{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T02:01:47Z","timestamp":1780624907161,"version":"3.54.1"},"reference-count":104,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Visceral pain is a central feature of chronic gastrointestinal disorders, yet the epithelial sensory mechanisms that shape afferent input before it enters pain-relevant neural pathways remain insufficiently integrated into current models. This review advances the concept that the intestinal epithelium is not only a barrier or endocrine interface, but also an active neuroepithelial regulatory layer positioned upstream of visceral sensory signaling. Neuropod-cell studies established that specialized epithelial cells can communicate rapidly with vagal neurons and preserve luminal stimulus identity through transmitter-selective coding. Enterochromaffin cells extend this framework as polymodal epithelial sensory transducers that detect chemical, microbial, neurohumoral, and mechanical cues, convert them into serotonergic afferent signaling, and can causally amplify visceral hypersensitivity in experimental models. Complementing these amplifying pathways, GUCY2Chigh (guanylate cyclase C-enriched) neuropod-like epithelial cells reveal a pain-restraining mechanism that regulates dorsal root ganglion excitability and preserves linaclotide-responsive suppression of nociceptive output in preclinical systems. Together, these findings support an integrative model in which epithelial sensory circuits may act as filters of biological meaning, amplifiers of afferent gain, and brakes on aberrant nociceptive escalation. This framework does not replace neural, immune, or central mechanisms of visceral pain, but adds an upstream epithelial tier that may shape pain vulnerability, persistence, or treatment responsiveness in selected contexts. Defining the cellular logic, molecular mediators, and human relevance of these circuits will be essential for advancing neuroepithelial pain biology toward disease-relevant and therapeutic applications.<\/jats:p>","DOI":"10.3390\/ijms27115109","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T01:23:21Z","timestamp":1780622601000},"page":"5109","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Epithelial Sensing to Visceral Pain: Neuropod and Enterochromaffin Cells in Gut Neuroepithelial Circuits"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5848-8788","authenticated-orcid":false,"given":"Agnieszka","family":"Nowacka","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toru\u0144, ul. Curie Sk\u0142odowskiej 9, 85-094 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej","family":"\u015aniegocki","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toru\u0144, ul. Curie Sk\u0142odowskiej 9, 85-094 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1822-3133","authenticated-orcid":false,"given":"Ewa A.","family":"Zi\u00f3\u0142kowska","sequence":"additional","affiliation":[{"name":"Department of Animal Biotechnology and Genetics, Faculty of Animal, Breeding and Biology, Bydgoszcz University of Science and Technology, Mazowiecka 28, 85-084 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Barton, J.R., Londregan, A., Alexander, T.D., Entezari, A.A., Covarrubias, M., and Waldman, S.A. (2023). Enteroendocrine Cell Regulation of the Gut-Brain Axis. Front. Neurosci., 17.","DOI":"10.3389\/fnins.2023.1272955"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1038\/s41378-023-00615-y","article-title":"Modeling Gut Neuro-Epithelial Connections in a Novel Microfluidic Device","volume":"9","author":"Yu","year":"2023","journal-title":"Microsyst. Nanoeng."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e2501525122","DOI":"10.1073\/pnas.2501525122","article-title":"Population Imaging of Enterochromaffin Cell Activity Reveals Regulation by Somatostatin","volume":"122","author":"Rossen","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1016\/S0140-6736(20)32115-2","article-title":"Functional Gastrointestinal Disorders: Advances in Understanding and Management","volume":"396","author":"Black","year":"2020","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4713","DOI":"10.1007\/s00018-021-03812-y","article-title":"The Enteric Nervous System in Gastrointestinal Disease Etiology","volume":"78","author":"Holland","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1038\/s41380-023-01972-w","article-title":"The Neurobiology of Irritable Bowel Syndrome","volume":"28","author":"Mayer","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s42234-023-00130-5","article-title":"Non-Invasive Neuromodulation: An Emerging Intervention for Visceral Pain in Gastrointestinal Disorders","volume":"9","author":"Alam","year":"2023","journal-title":"Bioelectron. