, immune cells, the enteric and central nervous systems, and the gut microbiota.
Context: Pathophysiology and mechanistic research.
Electronic searches were conducted in the following PubMed and Web of Science Core Collection. The search covered publications from inception until January, 2026. A combination of Medical Subject Headings (MeSH) terms and keywords was used, including but not limited “visceral hypersensitivity”, “visceral pain”, “irritable bowel syndrome”, “functional bowel disease”, “inflammatory bowel disease”, “intestinal barrier”, “enteroendocrine cell”, “mast cell”, “microbiota-gut-brain axis”, “TRPV1”, “central sensitization”, “stress”, “CRF”. Search strings were adapted for each database. The reference lists of key articles and recent reviews were also manually scanned to identify additional pertinent studies.
Studies were considered for inclusion based on the following
Included: Original research articles (clinical, translational, and basic science), high-impact review articles, and meta-analyses published in peer-reviewed journals. We prioritized studies that elucidated mechanistic pathways in visceral pain perception, including human studies, rodent models, and seminal in vitro findings that inform biological plausibility. The focus was on literature published within the last two decades, with particular emphasis on high-impact findings and consensus views established in the field.
Excluded: Editorials, letters, conference abstracts without full data, studies exclusively focused on somatic pain pathways without visceral relevance, and articles not available in English.
The initial pool of records retrieved from database searches was deduplicated. The lead author screened titles and abstracts against the eligibility criteria to identify potentially relevant papers. Full-text versions of these articles were then obtained and assessed for final inclusion. Given the narrative and integrative nature of this review aimed at constructing a coherent model, the selection of representative literature was based on scientific rigor, novelty, and contribution to the overarching narrative of the gut-brain axis in VH. Conflicting results are recognized and explored in the text. The data from the included studies were thematically extracted and narratively combined to form the conceptual model in this review.
As part of our commitment to SANRA's emphasis on explaining the level of evidence, we implemented supplementary evidence grading framework. Key mechanistic statements in the text are tagged by primary evidence source (Human Clinical Study, Animal Model, Ex Vivo/In Vitro). Moreover, Table 1 provides a summary of the confidence and consistency of evidence for key pathways. This method improves the critical evaluation of the compiled literature.
VH mainly arises from the abnormal activation of intestinal nociceptors. Some researches indicated that intestinal cells, such as intestinal epithelial cells (IECs), intestinal immune cells, and enteric glial cells (EGCs), directly sensitized nociceptors via different functional mediators.
The major cell types of the intestinal epithelium are enterocytes, enteroendocrine cells (EECs), Paneth cells, tuft cells, and goblet cells. In recent years, extensive researches have elucidated the role of the IECs on the DRG neurons in modulating visceral pain.
Enterocytes, as the main cell type in the intestine, play a key role in absorbing nutrients and secreting functional molecules like ATP, Glutamate (Glu), brain-derived neurotrophic factor (BDNF), IL-33, trypsin-3, and corticotropin-releasing factor (CRF).
ATP serves not only as the direct source of energy at the cellular level, but also as a signaling molecule to modulate the visceral sensation. After activated by heat, low osmolarity, mechanical stress, metabolites of arachidonic acid, and proinflammatory mediators via the TRPV4, enterocytes generate more ATP 112. Subsequently, excess ATP binds to P2X and/or P2Y purinoceptors to activate the nociceptors. For example, the P2X3 receptor subtype mediates the onset of pain sensitization by sensitizing TRPV1 expressed on DRG neurons or upregulation of β2 adrenergic signaling in primary sensory neurons, the P2X7 receptor subtype leads to increased release of IL-1β from immunocytes to indirectly induce VH, and the activation of P2Y receptors by ATP, UTP or ADP enhance the excitability of colonic pain sensation via the NaV1.9 channel co-expressed with P2Y on DRG neurons 20-22, 113.
Except ATP, the enterocyte activated by TRPV4 releases the excitatory neurotransmitter Glu. On the one hand, Glu directly excites the DRG neurons to participate in visceral pain 12, 25, on the other hand, Glu indirectly contributes to the visceral hypersensitive response through promoting the release of substance P (SP) and calcitonin gene-related peptide (CGRP) from DRG neurons and BDNF from enterocytes 12, 26-28, 114.
Furthermore, the enterocytes were found to secret more proteases and CRF in IBS patients and rodent IBS models. The proteases, predominantly trypsin-3, activate PAR2 of the enteric sensory neurons to induce VH 115. CRF indirectly contributes to VH by binding to CRF receptor 1 (CRFR1) on immune cells to promote inflammation via TLR4 and IL-1 pathways 116, 117. In both IBD patients and mouse models, the enterocytes secrete abundant IL-33, which subsequently acts on tumorigenicity 2 receptor (ST2) of mast cells. Activated mast cells disrupt the intestinal barrier and promote inflammatory responses, further contributing to the development of VH 41.
Another important cell type of the intestine is EECs. Among various EECs, enterochromaffin cells (ECs), neuropod cells and L cells are believed to play more important role in VH.
ECs are responsible for secreting approximately 95% of 5-HT in the body, which significantly influence intestinal movement and secretion 118. There are ongoing debates regarding the number of ECs in the patients with VH. Most research reported that patients with IBS showed a significant increase in ECs counts, and there was a significantly greater ECs number in patients with diarrhea-predominant IBS compared with patients with constipation-predominant IBS 32. A handful of studies reported that all IBS subtypes demonstrated a reduction in ECs 119, and there is still a small portion of research indicated that the quantity of ECs remains unchanged in IBS patients 36. Therefore, it is suggested that VH primarily attributed to alterations in ECs signaling rather than cell amount.
