# Reviewing the Peripheral and Central Mechanisms of Visceral Hypersensitivity in Intestinal Disorders

**Authors:** Wenhui Tang, Jiarui Wang, Wenlei Wang, Jiamiao Xue, Yuyan Wang, Fuhao Jiang, Dimkpa Christabel Kechiyerunda, Shengli Gao, Tao Yuan, Feifei Guo

PMC · DOI: 10.7150/ijms.126361 · 2026-02-18

## TL;DR

This paper reviews how internal organs become overly sensitive in intestinal disorders like IBS and IBD, and explores possible causes and mechanisms.

## Contribution

The paper synthesizes recent findings on peripheral and central mechanisms of visceral hypersensitivity, including the role of gut microbiota.

## Key findings

- VH is linked to factors like genes, gut microbiota, and psychological stress.
- Intestinal cells and brain nuclei may contribute to heightened pain sensitivity.
- More research is needed to understand and treat VH in IBS and IBD.

## Abstract

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.

## Linked entities

- **Diseases:** irritable bowel syndrome (MONDO:0005052), inflammatory bowel disease (MONDO:0005265)

## Full-text entities

- **Genes:** GPER1 (G protein-coupled estrogen receptor 1) [NCBI Gene 2852] {aka CEPR, CMKRL2, DRY12, FEG-1, GPCR-Br, GPER}, HTR3A (5-hydroxytryptamine receptor 3A) [NCBI Gene 3359] {aka 5-HT-3, 5-HT3A, 5-HT3R, 5HT3R, HTR3}, PROK2 (prokineticin 2) [NCBI Gene 60675] {aka BV8, HH4, KAL4, MIT1, PK2}, Trpv1 (transient receptor potential cation channel, subfamily V, member 1) [NCBI Gene 193034] {aka OTRPC1, TRPV1alpha, TRPV1beta, VR-1, Vr1}, SLC6A4 (solute carrier family 6 member 4) [NCBI Gene 6532] {aka 5-HTT, 5-HTTLPR, 5HTT, HTT, OCD1, SERT}, CLDN3 (claudin 3) [NCBI Gene 1365] {aka C7orf1, CPE-R2, CPETR2, HRVP1, RVP1}, TRPV1 (transient receptor potential cation channel subfamily V member 1) [NCBI Gene 7442] {aka VR1}, NGF (nerve growth factor) [NCBI Gene 4803] {aka Beta-NGF, HSAN5, NGFB}, SNAR-E (small NF90 (ILF3) associated RNA E) [NCBI Gene 100170220], GCG (glucagon) [NCBI Gene 2641] {aka GLP-1, GLP1, GLP2, GRPP}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, SCN9A (sodium voltage-gated channel alpha subunit 9) [NCBI Gene 6335] {aka ETHA, FEB3B, GEFSP7, HSAN2D, NE-NA, NENA}, CAMK2G (calcium/calmodulin dependent protein kinase II gamma) [NCBI Gene 818] {aka CAMK, CAMK-II, CAMKG, MRD59}, IGF1 (insulin like growth factor 1) [NCBI Gene 3479] {aka IGF, IGF-I, IGFI, MGF}, TLR4 (toll like receptor 4) [NCBI Gene 7099] {aka ARMD10, CD284, TLR-4, TOLL}, Nol3 (nucleolar protein 3) [NCBI Gene 85383] {aka Arc}, ST2 (suppression of tumorigenicity 2) [NCBI Gene 6761], PIEZO1 (piezo type mechanosensitive ion channel component 1 (Er blood group)) [NCBI Gene 9780] {aka DHS, ER, FAM38A, LMPH3, LMPHM6, Mib}, Tff2 (trefoil factor 2 (spasmolytic protein 1)) [NCBI Gene 21785] {aka SP, mSP}, FOS (Fos proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 2353] {aka AP-1, C-FOS, p55}, P2RX6 (purinergic receptor P2X 6) [NCBI Gene 9127] {aka P2RXL1, P2X6, P2XM}, Trpv4 (transient receptor potential cation channel, subfamily V, member 4) [NCBI Gene 63873] {aka 0610033B08Rik, OTRPC4, Trp12, VR-OAC, VRL-2, VROAC}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, Tnf (tumor necrosis factor) [NCBI