Pathophysiology of Gastroesophageal Reflux Disease

Abstract

Background

Gastroesophageal reflux disease (GERD) is a prevalent gastrointestinal disorder caused by the retrograde flow of gastric contents into the esophagus, leading to bothersome symptoms and complications. Its pathophysiology is complex and multifactorial, and recent research has aimed to explain the heterogeneity of GERD phenotypes, each influenced by different underlying mechanisms that contribute to symptom presentation and disease progression.

Summary

GERD arises from an imbalance between defensive mechanisms and disruptive factors. Key pathophysiological contributors include esophageal gastric junction dysfunction, transient lower esophageal sphincter relaxations, esophageal motility abnormalities, delayed gastric emptying, and thoracoabdominal pressure gradients. Mucosal damage is exacerbated by prolonged exposure to acid and bile, pepsin activity, and impaired esophageal volume and chemical clearance. Additionally, central and peripheral neural modulation influences symptom perception, with heightened visceral sensitivity and esophageal hypervigilance playing significant roles in symptom severity and treatment response. Emerging diagnostic techniques such as high-resolution manometry, impedance-pH monitoring, and EndoFLIP® are improving our ability to identify specific pathophysiological abnormalities, leading to more personalized approaches to GERD management.

Key Messages

(i) GERD results from a multifactorial interplay between anatomical, functional, and neurophysiological mechanisms. (ii) Esophageal clearance, EGJ structure and function, acid exposure, mucosal resistance, and neural modulation are crucial determinants of symptom severity and disease progression. (iii) The presence of different phenotypes of the reflux disease (e.g., GERD, functional heartburn, and reflux hypersensitivity) underscores the need for individualized diagnostic and therapeutic strategies. (iv) Advances in diagnostic technologies enhance our understanding of GERD pathophysiology, facilitating tailored management approaches beyond acid suppression therapies. Future research should focus on refining GERD phenotyping and integrating mechanistic insights into personalized treatment paradigms.

Introduction

Gastroesophageal reflux disease (GERD) is a prevalent gastrointestinal disorder characterized by the retrograde movement of gastric contents into the esophagus, leading to bothersome symptoms and potential complications, including esophagitis, esophageal strictures, Barrett esophagus (BE), and esophageal adenocarcinoma [1–3]. Its global prevalence varies significantly, with higher rates in Western countries than in Asian populations [4]. The incidence of GERD symptoms continues to rise worldwide, underscoring the need for efficacious treatment and a more comprehensive understanding of its pathophysiology [5–9].

The pathophysiology of GERD is complex and not yet completely understood, with its primary mechanisms depicted in Figure 1. It primarily involves dysfunction of the gastroesophageal anti-reflux barrier, which consists mainly of the lower esophageal sphincter (LES) and the crural diaphragm [10–13]. When this barrier fails, gastric secretions and biliopancreatic components reflux into the esophagus, where they interact with the mucosa [14–19]. The degree of mucosal exposure and potential damage is governed by volume clearance and buffering mechanisms, primarily esophageal peristalsis and salivary neutralization, and the epithelial resistance to injury [20–24]. In addition to anatomical and functional impairments, factors such as central and peripheral neural modulation contribute to symptom perception and disease progression [25].

Fig. 1.

Main mechanisms driving GERD and its symptoms. Created with Biorender.com (last accessed February 15, 2025).

A thorough understanding of GERD pathophysiology is crucial for accurate diagnosis [26–29] and management [30], especially in PPI-refractory cases [31–33]. This review explores GERD’s pathophysiology, including esophageal function, anti-reflux barrier integrity, refluxate effects, gastric factors, and neural and psychological influences on symptoms.