Studies suggested that individuals with IBS have notably elevated levels of 5-HT and 5-HT3R in the intestinal mucosal tissues compared to healthy people, and this abnormal overexpression was closely linked to the development of VH 34. Although the processes that elevate 5-HT release are still not completely defined, changes in intestinal pressure could play a role. Notably, mechanically gated ion channels of the Piezo family are expressed in intestinal epithelial cells 37, 38. Piezo1 and Piezo2 activate p38 signaling pathways, leading to increased expression of tryptophan hydroxylase 1 (TPH1), a key synthase for 5-HT in ECs, and thereby affecting 5-HT production 120. James et al. has proved that ECs establish synapses with intestinal mucosal afferent neurons to transmit visceral pain signals via the neurotransmitter 5-HT, which means more 5-HT releasing, higher visceral sensitivity 33. Besides, 5-HT might participate in VH by sensitizing TRPV1 and TRPV4 channels on DRG neurons 121, 122. All of the above suggests the pathway involving ECs, 5-HT, and mucosal afferent nerves (DRG) might play an important role in VH.
Neuropod cells, as a specialized subtype of EECs with highly expressed Guanylyl Cyclase C (GUCY2C), modulates the DRG-neuron excitability via synapses 39. Clinical studies indicated that patients with IBS exhibit reduced levels of endogenous GUCY2C ligands, such as urinary guanosine 123. It is consistent with the animal experiment, which showed that blocking GUCY2C signaling leads to VH, and, conversely, activation of GUCY2C signaling alleviates visceral pain in colitis model mice 40. Although the detailed mechanism is still not clear, the basic process of GUCY2C signaling pathway has been explored. Ligand-activating GUCY2C converts guanosine triphosphate into cyclic guanosine monophosphate (cGMP), then cGMP acts as a second messenger to phosphate protein kinases, which leads to inhibit visceral pain transmission either by suppressing the release of excitatory neurotransmitters or by promoting the release of inhibitory factors 124.
Another EECs L cells, were detected to secrete ATP, Glu, glucagon-like peptide 1, PYY and so on 24. ATP and Glu, like those released from enterocytes, can respectively act on P2X/P2Y receptors and glutamate receptors (N-methyl-D-aspartate receptors (NMDAR) and α-amino-5-hydroxy-3-methyl-4-isoxazolepropionic acid receptors (AMPAR)) located on neuronal endings, contributing to the onset of VH 125.
Table 2 summarizes intestinal epithelial cell-derived substances participate in VH by sensitizing nociceptors.
It is proved that VH of IBS and IBD patients is closely related to the activation of intestinal immune system, including enhanced infiltration of immunocytes, the low-grade inflammation, and so on. IBD is often characterized by infiltration of neutrophils, macrophages, innate lymphoid cells, mast cells, as well as Th1 (CD) and Th17 cells. Among these, neutrophils, macrophages, and mast cells play critical roles in the development of VH 127, 128. In contrast, mast cell and their close proximity to colonic nerves are more prominent in IBS, which is particularly evident in Diarrhea-predominant IBS-D and Post-infectious IBS (PI-IBS) 129. These immune cells contribute to VH primarily through two by releasing immune mediators that directly interact with nociceptive afferent neurons, and by altering intestinal permeability, thereby promoting VH 130, 131.
Studies have found that the number of mast cells (MCs) is increased in the intestines of both IBD and IBS patients, which may be closely related to the occurrence of VH 132, 133. MCs, as major effector cells of innate immunity and regulators of adaptive immunity, secrete a wide array of inflammatory cytokines including IL-1β, IL-4, IL-5, IL-6, TNF-α and IFN-γ, as well as diverse inflammatory mediators such as histamine, tryptase and prostaglandin E2 (PGE2) 134.
The inflammatory cytokines not only act directly on the afferent nerve endings of DRG neurons to sensitize nociceptor ion channels, but also disrupt the intestinal barrier to facilitate the translocation of harmful substances across the barrier and exacerbate intestinal inflammation, which has been widely recognized as an important inducer of VH 135.
Many studies have showed that histamine released from MCs could induce VH via histamine receptor 1 (H1HR). D. Balemans et al. further explored that incubation of IBS colon biopsy supernatants or histamine-supplemented supernatants of healthy subjects with isolated mouse DRG neurons overnight enhanced neuronal Ca^2+^ responses by sensitizing TRPV1, TRPA1, and TRPV4 ion channels on DRG neurons, reducing the threshold for painful stimuli and inducing VH 58, 136. Additionally, the role of TRPV4 in histamine induced neuronal sensitization is more highlighted, because a MAPKK-dependent increase of TRPV4 expression on plasma membranes of colonic sensory neuron was closely related to H1HR relocation 58, 121.
Tryptases secreted from MCs can bind to the PAR2 on the afferent nerve endings of DRG neurons, potentially sensitizing TRPV1 of DRG neurons in a protein kinase C (PKC)-dependent manner to increase neuronal excitability 50. Likewise, the PAR2 of IECs is also recognized by tryptases, which triggers the release of intestinal inflammatory mediators 137. Furthermore, tryptases are found to cleave tight junction proteins, such as junctional adhesion molecule-A (JAM-A), claudin-1, claudin-3 and claudin-5, leading to intestinal barrier dysfunction 138, 139. All of these effects of tryptases contribute to VH.