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Aulenkamp, J., Icenhour, A., and Elsenbruch, S. (2023). Nocebo Effects in Visceral Pain: Concept and Design of the Experimental Randomized-Controlled Pain Study \u2018NoVis\u2019. Front. Psychiatry, 14.","DOI":"10.3389\/fpsyt.2023.1270189"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Veldman, F., Black, C.J., Shin, A., and Keszthelyi, D. (2026). Novel Therapeutic Targets for Chronic Visceral Pain in Gastrointestinal Disorders. Br. J. Pharmacol., ahead of print.","DOI":"10.1111\/bph.70326"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e165578","DOI":"10.1172\/JCI165578","article-title":"Intestinal Neuropod Cell GUCY2C Regulates Visceral Pain","volume":"133","author":"Barton","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/s42003-024-06148-y","article-title":"Neural Circuits Regulating Visceral Pain","volume":"7","author":"Chang","year":"2024","journal-title":"Commun. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Zhou, Q., and Verne, G.N. (2025). Molecular Mechanisms and Pathways in Visceral Pain. Cells, 14.","DOI":"10.3390\/cells14151146"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.7150\/ijms.126361","article-title":"Reviewing the Peripheral and Central Mechanisms of Visceral Hypersensitivity in Intestinal Disorders","volume":"23","author":"Tang","year":"2026","journal-title":"Int. J. Med. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Malykhina, A.P. (2026). Shaping the Future of Abdominal and Pelvic Pain Research with Novel Scientific and Technological Advances. Front. Pain Res., 7.","DOI":"10.3389\/fpain.2026.1738762"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2166780","DOI":"10.1080\/19490976.2023.2166780","article-title":"Diet\u2013Microbial Cross\u2013Talk Underlying Increased Visceral Perception","volume":"15","author":"Palma","year":"2023","journal-title":"Gut Microbes"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3368","DOI":"10.1016\/j.cell.2023.07.007","article-title":"DRG Afferents That Mediate Physiologic and Pathologic Mechanosensation from the Distal Colon","volume":"186","author":"Wolfson","year":"2023","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9346","DOI":"10.1523\/JNEUROSCI.1663-18.2018","article-title":"Advances in Enteric Neurobiology: The \u201cBrain\u201d in the Gut in Health and Disease","volume":"38","author":"Kulkarni","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Najjar, S.A., Ejoh, L.L., Loeza-Alcocer, E., Edwards, B.S., Smith, K., Epouhe, A.Y., Gold, M.S., Davis, B.M., and Albers, K.M. (2020). Optogenetic Inhibition of Colon Epithelium Reduces Hypersensitivity in a Mouse Model of Inflammatory Bowel Disease. bioRxiv.","DOI":"10.1101\/2020.05.21.107110"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.tins.2019.12.007","article-title":"Epithelial-Neuronal Communication in the Colon: Implications for Visceral Pain","volume":"43","author":"Najjar","year":"2020","journal-title":"Trends Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e70221","DOI":"10.1111\/nmo.70221","article-title":"The Neuroepithelial Landscape of Enterochromaffin Cells Varies Across Gastrointestinal Location","volume":"38","author":"Jones","year":"2026","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1172\/JCI78361","article-title":"Neuroepithelial Circuit Formed by Innervation of Sensory Enteroendocrine Cells","volume":"125","author":"Shahid","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"eaat5236","DOI":"10.1126\/science.aat5236","article-title":"A Gut-Brain Neural Circuit for Nutrient Sensory Transduction","volume":"361","author":"Kaelberer","year":"2018","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.cell.2017.05.034","article-title":"Enterochromaffin Cells Are Gut Chemosensors That Couple to Sensory Neural Pathways","volume":"170","author":"Bellono","year":"2017","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"103045","DOI":"10.1016\/j.conb.2025.103045","article-title":"Molecular