Esophageal Mechanisms

Esophageal Volume Clearance

The primary defense against esophageal damage is the rapid clearance of refluxed gastric contents, which relies on both volume and chemical clearance mechanisms. Volume clearance is primarily facilitated by primary and secondary peristalsis, with primary peristalsis propelling the food bolus through the esophagus, while secondary peristalsis plays a critical role in removing residual refluxate and food debris, eliminating approximately 90% of refluxed material [34]. Moreover, reflux symptoms improve when patients assume an upright position, where gravity assists in esophageal clearance [35]. Following peristalsis, chemical clearance occurs through salivary bicarbonates and esophageal submucosal glands [36], which help restore the esophageal pH to physiological levels [37]. Additionally, the upper esophageal sphincter serves as the final line of defense against the reflux of gastric contents into the oropharynx [38].

Most patients with GERD conserve normal motility [39]. When motility disorders are present, ineffective esophageal motility (IEM) is the most frequently observed abnormality, occurring in 30–40% of GERD cases [40–42]. Studies have shown that GERD patients with IEM have higher acid exposure time (AET), particularly in the supine position [43, 44]. Notably, a study by Leite et al. [45] found that GERD patients with IEM had significantly more severe esophageal mucosal damage compared to those with normal motility. While esophageal motor dysfunctions impairing clearance mechanisms have been documented in GERD patients, it remains unclear whether these abnormalities are a consequence of the disease or a contributing factor. Absent contractility is a rare esophageal motility disorder, associated with scleroderma and autoimmune diseases, affecting up to 90% of cases [46, 47]. Absent contractility patients experience severe reflux and regurgitation and demonstrated greater GERD severity [48].

Post-reflux swallow-induced peristaltic wave (PSPW) represents an important mechanism to promote esophageal chemical clearance. PSPW occurs when esophageal mechanoreceptors detect reflux episodes, triggering a vagally mediated reflex that induces esophageal peristalsis. [49]. At impedance-pH monitoring, PSPW is identified as an antegrade 50% drop in impedance originating in the proximal esophagus, reaching all distal impedance sites within 30 s after a reflux episode [50]. The PSPW index (PSPW-I), calculated as the percentage of reflux episodes followed by a PSPW, provides a quantitative assessment of esophageal chemical clearance efficiency. PSPW-I has proven valuable in phenotyping GERD patients, particularly those with refractory symptoms [51–55]. Numerous studies have demonstrated that PSPW-I can effectively distinguish GERD from functional heartburn (FH) with higher sensitivity (>90%) than conventional parameters. PSPW-I correlates inversely with AET and directly with mucosal integrity measured by baseline impedance. Recent research shows that impaired PSPW response (PSPW-I <53%) is strongly associated with esophageal mucosal damage, with a PSPW-I cut-off of 61% considered the threshold for normal chemical clearance [56–58]. However, limitations include technical challenges in consistent identification during impedance-pH monitoring, potential interobserver variability, and the time-consuming nature of manual calculation, though standardized protocols and artificial intelligence systems are being developed to address these issues.

Acid Neutralization

After peristalsis clears most of the refluxate, the distal esophageal mucosa may remain acidic [37]. Chemical clearance then relies on saliva, which contains bicarbonate to neutralize acid and various growth factors such as epidermal growth factor (EGF), nerve growth factor (NGF), transforming growth factor-alpha and beta, bone morphogenetic protein (BMP), insulin-like growth factor, and fibroblast growth factor (FGF) that support mucosal repair [37, 59]. Hyposalivation, resulting from factors such as aging, medication use (including anticholinergics targeting M3 muscarinic receptors and antidepressants), radiotherapy, or conditions like chronic xerostomia in connective tissue disorders such as Sjögren’s syndrome, has been linked to impaired acid clearance, especially during sleep, thereby increasing the risk of esophageal mucosal damage [60]. Salivation follows a circadian rhythm, reaching its peak during wakefulness and decreasing substantially during sleep, which may partially explain why reflux events at night are often linked to prolonged acid clearance [61]. Additionally, bicarbonate-rich secretions from the esophageal submucosal glands may contribute in neutralizing acid and restoring esophageal pH following reflux episodes [62].

