Modern Concepts of the Pathogenesis of Gastro-Oesophageal Reflux Disease
DOI:
https://doi.org/10.32782/2415-8127.2026.74.22Keywords:
gastro-oesophageal reflux disease, pathogenesis, risk factors, visceral hypersensitivity, psychological disorders, clinical phenotypesAbstract
Introduction. Gastro-oesophageal reflux disease is one of the most common disorders of the gastrointestinal tract; it is characterised by considerable clinical variability and has a significant impact on patients’ quality of life. The aim of this study was to summarise current scientific evidence regarding the pathophysiological mechanisms underlying the development of GERD, the role of risk factors and psycho-emotional factors, as well as the characteristics of clinical phenotypes of GERD. Materials and methods. A literature review was conducted to summarise current scientific data. The literature search was carried out in the international electronic databases PubMed/MEDLINE, Scopus, Web of Science Core Collection and Google Scholar. The publications included in the analysis covered the period from 2015 to 2026, with priority given to clinical guidelines, consensus documents, systematic reviews, meta-analyses and original scientific studies. Results and discussion. The analysis showed that the development of GERD is a complex process involving mechanical, chemical, sensory and neuroregulatory factors. An important role is played by dysfunction of the anti-reflux barrier at the oesophagogastric junction, transient relaxation of the lower oesophageal sphincter, impaired oesophageal clearance and reduced resistance of the epithelial barrier. The role of modifiable risk factors, such as abdominal obesity, lifestyle factors, diet and sleep disturbances, has been established. There is a bidirectional association between GERD and psychological disorders, mediated by dysfunction of the ‘brain-gut’ axis, visceral sensitivity and oesophageal hypersensitivity. The current classification of GERD is based on phenotype, which is divided into erosive reflux disease, non-erosive reflux disease, reflux hypersensitivity and functional heartburn, each of which has its own pathophysiological mechanism and treatment approach. Conclusions. GERD is a multifactorial and heterogeneous condition involving structural, functional and psychosocial mechanisms. An understanding of current pathophysiological concepts enables a shift from a symptomatic approach to a personalised approach based on clinical, endoscopic and functional diagnostic assessment.
References
Maret-Ouda, J., Markar, S. R., & Lagergren, J. (2020). Gastroesophageal Reflux Disease: A Review. JAMA, 324(24), 2536-2547. https://doi.org/10.1001/jama.2020.21360
Alqassab, D. F., Hasan, M. J., AlSaadoon, A. M., AlMuqahwi, A. J., AlAwadhi, F. A., Bahram, S. A., & Alsayyad, A. S. (2024). Prevalence and risk factors of gastroesophageal reflux disease among adults attending primary healthcare in Bahrain. Journal of family medicine and primary care, 13(12), 5758-5765. https://doi.org/10.4103/jfmpc.jfmpc_968_24
Nirwan, J. S., Hasan, S. S., Babar, Z. U., Conway, B. R., & Ghori, M. U. (2020). Global Prevalence and Risk Factors of Gastro-oesophageal Reflux Disease (GORD): Systematic Review with Meta-analysis. Scientific reports, 10(1), 5814. https://doi.org/10.1038/s41598-020-62795-1
Katz, P. O., Dunbar, K. B., Schnoll-Sussman, F. H., Greer, K. B., Yadlapati, R., & Spechler, S. J. (2022). ACG Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease. The American journal of gastroenterology, 117(1), 27-56. https://doi.org/10.14309/ajg.0000000000001538
Argüero, J., & Sifrim, D. (2024). Pathophysiology of gastro-oesophageal reflux disease: implications for diagnosis and management. Nature reviews. Gastroenterology & hepatology, 21(4), 282-293. https://doi.org/10.1038/s41575-023-00883-z
Eusebi, L. H., Ratnakumaran, R., Yuan, Y., Solaymani-Dodaran, M., Bazzoli, F., & Ford, A. C. (2018). Global prevalence of, and risk factors for, gastro-oesophageal reflux symptoms: a meta-analysis. Gut, 67(3), 430–440. https://doi.org/10.1136/gutjnl-2016-313589