Mechanisms of Stimulus Detection and Secretion in Enteroendocrine Cells","volume":"92","author":"Davison","year":"2025","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/s41522-025-00810-x","article-title":"Enteroendocrine Cells: The Gatekeepers of Microbiome-Gut-Brain Communication","volume":"11","author":"Grundeken","year":"2025","journal-title":"npj Biofilms Microbiomes"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1126\/science.adl1460","article-title":"Description and Functional Validation of Human Enteroendocrine Cell Sensors","volume":"386","author":"Beumer","year":"2024","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"re3","DOI":"10.1091\/mbc.E24-03-0143","article-title":"Integration of Signal Transduction Pathways in Sensory Epithelial Enteroendocrine Cells","volume":"36","author":"Bellampalli","year":"2025","journal-title":"Mol. Biol. Cell"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Atanga, R., Singh, V., and In, J. (2023). Intestinal Enteroendocrine Cells: Present and Future Druggable Targets. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24108836"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1111\/j.1752-8062.2011.00299.x","article-title":"Axon-Like Basal Processes in Enteroendocrine Cells: Characteristics and Potential Targets","volume":"4","author":"Liddle","year":"2011","journal-title":"Clin. Transl. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1146\/annurev-neuro-091619-022657","article-title":"Neuropod Cells: The Emerging Biology of Gut-Brain Sensory Transduction","volume":"43","author":"Kaelberer","year":"2020","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Faniyi, A.A., Wijanarko, K., Tollitt, J., and Worthington, J.J. (2020). Helminth Sensing at the Intestinal Epithelial Barrier\u2014A Taste of Things to Come. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01489"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s00441-024-03879-6","article-title":"Identification of Vagal Afferent Nerve Endings in the Mouse Colon and Their Spatial Relationship with Enterochromaffin Cells","volume":"396","author":"Spencer","year":"2024","journal-title":"Cell Tissue Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Hasnah, R., Makhlouf, M., Zambon, M., Arietti, M., Alt\u00fan, Y.G.K., Scialdone, A., Saraiva, L.R., and Kaelberer, M.M. (2025). A Sensory Map of the Gastrointestinal Tract. [Doctoral Dissertation, Hamad Bin Khalifa University].","DOI":"10.1101\/2025.03.07.641228"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1038\/s41586-025-09228-z","article-title":"Nutrients Activate Distinct Patterns of Small-Intestinal Enteric Neurons","volume":"644","author":"Fung","year":"2025","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Boh\u00f3rquez, D.V., Samsa, L.A., Roholt, A., Medicetty, S., Chandra, R., and Liddle, R.A. (2014). An Enteroendocrine Cell\u2014Enteric Glia Connection Revealed by 3D Electron Microscopy. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0089881"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.conb.2018.08.004","article-title":"Axon Formation, Extension, and Navigation: Only a Neuroscience Phenomenon?","volume":"53","author":"Rich","year":"2018","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"17157","DOI":"10.1038\/s41598-018-35465-6","article-title":"Neurofilament Heavy Polypeptide Protects against Reduction in Synaptopodin Expression and Prevents Podocyte Detachment","volume":"8","author":"Wang","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Moore, R.E., Clarke, J., and Alexandre, P. (2020). Protrusion-Mediated Signaling Regulates Patterning of the Developing Nervous System. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.579073"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Buckley, M.M., O\u2019Brien, R.L., Brosnan, E., Ross, R.P., Stanton, C., Buckley, J.M., and O\u2019Malley, D. (2020). Glucagon-Like Peptide-1 Secreting L-Cells Coupled to Sensory Nerves Translate Microbial Signals to the Host Rat Nervous System. Front. Cell. Neurosci., 14.","DOI":"10.3389\/fncel.2020.00095"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4505","DOI":"10.1007\/s00018-020-03543-6","article-title":"Functional Circuits and Signal Processing in the Enteric Nervous System","volume":"77","author":"Fung","year":"2020","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/s41593-021-00982-7","article-title":"The Preference for Sugar over Sweetener Depends on a Gut Sensor Cell","volume":"25","author":"Buchanan","year":"2022","journal-title":"Nat. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Kreuch, D., Keating, D.J., Wu, T., Horowitz, M., Rayner, C.K., and Young, R.L. (2018). Gut Mechanisms Linking Intestinal Sweet Sensing to Glycemic Control. Front. Endocrinol., 9.","DOI":"10.3389\/fendo.2018.00741"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2714","DOI":"10.1017\/S1751731119001794","article-title":"Review: Chemosensing of Nutrients and Non-Nutrients in the Human and Porcine Gastrointestinal Tract","volume":"13","author":"Roura","year":"2019","journal-title":"Animal"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Buchanan, K., Rupprecht, L.E., Sahasrabudhe, A., Kaelberer, M.M., Klein, M.E., Villalobos, J., Liu, W., Yang, A., Gelman, J., and Park, S. (2020). A Gut Sensor for Sugar Preference. bioRxiv.","DOI":"10.1101\/2020.03.06.981365"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Moran, A.W., Al-Rammahi, M., Daly, K., Weatherburn, D., Ionescu, C., Blanchard, A., and Shirazi-Beechey, S.P. (2025). Luminal Sweet Sensing and Enteric Nervous System Participate in Regulation of Intestinal Glucose Transporter, GLUT2. Nutrients, 17.","DOI":"10.3390\/nu17091547"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Palmer, R.K., Nechiporenko, A.B., Ilies, M.A., Winnig, M., Gravina, S.A., Tiwari, R., and Prakash, I. (2024). Sodium-Dependent Glucose Co-Transport Proteins (SGLTs) Are Not Involved in Human Glucose Taste Detection. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0313128"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e1217252025","DOI":"10.1523\/JNEUROSCI.1217-25.2025","article-title":"Noncanonical Taste Transduction of Sugars Elicits Responses in a Dedicated Subset of Gustatory Afferent Neurons","volume":"46","author":"Rodriguez","year":"2025","journal-title":"J. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"RP90596","DOI":"10.7554\/eLife.90596","article-title":"Stratification of Enterochromaffin Cells by Single-Cell Expression Analysis","volume":"12","author":"Song","year":"2023","journal-title":"eLife"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1007\/s00418-021-01972-3","article-title":"5-HT containing enteroendocrine cells characterised by morphologies, patterns of hormone co-expression, and relationships with nerve fibres in the mouse gastrointestinal tract","volume":"155","author":"Koo","year":"2021","journal-title":"Histochem. Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Shaaban, A., Maa\u00df, F., Schwarze, V., Lund, M.L., Beuermann, S., Chan, M., Harenberg, C., Bewick, G.A., Keating, D.J., and Benseler, F. (2021). Dissecting Functional, Structural, and Molecular Requirements for Serotonin Release from Mouse Enterochromaffin Cells. bioRxiv.","DOI":"10.1101\/2021.05.28.446100"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/s41586-026-10281-5","article-title":"Parasites Trigger Epithelial Cell Crosstalk to Drive Gut\u2013Brain Signalling","volume":"653","author":"Touhara","year":"2026","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Bertrand, P. (2009). The Cornucopia of Intestinal Chemosensory Transduction. Front. Neurosci., 3.","DOI":"10.3389\/neuro.21.003.2009"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3295","DOI":"10.1523\/JNEUROSCI.20-09-03295.2000","article-title":"Activation of Intrinsic Afferent Pathways in Submucosal Ganglia of the Guinea Pig Small Intestine","volume":"20","author":"Pan","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1097\/MOG.0000000000000685","article-title":"Duodenal Chemosensory System: Enterocytes, Enteroendocrine Cells, and Tuft Cells","volume":"36","author":"Akiba","year":"2020","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"760076","DOI":"10.3389\/fcimb.2021.760076","article-title":"Enterochromaffin Cells: Sentinels to Gut Microbiota in Hyperalgesia?","volume":"11","author":"Xu","year":"2021","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3408","DOI":"10.1073\/pnas.0805323106","article-title":"TRPA1 Regulates Gastrointestinal Motility through Serotonin Release from Enterochromaffin Cells","volume":"106","author":"Nozawa","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"E7632","DOI":"10.1073\/pnas.1804938115","article-title":"A Population of Gut Epithelial Enterochromaffin Cells Is Mechanosensitive and Requires Piezo2 to Convert Force into Serotonin Release","volume":"115","author":"Alcaino","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"101610","DOI":"10.1016\/j.jcmgh.2025.101610","article-title":"Mechanisms of Activation and Serotonin Release from Human Enterochromaffin Cells","volume":"19","author":"Alcaino","year":"2025","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Morrow, N.M., Hanson, A.A., and Mulvihill, E.E. (2021). Distinct Identity of GLP-1R, GLP-2R, and GIPR Expressing Cells and Signaling Circuits Within the Gastrointestinal Tract. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.703966"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1152\/physrev.00038.2023","article-title":"Neuronal Glucose Sensing Mechanisms and Circuits in the Control of Insulin and Glucagon Secretion","volume":"104","author":"Thorens","year":"2024","journal-title":"Physiol. Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"7751","DOI":"10.1113\/JP287463","article-title":"Single-cell Transcriptomics of Human Organoid-derived Enteroendocrine Cell Populations from the Small Intestine","volume":"603","author":"Smith","year":"2024","journal-title":"J. Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e194115","DOI":"10.1172\/jci.insight.194115","article-title":"GPRC5B Preserves a Mature \u03b2-Cell State in Obesity by Controlling MafA Expression","volume":"10","author":"Wang","year":"2025","journal-title":"JCI Insight"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"5788","DOI":"10.1523\/JNEUROSCI.0837-18.2018","article-title":"Optogenetic Activation of Colon Epithelium of the Mouse Produces High-Frequency Bursting in Extrinsic Colon Afferents and Engages Visceromotor Responses","volume":"38","author":"Makadia","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/s41586-023-05829-8","article-title":"Gut Enterochromaffin Cells Drive Visceral Pain and Anxiety","volume":"616","author":"Bayrer","year":"2023","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1038\/s41467-023-44558-4","article-title":"Evolution of Chemosensory Tissues and Cells across Ecologically Diverse Drosophilids","volume":"15","author":"Bontonou","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Jo, Y. (2024). Differential Transcriptional Profiles of Vagal Sensory Neurons in Female and Male Mice. Front. Neurosci., 18.","DOI":"10.3389\/fnins.2024.1393196"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1111\/jnc.16022","article-title":"Fundamental Neurochemistry Review: The Role of Enteroendocrine Cells in Visceral Pain","volume":"167","author":"Londregan","year":"2023","journal-title":"J. Neurochem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2547029","DOI":"10.1080\/19490976.2025.2547029","article-title":"Gut Microbiota Dysbiosis Affects Intestinal Sensitivity through Epithelium-to-Neuron Signaling: Novel Insights from a Colon Organoid-Based Model to Improve Visceral Pain Therapy","volume":"17","author":"Margiotta","year":"2025","journal-title":"Gut Microbes"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Cappelli, K., Gialletti, R., Tesei, B., Bassotti, G., Fettucciari, K., Capomaccio, S., Bonfili, L., Cuccioloni, M., Eleuteri, A.M., and Spaterna, A. (2019). Guanylin, Uroguanylin and Guanylate Cyclase-C Are Expressed in the Gastrointestinal Tract of Horses. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.01237"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"R4761","DOI":"10.1096\/fasebj.2022.36.S1.R4761","article-title":"GUCY2C-Enriched Intestinal Neuropod Cells Modulate Visceral Pain","volume":"36","author":"Barton","year":"2022","journal-title":"FASEB J."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Prasad, H., Mathew, J.K.K., and Visweswariah, S.S. (2022). Receptor Guanylyl Cyclase C and Cyclic GMP in Health and Disease: Perspectives and Therapeutic Opportunities. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.911459"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e166703","DOI":"10.1172\/JCI166703","article-title":"Guanylyl Cyclase C Ameliorates Visceral Pain: An Unsuspected Link","volume":"133","author":"Liddle","year":"2023","journal-title":"J. Clin. Investig."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Cabri, W., Cantelmi, P., Corbisiero, D., Fantoni, T., Ferrazzano, L., Martelli, G., Mattellone, A., and Tolomelli, A. (2021). Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives. Front. Mol. Biosci., 8.","DOI":"10.3389\/fmolb.2021.697586"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e20210479","DOI":"10.1084\/jem.20210479","article-title":"Gut-Associated cGMP Mediates Colitis and Dysbiosis in a Mouse Model of an Activating Mutation in GUCY2C","volume":"218","author":"Mishra","year":"2021","journal-title":"J. Exp. Med."},{"key":"ref_75","first-page":"312-e84","article-title":"Guanylate Cyclase C-Mediated Antinociceptive Effects of Linaclotide in Rodent Models of Visceral Pain","volume":"22","author":"Bradesi","year":"2009","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1053\/j.gastro.2013.08.017","article-title":"Linaclotide Inhibits Colonic Nociceptors and Relieves Abdominal Pain via Guanylate Cyclase-C and Extracellular Cyclic Guanosine 3\u2032,5\u2032-Monophosphate","volume":"145","author":"Castro","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"C1411","DOI":"10.1152\/ajpcell.00082.2025","article-title":"CFTR High Expresser BEST4+ Cells Are pH-Sensing Neuropod Cells: New Implications for Intestinal Physiology and Cystic Fibrosis Disease","volume":"329","author":"Jin","year":"2025","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Wang, Y.B., de Lartigue, G., and Page, A.J. (2020). Dissecting the Role of Subtypes of Gastrointestinal Vagal Afferents. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.00643"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3623","DOI":"10.1016\/j.cell.2025.05.043","article-title":"Sensory Neurons That Detect Stretch and Nutrients in the Digestive System","volume":"188","author":"Williams","year":"2025","journal-title":"Cell"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1097\/MED.0000000000000299","article-title":"Gastrointestinal Hormones and the Gut Connectome","volume":"24","author":"Ye","year":"2016","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1111\/nmo.12754","article-title":"Enteroendocrine Cells: A Review of Their Role in Brain\u2013Gut Communication","volume":"28","author":"Latorre","year":"2016","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1172\/JCI81121","article-title":"The Gut Connectome: Making Sense of What You Eat","volume":"125","author":"Liddle","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.cell.2015.02.047","article-title":"Indigenous Bacteria from the Gut Microbiota Regulate Host Serotonin Biosynthesis","volume":"161","author":"Yano","year":"2015","journal-title":"Cell"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1038\/nrgastro.2015.121","article-title":"Towards a Systems View of IBS","volume":"12","author":"Mayer","year":"2015","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_85","first-page":"255","article-title":"Visceral Hypersensitivity Is Associated with GI Symptom Severity in Functional GI Disorders: Consistent Findings from Five Different Patient Cohorts","volume":"67","author":"Palsson","year":"2017","journal-title":"Gut"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e121841","DOI":"10.1172\/jci.insight.121841","article-title":"Chronic Linaclotide Treatment Reduces Colitis-Induced Neuroplasticity and Reverses Persistent Bladder Dysfunction","volume":"3","author":"Grundy","year":"2018","journal-title":"JCI Insight"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1053\/j.gastro.2019.04.019","article-title":"Cumulative Effects of Psychologic Distress, Visceral Hypersensitivity, and Abnormal Transit on Patient-Reported Outcomes in Irritable Bowel Syndrome","volume":"157","author":"Palsson","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s42977-024-00205-7","article-title":"Irritable Bowel Syndrome (IBS): Could We Decide What Is Behind?","volume":"75","year":"2024","journal-title":"Biol. Futur."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"S208","DOI":"10.1016\/j.ibneur.2023.08.330","article-title":"DRG neurons sensitization is induced by altered colon organoids: A novel in vitro model to mimic dysbiosis-associated pain","volume":"15","author":"Toti","year":"2023","journal-title":"IBRO Neurosci. Rep."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.4103\/1673-5374.386403","article-title":"Investigating Epithelial-Neuronal Signaling Contribution in Visceral Pain through Colon Organoid-Dorsal Root Ganglion Neuron Co-Cultures","volume":"19","author":"Margiotta","year":"2023","journal-title":"Neural Regen. Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/j.mucimm.2024.10.001","article-title":"Sensory Neuroimmune Interactions at the Barrier","volume":"17","author":"Wang","year":"2024","journal-title":"Mucosal Immunol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"vkaf283.755","DOI":"10.1093\/jimmun\/vkaf283.755","article-title":"A Neuronal-Epithelial Circuit Promotes Intestinal Immunity 2891","volume":"214","author":"Emanuel","year":"2025","journal-title":"J. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Chong, P.P., Chin, V.K., Looi, C.Y., Wong, W.F., Madhavan, P., and Yong, P.V.C. (2019). The Microbiome and Irritable Bowel Syndrome\u2014A Review on the Pathophysiology, Current Research and Future Therapy. Front. Microbiol., 10, Erratum in Front. Microbiol. 2019, 10, 1870. https:\/\/doi.org\/10.3389\/fmicb.2019.01870.","DOI":"10.3389\/fmicb.2019.01870"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1007\/s10620-024-08330-y","article-title":"Plecanatide Improves Abdominal Bloating and Bowel Symptoms of Irritable Bowel Syndrome with Constipation","volume":"69","author":"Brenner","year":"2024","journal-title":"Dig. Dis. Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/s41435-021-00124-w","article-title":"Epithelial Sensing of Microbiota-Derived Signals","volume":"22","author":"Eshleman","year":"2021","journal-title":"Genes Immun."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1186\/s12974-022-02510-1","article-title":"The Function of Gut Microbiota in Immune-Related Neurological Disorders: A Review","volume":"19","author":"Sittipo","year":"2022","journal-title":"J. Neuroinflamm."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Kaur, H., Ali, S.A., and Yan, F. (2022). Interactions between the Gut Microbiota-Derived Functional Factors and Intestinal Epithelial Cells\u2014Implication in the Microbiota-Host Mutualism. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1006081"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Masse, K.E., and Lu, V.B. (2023). Short-Chain Fatty Acids, Secondary Bile Acids and Indoles: Gut Microbial Metabolites with Effects on Enteroendocrine Cell Function and Their Potential as Therapies for Metabolic Disease. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1169624"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Yang, S., Liu, H., and Liu, Y. (2025). Advances in Intestinal Epithelium and Gut Microbiota Interaction. Front. Microbiol., 16.","DOI":"10.3389\/fmicb.2025.1499202"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"e190638","DOI":"10.1172\/JCI190638","article-title":"Distinct Human Small Intestinal Microbiome Communities Underlie Visceral Hypersensitivity in a Humanized Mouse Model","volume":"135","author":"Comba","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.chom.2020.11.011","article-title":"Enteroendocrine Cells Sense Bacterial Tryptophan Catabolites to Activate Enteric and Vagal Neuronal Pathways","volume":"29","author":"Ye","year":"2020","journal-title":"Cell Host Microbe"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Geesala, R., Lin, Y.-M., Zhang, K., and Shi, X. (2021). Targeting Mechano-Transcription Process as Therapeutic Intervention in Gastrointestinal Disorders. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.809350"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Spencer, N.J., Hibberd, T.J., Xie, Z., and Hu, H. (2022). How Should We Define a Nociceptor in the Gut-Brain Axis?. Front. Neurosci., 16.","DOI":"10.3389\/fnins.2022.1096405"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"17448069241305942","DOI":"10.1177\/17448069241305942","article-title":"Advances in the Pathological Mechanisms and Clinical Treatments of Chronic Visceral Pain","volume":"20","author":"Li","year":"2024","journal-title":"Mol. Pain"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/5109\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T01:30:27Z","timestamp":1780623027000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/5109"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,4]]},"references-count":104,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27115109"],"URL":"https:\/\/doi.org\/10.3390\/ijms27115109","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,4]]}}}