PGE2 is another important inflammatory mediator released from MCs. In patients with IBS-D, lipopolysaccharide acting in concert with trypsin was found to stimulate mucosal mast cells to release PGE2 54. PGE2 binds to E-type prostanoid receptor 2 located on the afferent nerve endings of nociceptive DRG neurons, activating TRPV1 and various sodium channels 53. Moreover, a mouse model study has demonstrated that in patients with IBS-D, substances such as lipopolysaccharide and trypsin can stimulate mast cells to release PGE2, downregulate the serotonin reuptake transporter, and elevate mucosal 5-HT levels, thereby contributing to the development of VH 54.
Surprisingly, some neurotrophin and neuropeptides secreted by MCs are involved in the modulation of nociceptors. Nerve growth factor (NGF) also activates TrkA receptors on nerve endings to promote Nav1.7 currents and sensitize TRPV1 channels 140. Simultaneously, the neuropeptide CRF modulates the macrophages to release inflammatory cytokines such as IL-1 and IL-6, which would reduce the expression of the tight junction protein claudin-2 in the colonic mucosa leading to increasing intestinal permeability and inflammatory response 116, 141. Therefore, it is believed that the effects of neurotrophin and neuropeptides on neurons, macrophage and IECs would further contributes to VH.
Figure 1 demonstrates the possible mechanisms of MCs involved in VH, which might be a novel promising therapeutic target for IBS or IBD.
In IBD patients, there is an increased infiltration of neutrophils and macrophages, which were proved to secret IL-1β, IL-6, TNF-α, PGE2, prokineticin 2 (PROK2) and insulin-like growth factor I (IGF-1). IL-1β, IL-6 and TNF-α lower the thresholds of Nav channels or enhance the expression of TRPV1 channels in the DRG neurons 46, 47, 142-145. The PROK2, an inflammatory cytokine-like molecule, increases intracellular calcium levels in enteric and dorsal root ganglia neurons, which plays a role in IBD caused by trinitrobenzene sulfonic acid (TNBS) 60. IGF-1 enhances TRPV1-mediated membrane currents in DRG neurons and promotes TRPV1 translocation to the cell membrane 146. In addition, patients with IBD and corresponding animal models exhibit elevated expression of transient receptor potential melastatin (TRPM) channels 2, 3, and 8. These channels play a key role in sensitizing DRG neurons and driving VH 147. However, how immune cells influence TRPM expression in IBD remains unclear.
From these contents, VH is greatly influenced by immunocytes, especially in IBD. The effectors secreted from immunocytes mainly increase intestinal permeability, expression of nociceptors, concentration of 5-HT, and so on. For better understand the potential contribution of immunocytes on VH, Table 3 summarizes the main mechanism of inflammatory effectors in the IBS or IBD.
In the enteric nervous system, there are plenty of EGCs, which not only support the growth of neurons but also regulate the neural activity. As known, EGCs release NGF to support the growth, survival, and maintenance of neurons 152. However, NGF levels significantly increase during inflammation, and NGF receptor TrkA are extensively coexpressed with TRPV1 in visceral afferents. The abnormal increased NGF not only promotes nerve ending growth, but also potentiates TRPV1 signaling, which might induce visceral hyperalgesia and hypersensitivity 153. Additionally, EGCs activated by inflammatory cytokines in IBD release PGE2, which further sensitizes TRPV1 on afferent nerve endings of DRG neurons via EP4 receptor 56. It is also found that more SP is released in a PLCγ1-dependent manner from EGCs in the IBS model mice. SP, as the first discovered member of the tachykinin family, has long been considered an effector of pain, acting on nociceptive nerve endings and participating in the development of VH 27. Therefore, it indicates that EGCs directly modulate sensibility of sensory neurons via various mechanisms.
Furthermore, Vladimir et al. demonstrated that in dextran sulfate sodium induced colitis, EGCs stimulated by IL-1β release TNF-α to activate macrophages, which could act on the terminals of DRG neurons inducing visceral nociceptor sensitization 62. Additionally, ECGs were found to regulate other types of immune cells, including MCs, antigen-presenting cells, and lymphocytes, which enhanced neuroinflammation, TRPV1-positive neuronal varicosities, and Glia-immunocytes interactions in the IBS to participate in VH 61, 63.
Therefore, the complex functions of EGCs make themselves play an important role in the development of VH.
While the drivers of VH often originate in the periphery, the pain experience is ultimately mediated and amplified by the central nervous system. As known, special brain nuclei are responsible for processing information of various visceral stimulation and producing pain perceptions. There are other different nuclei and neural circuits involved in modulation of visceral pain and generation of negative emotions. Therefore, exploring the central neuromodulation mechanism of VH in patients with intestinal disorders may provide suitable targets for the treatment of the visceral pain of such diseases 154.
The anterior cingulate cortex (ACC) and the paraventricular nucleus of hypothalamus (PVN) of the hypothalamus are extensively involved in the modulation of both ascending pain transmission and descending pain inhibition. Moreover, these regions serve as critical hubs in the neural circuitry responsible for processing emotions and pain signals. This review primarily focuses on potential alterations in these nuclei—particularly the ACC and PVN—in patients with intestinal disorders, as well as their functional roles in such conditions 155.