Taraszewska A. (2021). Risk factors for gastroesophageal reflux disease symptoms related to lifestyle and diet. Roczniki Panstwowego Zakladu Higieny, 72(1), 21-28. https://doi.org/10.32394/rpzh.2021.0145
Zamani, M., Alizadeh-Tabari, S., Chan, W. W., & Talley, N. J. (2023). Association Between Anxiety/Depression and Gastroesophageal Reflux: A Systematic Review and Meta-Analysis. The American journal of gastroenterology, 118(12), 2133-2143. https://doi.org/10.14309/ajg.0000000000002411
Miao, Y., Yuan, S., Li, Y., Chen, J., Li, X., Larsson, S. C., & Zhang, Q. (2022). Bidirectional Association between Major Depressive Disorder and Gastroesophageal Reflux Disease: Mendelian Randomization Study. Genes, 13(11), 2010. https://doi.org/10.3390/genes13112010
Wong, M. W., Liu, T. T., Yi, C. H., Lei, W. Y., Hung, J. S., Cock, C., Omari, T., Gyawali, C. P., Liang, S. W., Lin, L., & Chen, C. L. (2021). Oesophageal hypervigilance and visceral anxiety relate to reflux symptom severity and psychological distress but not to acid reflux parameters. Alimentary pharmacology & therapeutics, 54(7), 923-930. https://doi.org/10.1111/apt.16561
Yadlapati, R., Gyawali, C. P., Pandolfino, J. E., & CGIT GERD Consensus Conference Participants (2022). AGA Clinical Practice Update on the Personalized Approach to the Evaluation and Management of GERD: Expert Review. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 20(5), 984-994.e1. https://doi.org/10.1016/j.cgh.2022.01.025
Martin, Z., Spry, G., Hoult, J., Maimone, I. R., Tang, X., Crichton, M., & Marshall, S. (2022). What is the efficacy of dietary, nutraceutical, and probiotic interventions for the management of gastroesophageal reflux disease symptoms? A systematic literature review and meta-analysis. Clinical nutrition ESPEN, 52, 340-352. https://doi.org/10.1016/j.clnesp.2022.09.015
Lakananurak, N., Pitisuttithum, P., Susantitaphong, P., Patcharatrakul, T., & Gonlachanvit, S. (2024). The Efficacy of Dietary Interventions in Patients with Gastroesophageal Reflux Disease: A Systematic Review and Meta-Analysis of Intervention Studies. Nutrients, 16(3), 464. https://doi.org/10.3390/nu16030464
Gyawali, C. P., Yadlapati, R., Fass, R., Katzka, D., Pandolfino, J., Savarino, E., Sifrim, D., Spechler, S., Zerbib, F., Fox, M. R., Bhatia, S., de Bortoli, N., Cho, Y. K., Cisternas, D., Chen, C. L., Cock, C., Hani, A., Remes Troche, J. M., Xiao, Y., Vaezi, M. F., … Roman, S. (2024). Updates to the modern diagnosis of GERD: Lyon consensus 2.0. Gut, 73(2), 361-371. https://doi.org/10.1136/gutjnl-2023-330616
Fass, R., Boeckxstaens, G. E., El-Serag, H., Rosen, R., Sifrim, D., & Vaezi, M. F. (2021). Gastro-oesophageal reflux disease. Nature reviews. Disease primers, 7(1), 55. https://doi.org/10.1038/s41572-021-00287-w
Bertin, L., Savarino, V., Marabotto, E., Ghisa, M., de Bortoli, N., & Savarino, E. V. (2026). Pathophysiology of Gastroesophageal Reflux Disease. Digestion, 107(2), 185-201. https://doi.org/10.1159/000547023
Sharma, P., & Yadlapati, R. (2021). Pathophysiology and treatment options for gastroesophageal reflux disease: looking beyond acid. Annals of the New York Academy of Sciences, 1486(1), 3-14. https://doi.org/10.1111/nyas.14501
Zikos, T. A., & Clarke, J. O. (2020). Non-acid Reflux: When It Matters and Approach to Management. Current gastroenterology reports, 22(9), 43. https://doi.org/10.1007/s11894-020-00780-4
Gyawali, C. P., Carlson, D. A., Chen, J. W., Patel, A., Wong, R. J., & Yadlapati, R. H. (2020). ACG Clinical Guidelines: Clinical Use of Esophageal Physiologic Testing. The American journal of gastroenterology, 115(9), 1412-1428. https://doi.org/10.14309/ajg.0000000000000734
Chen, J. W., Vela, M. F., Peterson, K. A., & Carlson, D. A. (2023). AGA Clinical Practice Update on the Diagnosis and Management of Extraesophageal Gastroesophageal Reflux Disease: Expert Review. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 21(6), 1414-1421.e3. https://doi.org/10.1016/j.cgh.2023.01.040
Li, T., Jawish, M. A., Badurdeen, D., & Koop, A. H. (2024). Diagnosis and Management of Noncardiac Chest Pain. Gastroenterology & hepatology, 20(9), 533-541.