Mucosal Integrity

The esophageal mucosa is composed of a partially keratinized stratified squamous epithelium, which is functionally divided into three distinct layers: the stratum corneum, stratum spinosum, and stratum germinativum [63]. The stability of mucosal integrity is maintained by apical junctional complexes, which consist of tight junctions, adherens junctions and desmosomes [64]. These structures are composed of proteins like claudins and occludins in tight junctions and cadherins in adherens junctions. When these complexes become dysfunctional, they may contribute to increased permeability of the mucosal barrier. Mucosal integrity impairment is a key factor in GERD, not only in erosive esophagitis (EE), where it may lower the threshold for acid clearance and exacerbate mucosal damage, but also in patients without visible lesions on endoscopy, who account for over 70% of those experiencing reflux symptoms [65–67]. Beyond traditional histopathological changes such as papillary elongation and basal cell hyperplasia, the dilation of intercellular spaces has emerged as a key microscopic marker of esophageal mucosal damage [68]. Studies utilizing both electron and light microscopy on esophageal biopsy samples have confirmed this alteration, which has also been detected through basal impedance measurements [69–71]. Mean nocturnal baseline impedance is a key parameter obtained from multichannel intraluminal impedance-pH monitoring, serving as a sensitive marker of esophageal mucosal integrity [24, 34, 72, 73]. It holds significant value in differentiating GERD from FH, a gut-brain interaction disorder characterized by heartburn symptoms unrelated to reflux events and reflux hypersensitivity (RH), a condition where patients exhibit an exaggerated perception of reflux despite normal acid exposure [74]. Additionally, mean nocturnal baseline impedance aids in predicting treatment response [53, 54, 56] and enhances the diagnostic evaluation of inconclusive GERD cases [26, 55, 75]. While microscopic esophagitis is more pronounced in EE than in non-erosive reflux disease (NERD), it is nearly absent in FH [76]. The compromise of the mucosal barrier can influence symptom perception by allowing refluxate to reach sensory nerve endings in the submucosal layer, whose activation has been associated with esophageal hypersensitivity [77, 78]. These findings highlight the potential of topical therapies, especially for patients with symptoms resistant to PPIs, by targeting the underlying mucosal issues [79].

Esophagogastric Junction Dysfunction

LES Pressure

The esophagogastric junction (EGJ) serves as the anatomical and functional interface between the esophagus and stomach. This structurally intricate region comprises the LES, the crural diaphragm, and supporting structures, such as the phreno-esophageal ligament and the gastric sling fibers, along with the angle of His. Functioning as a dynamic anti-reflux barrier, the EGJ relies on a coordinated interaction between intrinsic LES pressure and diaphragmatic contractions to regulate the passage of gastric contents and prevent gastroesophageal reflux. The crural diaphragm plays a pivotal role in reinforcing LES function by increasing EGJ pressure during physiological activities such as inspiration, coughing, sneezing, and bending, thereby preserving the pressure gradient between the thoracic and abdominal cavities. Under normal conditions, the LES and crural diaphragm work synergistically.

The LES is a 2- to 3-cm region of tonically contracted smooth muscle. Its resting pressure typically ranges between 10 and 30 mm Hg, though this can vary among healthy individuals and fluctuates significantly during the day [80]. Several factors influence LES pressure, including respiration, intra-abdominal pressure, diet, and medications. While the LES tone is primarily myogenic [81], it is also regulated by excitatory and inhibitory neurons of the myenteric plexus, as well as various hormonal and paracrine factors, including gastrin, glucagon, and progesterone [82]. While low LES pressure predisposes to gastroesophageal reflux, reflux can still occur despite normal LES pressure [83]. Persistent low LES pressure (0–4 mm Hg) is uncommon among GERD patients and is primarily observed in those with severe scleroderma or in individuals who have undergone myotomy for achalasia [84]. In such cases, free reflux occurs, marked by a drop in intra-esophageal pH without a corresponding change in intragastric pressure or LES pressure [85].