The ACC, as a crucial area within the limbic system, is involved in the processing of sensory and emotional components of chronic pain. Functional magnetic resonance imaging studies have shown heightened ACC activation in individuals with IBS 156. Studies showed that chemical and electrical stimulation on ACC enhanced the visceral motor response to colorectal distention (CRD) and nociceptive sensitization in normal or IBS rats, while ACC impairment lessens the response 65. The IBS patients also demonstrated higher activation levels of ACC and greater intensity of pain than healthy control 157. During IBD, ACC exhibits more activation of neuron or microglia in animal model, and shows higher low-frequency fluctuation values and degree centrality values in patients, indicating abnormal brain metabolism within the ACC of IBD patients 64.
These findings collectively demonstrate that the ACC plays an essential role in processing the affective dimension, anticipation, and memory formation of pain. Meanwhile, ACC has a wide range of fiber connections with different brain nuclei (including the substantia nigra, hippocampus, and insular cortex), which are involved in the modulation of emotions and sensations linked to pain 158, 159.
The central lateral nucleus (CL), positioned between the insular cortex and the striatum with broad links to the cerebral cortex, is essential in the transmission of visceral pain. Xu's experiments utilized neonatal maternal deprivation (NMD)-induced VH mice to evaluate the functional role of nerve fiber projections from CL to ACC in visceral pain processing 66. The results demonstrated that c-Fos expression was significantly increased in the CL of NMD mice, indicating that visceral pain can activate the CL. The activation of glutamatergic neurons in the CL can lead to the activation of those in the ACC, potentially contributing to the development of persistent internal pain. For VH, overexpression of NMDAR and hyperactivation of calcium-calmodulin-dependent protein kinase II α (CaMKIIα) in the postsynaptic density region of the ACC may sensitize the CL-ACC neural circuitry in NMD mice. This was further supported by other experiments showing that an inhibitor targeting NMDAR in glutamatergic neurons of the ACC might be a new point for relieving visceral pain in IBS 67.
Medial thalamus (MT), the primary relay station for transmitting noxious information to the ACC, has been shown to modulate visceral pain via the MT-ACC pathway 68. The increase in local field potential of rats with VH indicates enhanced synaptic activity at the MT-ACC interface. θ burst stimulation could induce long-term potentiation (LTP) at MT-ACC synapses of normal rats. These findings suggest that electrically induced LTP and VH may share a common mechanism. To test this hypothesis, repeated application of θ-mode stimulation at MT in normal rats enhanced CRD-induced ACC responses and increased visceral pain. The results imply that the MT-ACC pathway might be an important regulating mechanism of visceral pain 69.
The PVN serves as a critical neuroendocrine hub, releasing several neuropeptides including CRF, arginine vasopressin, oxytocin, and thyrotropin-releasing hormone 72. Its best-characterized role lies in initiating the hypothalamic-pituitary-adrenal (HPA) CRF from the PVN stimulates pituitary adrenocorticotropic hormone secretion, which in turn promotes glucocorticoid release from the adrenal cortex 160. Zhang et al. revealed that administration of CRF-RNAi effectively prevented VH in rats 70. Mechanistic studies indicate that increased CRF elevated glucocorticoid secretion, which might lead to the overexpression of proinflammatory cytokines such as TNF-α, IL-1β, TLR4 et al. 70, 71. Prolonged excessive glucocorticoid exposure was found to cause impairment of hippocampal function, which weakened the inhibitory effect of hippocampus on the HPA axis, leading to sustained release of CRF 161. This vicious CRF- glucocorticoid circle might be an important promoter of VH. These discoveries emphasis the key role of PVN in the regulation of visceral sensory. The PVN also has widely bidirectional fiber connection with brain nuclei, such as lateral septal nucleus (LSV), ventral tegmental area (VTA), BNST, prefrontal cortex (PFC), arcuate nucleus (ARC), which are involved in different functional modulations, including sensory modulation.
The LSV is capable of modulating affective behavior and visceral pain. For example, activating the PVN-LSV glutamatergic projections intensifies visceral pain in NMD mice, reversely inhibiting the circuits relieves the visceral pain 73.
The VTA is an important center processing reward, addiction, learning, sleep-wakefulness cycles, and so on. The projections of CRF neurons to the VTA are found to be involved in colonic distension-induced pain 74. In IBS model mice, the active CRF neurons significantly increased c-Fos expression and calcium ion activity of VTA glutamatergic neurons, and selective NMDA receptor 2A inhibitor administrated in VTA decreased the number of visceral pain-induced c-Fos positive neurons and attenuated visceral pain 83. Therefore, the paraventricular nucleus of the thalamus (PVT)-VTA circuit might be another molecular target involved in chronic visceral pains.
The PFC is the anterior portion of the frontal lobe of the cerebral cortex. The PFC is not only important in executive functions such as planning, problem solving, and social control, but also pain processing, which is dependent on neural circuits with hypothalamus, hippocampus, periaqueductal gray (PAG), amygdala, and other pain-related areas of brain. Recent studies have demonstrated that PVN oxytocin signaling boosts PFC neuronal activity in response to acute pain stimulation. However, in the context of chronic visceral pain, PVN oxytocin signaling to the PFC alleviates both the emotional and sensory dimensions of pain induced by mechanical stimuli and suppresses the development of VH 75.
As a part of the extended amygdala, the BNST plays a critical role in stress response, fear memory, and social behavior. It has been reported that the anteroventral BNST (avBNST) directly projects GABAergic and glutamatergic neural fibers to the PVN. The avBNST GABAergic neurons inhibits activity of PVN CRF neuron to alleviate visceral pain. Conversely, glutamatergic inputs from the avBNST to the PVN exert an excitatory effect. In mice prone to VH, an imbalance between two types of inputs was noted, leading to heightened excitability of PVN CRF neurons and increased CRF release, which triggers the HPA axis 71, 76, 77. Therefore, stimulating glutamatergic neurons or suppressing GABAergic neurons within the avBNST-PVN neural pathway promotes VH.
