REVIEW article
Front. Immunol.
Sec. Inflammation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1629944
Multidimensional Mechanisms and Therapies Underlying Gastroesophageal Reflux Disease: Focus on Immunity, Signaling Pathways, and the Microbiota-Gut-Brain Axis
Provisionally accepted
Jiajing Zheng
Lin Tao*- Department of Digestive, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China
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Gastroesophageal reflux disease (GERD) has a high incidence rate and a complex pathogenesis that is not yet fully understood. This review aims to provide a comprehensive exploration of the mechanisms underlying GERD, emphasizing the interplay between immune responses, signaling pathways, and the microbiota-gut-brain axis. Specifically, it highlights the contributions of immune cells (e.g., T-lymphocytes, dendritic cells, mast cells), pro-inflammatory cytokines, and key signaling pathways, including nuclear factor (NF)-κB, mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), in driving esophageal inflammation and barrier dysfunction. Furthermore, the review examines the bidirectional interactions between psychological stress, gut microbiota dysbiosis, and GERD pathophysiology via the gut-brain axis. In bridging these mechanisms to potential therapeutic strategies, this review evaluates both established pharmacological treatments, such as proton pump inhibitors (PPIs) and immunotherapy, and emerging approaches, including herbal formulations and neuromodulation techniques. By synthesizing current evidence, the review identifies critical knowledge gaps, particularly in understanding the cross-talk between immune pathways and therapeutic targets. These findings underscore the need for mechanism-driven research to facilitate the development of personalized treatment strategies and address unresolved challenges in GERD management.
Keywords: gastroesophageal reflux disease1, lower esophageal sphincter2, Immune cells3, cytokines4, NF-κB5, MAPK6, PI3K-Akt7, Microbiota-gut-brain axis
Received: 16 May 2025; Accepted: 27 Jun 2025.
Copyright: © 2025 Zheng and Tao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Lin Tao, Department of Digestive, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China
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