Yadlapati, R., & Pandolfino, J. E. (2020). Personalized Approach in the Work-up and Management of Gastroesophageal Reflux Disease. Gastrointestinal endoscopy clinics of North America, 30(2), 227-238. https://doi.org/10.1016/j.giec.2019.12.002
Targownik, L. E., Fisher, D. A., & Saini, S. D. (2022). AGA Clinical Practice Update on De-Prescribing of Proton Pump Inhibitors: Expert Review. Gastroenterology, 162(4), 1334-1342. https://doi.org/10.1053/j.gastro.2021.12.247
Zerbib, F., Bredenoord, A. J., Fass, R., Kahrilas, P. J., Roman, S., Savarino, E., Sifrim, D., Vaezi, M., Yadlapati, R., & Gyawali, C. P. (2021). ESNM/ANMS consensus paper: Diagnosis and management of refractory gastro-esophageal reflux disease. Neurogastroenterology and motility, 33(4), e14075. https://doi.org/10.1111/nmo.14075
Provenza, D., Gillette, C., Peacock, B., & Rejeski, J. (2024). Managing heartburn and reflux in primary care. JAAPA : official journal of the American Academy of Physician Assistants, 37(3), 24-29. https://doi.org/10.1097/01.JAA.0001005620.54669.f4
Bhatia, S., Pareek, K. K., Kumar, A., Upadhyay, R., Tiwaskar, M., Jain, A., Gupta, P., Nadkar, M. Y., Prakash, A., Dutta, A., Chavan, R., Kedia, S., Ahuja, V., Ghoshal, U., Agarwal, A., & Makharia, G. (2020). API-ISG Consensus Guidelines for Management of Gastrooesophageal Reflux Disease. The Journal of the Association of Physicians of India, 68(10), 69-80.
Chen, L., Yang, X., Hu, M., Zhou, L., Ding, Y., Wang, Z., Liu, Y., & Shi, R. (2025). Global, regional and national burdens of gastroesophageal reflux disease from 1990 to 2021 and projections to 2050: a finding from the global burden of disease study 2021. BMC public health, 25(1), 3943. https://doi.org/10.1186/s12889-025-25121-w
Zhan, J., Yuan, M., Zhao, Y., Zhang, X., Qiao, T., Ji, T., Gao, H., Cao, Z., Wang, D., & Ding, N. (2022). Abdominal obesity increases the risk of reflux esophagitis: a systematic review and meta-analysis. Scandinavian journal of gastroenterology, 57(2), 131-142. https://doi.org/10.1080/00365521.2021.1994643
Yuan, S., & Larsson, S. C. (2022). Adiposity, diabetes, lifestyle factors and risk of gastroesophageal reflux disease: a Mendelian randomization study. European journal of epidemiology, 37(7), 747-754. https://doi.org/10.1007/s10654-022-00842-z
Shi, H. X., Wang, Z. F., & Sun, X. H. (2021). Characteristics of esophageal motility and clinical presentation in gastroesophageal reflux disease patients of different age groups. Zhonghua yi xue za zhi, 101(14), 1015-1019. https://doi.org/10.3760/cma.j.cn112137-20200713-02110
Gyawali, C. P., Kahrilas, P. J., Savarino, E., Zerbib, F., Mion, F., Smout, A. J. P. M., Vaezi, M., Sifrim, D., Fox, M. R., Vela, M. F., Tutuian, R., Tack, J., Bredenoord, A. J., Pandolfino, J., & Roman, S. (2018). Modern diagnosis of GERD: the Lyon Consensus. Gut, 67(7), 1351-1362. https://doi.org/10.1136/gutjnl-2017-314722
Zachariah, R. A., Goo, T., & Lee, R. H. (2020). Mechanism and Pathophysiology of Gastroesophageal Reflux Disease. Gastrointestinal endoscopy clinics of North America, 30(2), 209-226. https://doi.org/10.1016/j.giec.2019.12.001
Kahrilas, P. J., Mittal, R. K., Bor, S., Kohn, G. P., Lenglinger, J., Mittal, S. K., Pandolfino, J. E., Serra, J., Tatum, R., & Yadlapati, R. (2021). Chicago Classification update (v4.0): Technical review of high-resolution manometry metrics for EGJ barrier function. Neurogastroenterology and motility, 33(10), e14113. https://doi.org/10.1111/nmo.14113
Tack, J., & Pandolfino, J. E. (2018). Pathophysiology of Gastroesophageal Reflux Disease. Gastroenterology, 154(2), 277–288. https://doi.org/10.1053/j.gastro.2017.09.047
Dao, H. V., Matsumura, T., Kaneko, T., Takahashi, S., Tokunaga, M., Oura, H., Ishikawa, K., Akizue, N., Kikuchi, A., Fujie, M., Saito, K., Okimoto, K., Maruoka, D., Nakagawa, T., Arai, M., Kato, J., & Kato, N. (2020). Impact of ineffective esophageal motility on chemical clearance in patients with gastroesophageal reflux symptoms. Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus, 33(9), doaa026. https://doi.org/10.1093/dote/doaa026