The neural circuits of the ACC and PVN involved in the context of visceral pain were summarized and illustrated in Figure 2.
The ARC is a critical hypothalamus area involved in energy homeostasis and mediating pain sensation. In the ARC of chronic pancreatitis (CP) model rats, expression of cystathionine β-synthetase (CBS) and PKC were significantly upregulated, accompany with higher phosphorylation level of the NMDA receptor GluN2B subunit 78. Microinjection of the CBS inhibitor aminooxyacetic acid into the ARC of CP rats reversed the upregulation of PKC and alleviated VH. The results indicate that CP causes an increase in CBS expression in the ARC, which may play a role in VH by activating NMDA receptor.
NF-κB is another important molecule in the ARC to affect the processing of visceral pain. The selective NF-κB inhibitor pyrrolidine dithiocarbamate alleviated visceral pain in NMD rats 79. G Protein-Coupled Receptor Kinase 6 (GRK6) is a kind of endogenous protein suppressing NF-κB expression, and was found to be low expressed in the ARC of NMD rats, which is believed to be an important modulator of VH.
The rostral ventromedial medulla (RVM) is a relay station connecting some brain regions like the PAG and amygdala to the dorsal horn of the spinal cord. The RVM dynamically balances pain signals through two types of ON cells promoting the transmission of pain signals in the spinal cord and OFF cells inhibiting the transmission. ON cells specifically express G protein-coupled estrogen receptor (GPER), which is recognized by estrogen to significantly enhance ON cells activation via the Ca²⁺/PKC pathway. Once activated, these GABAergic ON neurons reduce the inhibitory tone of spinal interneurons, thereby facilitating ascending pain transmission 162. Estrogen also inhibits opioid signaling in ON cells, leading to increased pain and reducing the analgesic effects of morphine 82. In contrast, testosterone exerts sex-dependent effects in the RVM: it downregulates serotonin transporter expression while upregulating 5-HT2A receptor mRNA. These changes are associated with reduced hyperalgesia in female preclinical models, but not in males 163. Collectively, estrogen-mediated facilitation via GPER and opioid interference, together with testosterone-modulated serotonergic signaling, provide a mechanistic basis for the pronounced female predominance observed in functional visceral pain disorders.
The reuniens (Re) is a component of the ventral midline thalamus, and is associated with diverse cognitive functions, such as working memory and attentional processes. A significant increase of c-Fos-positive neurons, primarily the glutamatergic neurons, was observed following CRD stimulation in the Re of mice with NMD-induced VH, accompanied by an upregulation of 5-HT2B receptor levels in glutamatergic neurons within Re. Then, blocking 5-HT2B receptors in Re led to decreased c-Fos expression and eased visceral pain 80. The findings suggest that enhancing 5-HT2B receptor levels in glutamatergic neurons of Re might be a key factor contributing to VH.
The insula cortex integrates autonomic activity from the viscera and has been referred to as the "visceral brain." In mice with an NMD-induced IBS model or a TNBS-induced IBD model, there was an increase in c-Fos expression in the insula cortex and a boost in excitatory synaptic transmission. Compared with healthy controls, the insula cortex of IBS patients exhibited persistent activation both at rest and during CRD stimulation 155. Further studies show that glutamatergic neurons of the insula cortex are significantly increased by CRD in the neonatal colonic inflammation (NCI)-induced IBS model, and neural signals transmitted from PVT glutamatergic neurons to insula cortex glutamatergic neurons promoted colonic pain in NCI mice 81. These findings suggest that the insula cortex might be involved in the formation of visceral pain.
It has been known that the structure and function of mammal brain undergo tremendous changes with development. Based on the brain's plasticity and adaptive capacity, the timing of initial VH is a key determinant of pathogenesis and long-term outcomes. Comparing with the results of stress in adult, NMD primarily simulates severe psychosocial trauma during early life, and particularly activates stress-related regions like PFC, amygdala, hypothalamus, and hippocampus, even the HPA axis. Phenotypic features generated by NMS models permanent alterations in central stress circuits (e.g., amygdala, PFC), hyperactivity of the HPA axis with elevated baseline CRF levels, long-term gut dysfunction (permeability, microbiome alterations), more severe and treatment-resistant VH in adulthood. In contrast, adult-onset models typically induce physiological and psychological responses, and produce transient hypersensitivity that resolves more readily, highlighting distinct underlying neuroplasticity mechanisms. These studies suggest that early intervention in children with functional abdominal pain or a history of adversity may prevent the development of chronic, severe clinical symptoms in adulthood 164.
The human gastrointestinal tract is colonized by a diverse array of microorganisms, encompassing bacteria, viruses, fungi, and protozoa, with bacteria being the most predominant component. Gut microbes are involved in numerous physiological processes, including nutrition, metabolism, defense, and immunity. The microbiota serves not merely as a local factor but as the core biological interface connecting the peripheral gut and the central brain. It drives a complete sensitization loop between the periphery and the central nervous system, thereby forming a “brain-gut” sensitization system. Dysbiosis of the intestinal flora is frequently observed in patients with VH, characterized by altered abundance of specific bacterial populations and an imbalance between beneficial and opportunistic pathogenic bacteria 165.