Gene 24835] {aka RATTNF, TNF-alpha, Tnfa}, Cyp7a1 (cytochrome P450, family 7, subfamily a, polypeptide 1) [NCBI Gene 13122] {aka CYPVII, CYPVIIc}, Il1b (interleukin 1 beta) [NCBI Gene 24494] {aka IL-1F2}, Ngfr (nerve growth factor receptor (TNFR superfamily, member 16)) [NCBI Gene 18053] {aka LNGFR, Tnfrsf16, p75, p75NGFR, p75NTR}, TRPV4 (transient receptor potential cation channel subfamily V member 4) [NCBI Gene 59341] {aka BCYM3, CMT2C, HMSN2C, OTRPC4, SMAL, SPSMA}, Grin1 (glutamate receptor, ionotropic, NMDA1 (zeta 1)) [NCBI Gene 14810] {aka GluN1, GluRdelta1, GluRzeta1, M100174, NMD-R1, NMDAR1}, Plcg1 (phospholipase C, gamma 1) [NCBI Gene 18803] {aka Cded, Plc-1, Plc-gamma1, Plcg-1}, CALCA (calcitonin related polypeptide alpha) [NCBI Gene 796] {aka CALC1, CGRP, CGRP-I, CGRP-alpha, CGRP1, CT}, Camk2a (calcium/calmodulin-dependent protein kinase II alpha) [NCBI Gene 12322] {aka CaMKII, mKIAA0968}, Avp (arginine vasopressin) [NCBI Gene 24221] {aka ADH, DI, VP, Vas}, SCN11A (sodium voltage-gated channel alpha subunit 11) [NCBI Gene 11280] {aka FEPS3, HSAN7, NAV1.9, NaN, PN5, SCN12A}, DDC (dopa decarboxylase) [NCBI Gene 1644] {aka AADC}, mucin [NCBI Gene 100508689], Prkcg (protein kinase C, gamma) [NCBI Gene 24681] {aka PKC, PKCI, Prkc, Prkcc, RATPKCI}, IL33 (interleukin 33) [NCBI Gene 90865] {aka C9orf26, DVS27, IL1F11, NF-HEV, NFEHEV}, P2RX7 (purinergic receptor P2X 7) [NCBI Gene 5027] {aka P2X7}, PIEZO2 (piezo type mechanosensitive ion channel component 2) [NCBI Gene 63895] {aka C18orf30, C18orf58, DA3, DA5, DAIPT, FAM38B}, Ngf (nerve growth factor) [NCBI Gene 18049] {aka Ngfb, beta-NGF}, Cyp8b1 (cytochrome P450, family 8, subfamily b, polypeptide 1) [NCBI Gene 13124], Nr1h4 (nuclear receptor subfamily 1, group H, member 4) [NCBI Gene 20186] {aka Fxr, HRR1, RIP14, Rxrip14}, CLDN5 (claudin 5) [NCBI Gene 7122] {aka AWAL, BEC1, CPETRL1, TMDVCF, TMVCF}, ARRB1 (arrestin beta 1) [NCBI Gene 408] {aka ARB1, ARR1}, Ntrk1 (neurotrophic tyrosine kinase, receptor, type 1) [NCBI Gene 18211] {aka Tkr, TrkA, trk}, CRH (corticotropin releasing hormone) [NCBI Gene 1392] {aka CRF, CRH1}, BDNF (brain derived neurotrophic factor) [NCBI Gene 627] {aka ANON2, BULN2}, Fos (Fos proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 14281] {aka D12Rfj1, c-fos, cFos}, CLDN1 (claudin 1) [NCBI Gene 9076] {aka CLD1, ILVASC, SEMP1}, CLDN2 (claudin 2) [NCBI Gene 9075] {aka OAZON, claudin-2}, HTR2A (5-hydroxytryptamine receptor 2A) [NCBI Gene 3356] {aka 5-HT2A, HTR2}, PAG1 (phosphoprotein membrane anchor with glycosphingolipid microdomains 1) [NCBI Gene 55824] {aka CBP, PAG}, TPH1 (tryptophan hydroxylase 1) [NCBI Gene 7166] {aka TPRH, TRPH}, P2RX4 (purinergic receptor P2X 4) [NCBI Gene 5025] {aka P2X4, P2X4R}, PYY (peptide YY) [NCBI Gene 5697] {aka PYY-I, PYY1}, NR1H4 (nuclear receptor subfamily 1 group H member 4) [NCBI Gene 9971] {aka BAR, FXR, HRR-1, HRR1, PFIC5, RIP14}, CRP (C-reactive protein) [NCBI Gene 1401] {aka PTX1}, NTRK1 (neurotrophic receptor tyrosine kinase 1) [NCBI Gene 4914] {aka MTC, TRK, TRK1, TRKA, Trk-A, p140-TrkA}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}