Samuels, T. L., & Johnston, N. (2020). Pepsin in gastroesophageal and extraesophageal reflux: molecular pathophysiology and diagnostic utility. Current opinion in otolaryngology & head and neck surgery, 28(6), 401-409. https://doi.org/10.1097/MOO.0000000000000664
Liang, S. W., Wong, M. W., Yi, C. H., Liu, T. T., Lei, W. Y., Hung, J. S., Lin, L., Rogers, B. D., & Chen, C. L. (2022). Current advances in the diagnosis and management of gastroesophageal reflux disease. Tzu chi medical journal, 34(4), 402-408. https://doi.org/10.4103/tcmj.tcmj_323_21
Sawada, A., Sifrim, D., & Fujiwara, Y. (2023). Esophageal Reflux Hypersensitivity: A Comprehensive Review. Gut and liver, 17(6), 831-842. https://doi.org/10.5009/gnl220373
Lages, R. B., Fontes, L. H. S., Barbuti, R. C., & Navarro-Rodriguez, T. (2024). Esophageal Mucosal Impedance Assessment for the Diagnosis of Gastroesophageal Reflux Disease. Journal of neurogastroenterology and motility, 30(3), 352-360. https://doi.org/10.5056/jnm23063
Leech, T., & Peiris, M. (2024). Mucosal neuroimmune mechanisms in gastro-oesophageal reflux disease (GORD) pathogenesis. Journal of gastroenterology, 59(3), 165-178. https://doi.org/10.1007/s00535-023-02065-9
Mutha, P. R., Fasullo, M., Chu, S., Schubert, M. L., Zfass, A., Cooper, P., Gill, M., Kang, L., Vaezi, M., Wildhorn, S., Slaughter, C., & Shah, T. (2022). Correlation of Probe-Based Confocal Laser Endomicroscopy (pCLE) and Mucosal Integrity Testing (MIT) with Epithelial Barrier Function and Presence of Gastroesophageal Reflux Disease (GERD). Digestive diseases and sciences, 67(5), 1773-1782. https://doi.org/10.1007/s10620-021-06980-w
Ma, T., Gu, J., Zhao, Y., Li, S., Zou, D., & Ge, D. (2022). EZH2-mediated suppression of CLDN1 leads to barrier dysfunction in PPI-refractory gastroesophageal reflux disease. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, 54(6), 776–783. https://doi.org/10.1016/j.dld.2021.10.006
He, M., Wang, Q., Yao, D., Li, J., & Bai, G. (2022). Association Between Psychosocial Disorders and Gastroesophageal Reflux Disease: A Systematic Review and Meta-analysis. Journal of neurogastroenterology and motility, 28(2), 212-221. https://doi.org/10.5056/jnm21044
Zheng, J., & Tao, L. (2025). Multidimensional mechanisms and therapies underlying gastroesophageal reflux disease: focus on immunity, signaling pathways, and the microbiota-gut-brain axis. Frontiers in immunology, 16, 1629944. https://doi.org/10.3389/fimmu.2025.1629944
Cho Y. K. (2017). Can Acute Stress Cause Esophageal Hypersensitivity in Healthy Individuals?. Journal of neurogastroenterology and motility, 23(4), 483-484. https://doi.org/10.5056/jnm17118
Guadagnoli, L., Yadlapati, R., Taft, T., Pandolfino, J. E., Tye, M., & Keefer, L. (2021). Esophageal hypervigilance is prevalent across gastroesophageal reflux disease presentations. Neurogastroenterology and motility, 33(8), e14081. https://doi.org/10.1111/nmo.14081
Tan, X., Wang, S., Wu, F., & Zhu, J. (2024). Bidirectional correlation between gastroesophageal reflux disease and sleep problems: a systematic review and meta-analysis. PeerJ, 12, e17202. https://doi.org/10.7717/peerj.17202
Kurin, M., Shibli, F., Kitayama, Y., Kim, Y., & Fass, R. (2021). Sorting out the Relationship between Gastroesophageal Reflux Disease and Sleep. Current gastroenterology reports, 23(9), 15. https://doi.org/10.1007/s11894-021-00815-4
Katzka, D. A., Pandolfino, J. E., & Kahrilas, P. J. (2020). Phenotypes of Gastroesophageal Reflux Disease: Where Rome, Lyon, and Montreal Meet. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 18(4), 767-776. https://doi.org/10.1016/j.cgh.2019.07.015
Shibli, F., Alberto Jiménez-Castillo, R., & Fass, R. (2026). Lyon Consensus 2.0: what has changed for GERD diagnosis?. Expert review of gastroenterology & hepatology, 20(6), 525-536. https://doi.org/10.1080/17474124.2026.2683677
Savarino, E., Marabotto, E., & Savarino, V. (2022). Recent insights on functional heartburn and reflux hypersensitivity. Current opinion in gastroenterology, 38(4), 417-422. https://doi.org/10.1097/MOG.0000000000000846