Bifidobacterium and Lactobacillus are gram-positive bacterial genus, and common probiotics in the human gastrointestinal tract. The strictly anaerobic* Bifidobacterium* belongs to the phylum Actinobacteria, and primarily resides in the colon. Lactobacillus, a member of the family Lactobacillaceae, is either partially anaerobic or microaerophilic and predominantly colonizes the small intestine and stomach. Studies about VH have noted the involvement of the bacteria in both genus, such as Bifidobacterium longum (B. longum), Bifidobacterium infantis (BCM), and* Lactobacillus acidophilus* (LCM) 88.
B. longum is one of the major probiotics colonizing the human gastrointestinal tract. In IBS patients, the colonization of B. longum in the intestines was significantly reduced compared to that in normal subjects 166. Administration of B. longum not only reduced depression scores and alleviated stress in IBS patients, but also reversed the reduction in crypt depth and villus length, decreased intestinal permeability, and restored the proliferation of intestinal mucosal IECs 84, 85. BCM and LCM were found to normalize the protein expression of claudin-1 and occluding, thereby protecting the intestinal barrier and preventing inflammation 86, 87, 89. Furthermore, it's shown that the combination of Lactobacillus and Bifidobacterium reduced CRF secretion and HPA axis activity, contributing to recover of VH, anxiety, and depression 90. Therefore, Bifidobacterium and Lactobacillus exert the function of “probiotics” via various ways, Figure 3A shows their mechanisms for relieving VH.
Ruminococcus gnavus is Gram-positive, anaerobic bacterium that exhibits spherical or spheroidal morphologies, and is involved in digestion and immune regulation 93. It was demonstrated that Ruminococcus gnavus was enriched in IBD patients and increased with disease activity 167.
Ruminococcus gnavus was found to increased serum 5-HT levels, which was drawn by analyzing the correlation between intestinal flora composition and serum 5-HT levels in IBS-D patients 91. Increased Ruminococcus gnavus promotes the conversion of phenylalanine and tryptophan into phenethylamine and tryptamine, which in turn activate protein kinase A (PKA) and CaMKII, leading to an increase in TPH1 and aromatic L-amino acid decarboxylase (AADC), and subsequently causing 5-HT biosynthesis. Then, 5-HT contributes to VH development by acting on the afferent nerve endings of nociceptive DRG neurons (Figure 3B) 92.
Clostridium, an anaerobic Gram-positive bacterium of the Firmicutes phylum, participates in various metabolic activities, such as carbohydrate fermentation, protein breakdown, and bile acid (BA) metabolism. About the BA metabolism, experiments in pseudo-germ-free mice colonized with Clostridium revealed upregulated expression of Cyp7a1 and Cyp8b1, key enzymes in BA synthesis, thereby enhancing hepatic BA production. Concurrently, reduced ileal Fgf15 expression attenuated farnesoid X receptor (FXR)-mediated BA reabsorption, while increased taurine-conjugated BAs in the intestinal lumen inhibited FXR activation, further diminishing BA reuptake 168.
Researches indicated a positive relationship between elevated levels of fecal BA and the severity of abdominal pain in IBS patients and visceral pain model rats 94, 169, highlighting the critical role of BAs in the pathogenesis of VH. Regarding the mechanisms underlying BA-induced visceral sensitivity, two principal pathways have been proposed. One explanation is that BA activates the FXR on MCs, leading to increased release of NGF. This, in turn, enhances the expression of TRPV1 in DRG neurons, ultimately promoting VH 96. An alternative mechanism suggests that BA can trigger the release of 5-HT from EECs through activation of the Takeda G protein-coupled receptor 5 170.
Therefore, there is a strong association between Clostridium-rich microbiota, elevated BA indices, and VH, and Figure 3C shows the mechanisms in a diagram.
Adherent-Invasive Escherichia coli (AIEC) is a subtype of diarrhea-inducing E. coli isolated from the enteropathogenic E. coli group. This strain exhibits the ability to adhere to IECs and proliferate on the surface of IECs, leading to microvillous lesions. Researches showed that patients with CD have a higher occurrence of AIEC in the ileal mucosa, along with unusual expression of carcinoembryonic antigen-related cell adhesion molecules (CEACAM) 5 and CEACAM6 in the ileum 98. Individuals with IBS frequently exhibit increased levels of AIEC.
The potential mechanism of VH induced by* AIEC LF82* is complicated (Figure 3D). One reason is that the protein hydrolase Vat-AIEC secreted by AIEC promotes mucin degradation and disrupts the intestinal barrier, thereby increasing intestinal permeability 171. Another reason is the level of CEACAM6 receptor is elevated in patients with IBS and IBD, facilitating the adhesion of AIEC to IECs. Additionally, AIEC enhances the expression of P2XRs in the colon, which are involved in the formation and transmission of visceral pain 97. Furthermore, AIEC was found to activate pTh17 cells in vivo or in vitro, leading to the production of pro-inflammatory cytokines that promote the development of VH 100.