The introduction of high-resolution manometry (HRM) has improved the ability to evaluate EGJ morphology and function [86–89]. The EGJ contractile integral (EGJ-CI) was developed as a quantitative measure of EGJ strength as an anti-reflux barrier [90]. This metric assesses LES and crural diaphragm contractility relative to intragastric pressure over three respiratory cycles. Lower EGJ-CI values are associated with abnormal AET and predict better symptom response to anti-reflux surgery compared to medical therapy [91] but do not significantly impact the response to PPI treatment in GERD patients [92]. EGJ-CI has proven useful in differentiating FH from refractory GERD in PPI non-responders undergoing impedance-pH testing [93, 94], but further refinement is needed.

A recent study by Siboni et al. [95] demonstrated how the thoracoabdominal pressure gradient influences GERD by using the straight leg raise (SLR) maneuver during HRM. The SLR maneuver is a test that reproduces strain-induced reflux, which occurs when a hypotensive LES is forced open by a sudden increase in intra-abdominal pressure [96]. HRM studies indicate that strain-induced reflux is unlikely when LES pressure is conserved and is rare in individuals without a hiatal hernia (HH) [85, 96, 97]. SLR was found to effectively predict abnormal esophageal AET with a diagnostic accuracy of 84% (area under the curve, AUC). These findings suggest that assessing pressure gradients and their effect on EGJ function can improve GERD diagnostics, and ongoing research continues to refine these assessment methods.

Recent studies have highlighted the role of Endoluminal Functional Lumen Imaging Probe (EndoFLIP^®) in evaluating EGJ distensibility for GERD diagnosis [98]. This technique provides real-time measurements of EGJ compliance, and studies have shown that GERD patients have significantly higher EGJ distensibility compared to normal subjects, making EndoFLIP^® an interesting tool to integrate for diagnosing GERD and guiding treatment [99].

Transient LES Relaxations

Transient LES relaxations (TLESRs) are triggered primarily by gastric distension, particularly following meals, through a vagally mediated reflex. When the vagal afferents in the stomach detect distension, triggering signals are transmitted to the nucleus tractus solitarii in the brainstem for processing and then relayed to the dorsal motor nucleus of the vagus, which activates inhibitory neurons in the myenteric plexus of the distal esophagus. In response, vagal efferents stimulate the release of nitric oxide and vasoactive intestinal peptide at the LES, leading to its temporary relaxation. This swallow-independent mechanism acts as a physiological process that allows the venting of gastric gas and is the primary cause of reflux in healthy individuals [100], as confirmed by HRM findings. Studies suggest that an increased frequency of inappropriate TLESRs, rather than just low LES pressure, is the predominant cause of reflux episodes [101, 102]. However, in EE and patients with HH, TLESRs play a less dominant role in reflux pathophysiology [103, 104].

Thoracoabdominal Pressure Gradient

The thoracoabdominal pressure gradient is a key determinant in gastroesophageal reflux dynamics. Under normal conditions, fluctuations in this gradient are effectively regulated by the LES and CD. However, during episodes of deep inspiration, straining, or coughing, intra-abdominal pressure increases, which could potentially promote reflux. To counteract this, the crural diaphragm contracts reflexively, significantly increasing EGJ pressure, sometimes reaching levels up to 150 mm Hg, thereby maintaining the pressure differential between the thoracic and abdominal cavities and preventing reflux [105].

An elevated thoracoabdominal pressure gradient is recognized as a key factor in GERD development [106], especially in individuals with obesity, pregnancy, chronic respiratory diseases, or ascites. A persistently high gradient may overcome the anti-reflux mechanisms, making GERD more severe or resistant to conventional treatment, even in individuals with normal LES pressure and no HH [107].

Hiatal Hernia

A HH disrupts the normal alignment between the LES and the diaphragm, increasing the likelihood of acid reflux. This disruption happens because the opening in the hiatal orifice widens beyond its usual maximum length of 2 cm, allowing the diaphragm’s crura to shift and spread, ultimately displacing the LES [108]. Evidence shows that esophageal acid exposure is significantly higher in patients with HH, and reflux esophagitis is frequently associated with HH [109]. Additionally, patients with BE have the highest prevalence of HH [110]. HH contributes to GERD through several mechanisms beyond disrupting the anti-reflux barrier, including proximal displacement of the acid pocket, reduced LES pressure, and serving as a reservoir for gastric contents. Additionally, motility disorders, such as impaired esophageal clearance, may further exacerbate reflux severity. Recent studies suggest that HH contributes to esophageal dysmotility, particularly ineffective peristalsis, independent of GERD [111].