- **Diseases:** Dysbiosis (MESH:D064806), psychiatric (MESH:D001523), impairment of (MESH:D060825), anxiety (MESH:D001007), neuroinflammation (MESH:D000090862), abdominal pain (MESH:D015746), trauma (MESH:D014947), NCI (MESH:D007249), gut dysfunction (MESH:C535334), pain (MESH:D010146), colonic pain (MESH:D003110), CL (MESH:C537927), acute pain (MESH:D059787), IECs (MESH:C567703), hyperactivity of the HPA axis (MESH:D007029), chronic visceral pains (MESH:D059265), Diarrhea (MESH:D003967), PI-IBS (MESH:D000094025), colitis (MESH:D003092), CD (MESH:D003424), nociceptive (MESH:D059226), CP (MESH:D050500), NMS (MESH:D009459), CRD (MESH:D015179), hyperalgesia (MESH:D006930), Intestinal Disorders (MESH:D007410), EECs (MESH:D002292), UC (MESH:D003093), dorsal root ganglion (MESH:D045888), organic diseases (MESH:D000092124), IBD (MESH:D015212), chronic pain (MESH:D059350), depression (MESH:D003866), NMD (MESH:D012892), IBS (MESH:D043183), inflammatory cytokines (MESH:D000080424), EGCs (MESH:D004751), constipation (MESH:D003248), VH (MESH:D004342)
- **Chemicals:** prostaglandin (MESH:D011453), ADP (MESH:D000244), Histamine (MESH:D006632), indole-3-acrylic acid (MESH:C001446), guanosine triphosphate (MESH:D006160), cGMP (MESH:D006152), pyrrolidine dithiocarbamate (MESH:C020972), Glu (MESH:D018698), norepinephrine (MESH:D009638), alosetron (MESH:C090840), PGE2 (MESH:D015232), testosterone (MESH:D013739), arachidonic acid (MESH:D016718), butyrate (MESH:D002087), phenethylamine (MESH:C029261), carbohydrate (MESH:D002241), Propionate (MESH:D011422), phenylalanine (MESH:D010649), sodium cromoglycate (MESH:D004205), BA (MESH:D001647), CRD (-), sodium (MESH:D012964), TRPs (MESH:D014364), guanosine (MESH:D006151), indole-3-acetic acid (MESH:C030737), gabapentin (MESH:D000077206), UTP (MESH:D014544), tryptamine (MESH:C030820), acetate (MESH:D000085), morphine (MESH:D009020), Dopamine (MESH:D004298), SCFA (MESH:D005232), BAs (MESH:D001464), cannabinoid (MESH:D002186), calcium (MESH:D002118), 5-HT (MESH:D012701), aminooxyacetic acid (MESH:D000625), TNBS (MESH:D014302), taurine (MESH:D013654), dextran sulfate sodium (MESH:D016264), ATP (MESH:D000255), lipopolysaccharide (MESH:D008070), amitriptyline (MESH:D000639)
- **Species:** Mediterraneibacter gnavus (species) [taxon 33038], Mus musculus (house mouse, species) [taxon 10090], Prevotella sp. (species) [taxon 59823], Proteus (genus) [taxon 210425], Bifidobacterium longum (species) [taxon 216816], Escherichia coli (E. coli, species) [taxon 562], Bacillus subtilis (species) [taxon 1423], Fusobacterium varium (species) [taxon 856], Bifidobacterium pseudocatenulatum (species) [taxon 28026], Lactobacillus acidophilus (species) [taxon 1579], Veillonella (genus) [taxon 29465], Phocaeicola plebeius (species) [taxon 310297], Rattus norvegicus (brown rat, species) [taxon 10116], Homo sapiens (human, species) [taxon 9606], Clostridium (genus) [taxon 1485], Bifidobacterium longum subsp. infantis (subspecies) [taxon 1682], Corynebacterium (genus) [taxon 1716], Bacillota (clostridial firmicutes, phylum) [taxon 1239]

## Figures

3 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12965073/full.md

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Source: https://tomesphere.com/paper/PMC12965073