Chen et al. showed that fecal microbiota transplantation (FMT) from IBS-D patients into germ-free mice induced VH and intestinal motility dysfunction. These mice also exhibited significantly increased Piezo2 expression in the colon and DRG. Through fecal 16S rRNA sequencing, Fusobacterium varium (F. varium) was identified as a key bacterial genus. F. varium is suggested to elevate Piezo2 levels and increase production of the metabolites indole-3-acetic acid and indole-3-acrylic acid, which can bind to Piezo2. Knocking down Piezo2 alleviated the IBS-D-like symptoms induced by the microbiota transplant 111. Furthermore, F. varium, isolated from the colonic mucosa of patients with UC, successfully induced symptom and pathological changes of VH in mice via the metabolic production butyrate, which might disrupt the intestinal barrier and induce release of cytokines 172. Therefore, it indicates that the increased abundance of F. varium induces VH by upregulating Piezo2 expression and producing specific ligands (or metabolites) that bind to and activate the target effectors (Figure 3E).
Certainly, there are many other microorganisms involved in the regulation of visceral sensory, but the detailed functioning manners are still unclear.
Figure 3 illustrates the impact of alterations in gut microbiota abundance on visceral sensitivity and their potential underlying mechanisms.
Gut microbiota-derived metabolites are key regulators of visceral sensitivity, achieved through their interactions with the host's nervous, immune, and endocrine systems. A balanced metabolic profile supports homeostasis, whereas dysbiosis-induced shifts can promote VH.
SCFAs—primarily acetate, propionate, and butyrate—are key metabolites produced from dietary fiber fermentation. Although recognized as contributors to conditions like IBS, their precise roles remain incompletely understood, and clinical associations across studies are inconsistent, presenting an ongoing controversy 108.
Clinical and microbial observations highlight specific patterns. IBS-D patients exhibit elevated fecal propionate and reduced acetate levels, changes positively correlated with an increase in Prevotella 9 and Escherichia-Shigella abundance, suggesting a link to hypersensitivity 101. More broadly, IBS patients often show higher overall SCFA levels and an increased abundance of producer bacteria like Veillonella and Lactobacillus 102. Notably, the correlation between gut bacterial abundance and SCFA concentration is strongest in IBS-D, with specific taxa such as Bacteroides plebeius, Prevotella sp, CAG:1031, and Bifidobacterium pseudocatenulatum being positively associated 103. In summary, these findings solidify the connection between a dysbiotic microbiota, altered SCFA profiles, and the pathophysiology of IBS, particularly the diarrhea-predominant subtype.
Mechanistically, SCFAs influence visceral sensitivity through multiple pathways. Propionate, for instance, can directly activate the vagus nerve via the GPR41 receptor or indirectly stimulate it by promoting 5-HT release from enterochromaffin cells. SCFAs also modulate ion channel function and regulate the release of inflammatory mediators 173. Thus, SCFAs act at the intersection of neural, endocrine, and immune signaling to modulate gut-brain communication.
The role of butyrate is complex and context-dependent. Some studies indicate it promotes hypersensitivity by upregulating neuropeptides (e.g., substance P, CGRP) in dorsal root ganglion neurons 104 or by activating the MAPK-ERK1/2 pathway 105. Conversely, other research demonstrates that butyrate can alleviate hypersensitivity via anti-inflammatory pathways such as AMPK and PPAR-γ 106. This “double-edged sword” effect appears to be dose-dependent: low physiological concentrations support barrier integrity and exert anti-inflammatory effects, while high concentrations overstimulate neuronal receptors, increasing excitability. This concept is supported by animal studies where VH coincided with elevated* Clostridium sensu stricto 1* and fecal butyrate, both of which decreased after probiotic treatment 107. Therefore, the net effect of butyrate is not inherently beneficial or detrimental but is determined by its local concentration and the physiological context, underscoring the nuanced role of microbial metabolites in health and disease.
Dopamine is a key catecholamine neurotransmitter, with roughly half of its total production occurring in the intestine. Specific gut bacteria, including Proteus, Bacillus subtilis, and Corynebacterium, are known to produce dopamine. Animal studies support this gut-brain link; FMT from specific pathogen-free mice into germ-free mice alleviated anxiety-like behavior and significantly altered dopamine metabolism. However, clinical findings in IBS patients are inconsistent. One study reported elevated dopamine levels in IBS-C patients compared to healthy controls, with no significant change in IBS-D patients 109. Conversely, another study found lower dopamine levels in the serum and urine of IBS patients overall 110. Despite these discrepancies, the collective evidence indicates an association between altered dopamine signaling and IBS, highlighting this pathway as a potential target for therapeutic strategies.
Table 4 summarizes the common gut microbiota alterations in IBS and IBD.
Although visceral pain is a common hallmark in both IBS and IBD, the underlying pathways leading to hypersensitivity differ fundamentally. Clarifying these distinctions is crucial for both mechanistic research and clinical management.
The primary drivers of VH in IBD and IBS originate from distinct pathological processes. In IBD, hypersensitivity is primarily driven by tissue damage and inflammation. Active intestinal inflammation acts as a prerequisite, wherein pro-inflammatory cytokines (e.g., TNF-α, IL-1β) and infiltrating immune cells directly stimulate and sensitize peripheral nociceptive neurons 178. By contrast, in IBS the process is best characterized as functional and perceptual dysregulation, centered on aberrant visceral perception arising from brain-gut axis dysfunction. This persistent hypersensitive state stems largely from the central nervous system's misinterpretation of normal gut signals. The dysregulation can be initiated by diverse triggers, such as post-infectious immune activation, gut microbiota dysbiosis, or early-life stress. Although overt inflammation is absent, low-grade immune activation and increased intestinal permeability are often observed 179.