However, the severity and mechanism of reflux vary depending on the size and reducibility of the HH [112]. A physiological hernia occurs briefly during swallowing when esophageal shortening temporarily elevates the EGJ above the diaphragm. This movement also causes a temporary herniation of the stomach into the chest, visible on barium swallow studies as the phrenic ampulla, that empties as the LES descends from an intrathoracic to an intra-abdominal position [113].

In patients with HH, the crural diaphragm’s contraction during inspiration creates a pressure compartment within the herniated portion of the stomach, positioned between the LES and the diaphragm. This buildup of pressure increases the likelihood of reflux episodes [114]. Furthermore, larger, nonreducing hernias are more strongly associated with motility dysfunction, leading to prolonged acid and bile exposure within the hernia sac [115]. Each centimeter increase in HH size raises the risk of ineffective peristalsis by 30%, reinforcing a continuity spectrum linking HH to motility dysfunction and GERD [111]. These mechanisms could explain why HH may serve as a reservoir for gastric content, as previously mentioned. In patients with large non-reducing HH, refluxed material becomes trapped within the hernia sac, prolonging acid and bile exposure to the esophagus [116]. Additionally, during the LES swallow-associated relaxations, the acidic fluid retained in the hernia sac may flow back into the esophagus, resulting in repeated acid exposure to the esophageal mucosa and potentially aggravating symptoms [116]. Recent research indicates that esophageal mucosal baseline impedance is lower in HH patients compared to those with similar acid exposure but no hernia, suggesting greater mucosal injury [117]. This could be due to increased bile reflux, further damaging the esophageal lining in HH patients.

HH is more common among obese individuals and serves as one of the key mechanisms linking higher BMI to GERD [118–120]. Obesity contributes to GERD through multiple pathways, including increased intra-abdominal pressure [115] and lower LES pressure [121], proposed delayed gastric emptying [122] and fundic distension triggering more TLESRs, and obesity-related hormonal changes that predispose individuals to reflux and its complications [123]. High-calorie meals in individuals with obesity further exacerbate reflux by prolonging gastric retention and increasing AET [121]. Additionally, as BMI rises, the prevalence of GERD symptoms and esophagitis increases [124], with bariatric surgery, particularly Roux-en-Y gastric bypass, offering potential therapeutic benefits [125–127].

Gastric Contributions

Composition of the Refluxate

The composition and distribution of gastric contents vary based on diet, gastric and biliopancreatic secretions, and gastroduodenal motility. Key components of refluxate include hydrochloric acid, pepsin, biliopancreatic enzymes, microbial pathogens, and bicarbonate [128]. Depending on pH, refluxate can be acidic (pH <4), weakly acidic (pH 4–7), or non-acidic (pH >7) [129]. The composition and pH levels can affect mucosal damage and symptom perception, with increased esophageal acid exposure being associated with more severe mucosal injury [130]. While reducing stomach acid is the primary GERD treatment [131], research indicates that abnormal acid secretion is not the fundamental cause, since acid production is similar in GERD patients and asymptomatic individuals [132, 133]. Studies monitoring 24-h gastric pH indicate that patients with NERD do not have lower pH levels than healthy individuals, particularly at night [134]. Nevertheless, hypersecretory conditions like Zollinger-Ellison syndrome have been linked to severe reflux disease [135].

The perception of symptoms may become more pronounced with extended acid exposure, refluxate reaching the upper esophagus, and the presence of gas [136]. Weakly acidic reflux, commonly observed in patients on acid-suppressive therapy, along with nonacid reflux, has also been associated with esophageal and extra-esophageal symptoms [137]. Meanwhile, although bile can compromise esophageal cell membranes and junctions, studies utilizing the Bilitec device suggest that only a small proportion of reflux symptoms are directly associated with bile reflux [138]. However, bile reflux has been associated with the severity of reflux disease, in both patients with typical and atypical manifestations [19, 139–142]. Studies have shown that post-gastrectomy patients experience reflux containing acid, bile, and pancreatic enzymes, with mixed reflux leading to mucosal injury and symptom variations based on acid presence [143].