The mechanisms and primary drivers of neuro-immune communication differ substantially between IBD and IBS. In IBD, the neuro-immune communication is initiated by the inflammatory response. The abnormal activation of innate and adaptive immunity produces a large amount of inflammatory mediators, which act on enteric nerve endings, driving intense peripheral sensitization 180. In contrast, IBS involves a bidirectional interaction between neural system and immune reaction. At the gut level, low-grade immune activation promotes neuronal sensitization via mast cell-neuron axis or mediator such as PAR2, PGE2, histamine and so on 135. Concurrently, central factors including long-term stress, anxiety and depression induce functional and structural plasticity particularly in emotion-sensory integration brain regions such as ACC and PVN. These central changes can, in turn, amplify peripheral immune responses and intestinal permeability. This bidirectional dysregulation creates a persistent vicious cycle that underpins the chronicity of IBS symptoms 181.
The relative contributions of peripheral and central sensitization to visceral pain differ markedly between IBD and IBS. In IBD, pain during active inflammation is thought to be primarily driven by peripheral sensitization. This process is characterized by a direct lowering of nociceptor thresholds at the site of inflammation, mediated by local inflammatory mediators 182. As the disease progresses to a chronic stage, persistent peripheral nociceptive signaling can induce secondary central sensitization 183. Conversely, in IBS, although peripheral triggers exist, evidence indicates that central sensitization plays a more significant and enduring role 184. This conclusion is supported by functional neuroimaging showing enhanced reactivity in the limbic system and is further corroborated by strong clinical associations with psychiatric comorbidities and stress reactivity, suggesting dysregulation of the HPA axis and descending pain modulatory systems 185.
The pathophysiological divergence of VH in IBD and IBS carry direct clinical relevance for diagnosis and management. In terms of diagnosis, pain in IBD correlates with the degree of endoscopic inflammation and serum/fecal inflammatory markers (such as C-reactive protein and fecal calprotectin) 186. In contrast, the diagnosis of IBS is based on symptomatic criteria, primarily the Rome criteria, after excluding organic diseases; the biomarkers (e.g., fecal calprotectin) are mainly used to rule out IBD 154. Regarding treatment, the cornerstone of IBD management is the suppression of immune inflammation (e.g., using biologics), and pain often resolves with the control of inflammation. Treatment for IBS, however, focuses on modulating the brain-gut axis, including the use of visceral analgesics (e.g., opioid receptor modulators), a low-FODMAP diet, neuromodulators (e.g., tricyclic antidepressants), and cognitive-behavioral therapy 2, 154, 187.
This article reviews recent studies investigating the pathogenesis of VH, a common symptom in IBS and IBD. It examines the following 1) the peripheral neural circuits underlying visceral pain, with a focus on the role of intestinal components, including IECs, immune cells, and EGCs in driving peripheral sensitization of nociceptors on DRG neurons; 2) the sensitization of brain nuclei and associated neural circuits; 3) the mechanisms by which microbes contribute to both peripheral and central pathways leading to VH. These three aspects dynamically interact through neural, endocrine, and immune pathways. The gut microbiota affects the functional states of both the intestine and the brain. In turn, the brain modulates gastrointestinal secretion, immunity, and motility, thereby influencing the diversity and composition of the gut microbial community. This complex interaction constitutes the microbiota-gut-brain axis—a highly coordinated and sophisticated system.
There has been a notable shift in therapeutic paradigms from merely alleviating symptoms to implementing targeted interventions that address the underlying pathophysiology of these conditions. This transition is clearly reflected in the growing clinical adoption of various central modulators, such as low-dose amitriptyline and gabapentin, which specifically target central sensitization. Additionally, mast cell stabilizers like sodium cromoglycate are being utilized to tackle immune activation, while 5-HT receptor antagonists, such as alosetron, are employed to modulate enteroendocrine function. Furthermore, microbiota-directed strategies, such as low FODMAP diets and the use of Bifidobacterium longum probiotics, are gaining traction as effective treatment options. The mechanism-targeted therapeutic strategies for VH phenotypes are listed in Table 5, including molecular targets, representative drugs, proposed mechanism, target phenotype, biomarker and clinical evidence status. However, despite these promising developments, significant translational barriers remain. A lack of non-invasive and objective diagnostic tools, together with over-reliance on subjective patient feedback or invasive interventions like colorectal distension, poses challenges to standardization in treatment protocols. Moreover, the inherent heterogeneity of these diseases complicates the ability to target specific mechanisms effectively, as patients may present with varying contributions from intestinal immunity, microbiota, central regulation, or neuroendocrine pathways. Therefore, real-world implementation of these advanced therapeutic strategies necessitates overcoming these obstacles to facilitate the selection of personalized therapies that cater to the unique needs of each patient.
Further research holds substantial promise in these The construction of a cross-species transcriptomic atlas through single-cell analysis of DRG neurons offers key molecular insights. These include nociceptor signatures, species variations, and gene expression correlates of pain and inflammation, which collectively form a consensus framework for exploring the mechanisms of VH. In-depth characterization of neuronal subtypes thereby supports precise etiological identification 200; identifying multi-omics-derived biomarkers to stratify patients by pathophysiological subtype, enabling mechanism-based targeting; developing novel therapeutics against validated molecular targets; and optimizing combination strategies (pharmacological, dietary, psychosocial) to leverage synergistic effects. VH management will likely remain chronic, but the definitive endpoint—accurate diagnosis, prevention, and personalized care—remains achievable with continued innovation. Collectively, these advancements will shift the paradigm of VH from a poorly defined symptom cluster to a precisely characterized, mechanism-driven clinical entity.