Pepsin, a gastric proteolytic enzyme, is activated by acidic pH or intracellular uptake after epithelial cell absorption [144]. It contributes to mucosal damage by degrading extracellular proteins and disrupting cellular defenses [145]. The presence of pepsin together with acid is thought to be more aggressive than acid alone [146].

The connection between microbiome and GERD remains a topic of debate. Studies have shown a shift from Gram-positive commensal bacteria (e.g., Streptococcus and Lactobacillus) to Gram-negative species (e.g., Fusobacteria, Campylobacter, and Proteobacteria) in the esophageal microbiome [147]. This microbial imbalance is particularly evident in EE and BE, where an increased presence of lipopolysaccharide-producing bacteria has been linked to inflammation and mucosal damage [148]. The relationship between bacteria and GERD has been most extensively studied in the context of Helicobacter pylori (H. pylori) infection. Epidemiological studies suggest an inverse correlation between H. pylori prevalence and GERD incidence [149, 150], and some research indicates that eradicating H. pylori may elevate the risk of GERD in certain individuals [151]. However, other studies have found no significant difference in esophageal acid exposure between H. pylori-positive and H. pylori-negative individuals, suggesting that H. pylori infection itself may not be a direct factor in GERD pathogenesis [152]. A metanalysis published in 2021 found that H. pylori infection is associated with a lower likelihood of reflux symptoms and EE but does not significantly impact the risk of BE [138]. The potential protective role of H. pylori against GERD is thought to be linked to reduced gastric acid secretion in corpus-predominant gastritis [153]. Conversely, antrum-predominant gastritis increases gastrin levels and acid production, supposedly heightening GERD risk [154]. However, most H. pylori-infected individuals and patients with GERD exhibit normal gastric acid production [155, 156]. The inconsistent findings in the literature underscore the need for further research to clarify this relationship, which may involve other mechanisms such as host immune responses and bacterial virulence factors.

Esophageal impedance-pH monitoring has allowed for the evaluation of intra-esophageal gas movement, distinguishing between anterograde and retrograde directions and the differentiation between supragastric belching (SGB) and gastric belching [157–160]. While gastric belching is a physiological process where TLESR relaxation allows air from the stomach to escape through the esophagus and UES and is often associated with both acid and nonacid reflux symptoms [161], SGB is a self-induced learned behavior where air is either sucked into the esophagus via UES relaxation (air-suction method) or pushed into the esophagus through pharyngeal contraction (air-injection method), and then immediately expelled before reaching the gastric lumen [162]. This process is typically absent during sleep and is influenced by psychological factors such as stress and anxiety [157].

The relationship between SGB and GERD is believed to be bidirectional [163]. Research indicates that SGB precedes reflux episodes in about one-third of cases, suggesting that SGB may contribute to acid reflux by increasing intra-abdominal pressure or by causing esophageal distension, potentially weakening the LES [157]. Notably, excessive SGB can directly contribute to pathological acid exposure. Glasinovic et al. [164] demonstrated that SGB-induced acid reflux accounts for approximately 26% of total AET in patients with excessive SGB, while therapeutic interventions targeting SGB reduction significantly decrease acid exposure. Conversely, it is thought that some GERD patients may develop excessive SGB as a response to the discomfort caused by reflux and may unconsciously belch in an effort to relieve symptoms [165], but this behavior can exacerbate reflux episodes, creating a cycle of worsening symptoms and being a potential mechanism underlying PPI refractoriness [166].

The relationship between GERD and SGB remains unclear, but SGB is recognized as a GERD-mimicking condition. Treatment prioritizes behavioral interventions over medication, focusing on speech therapy, cognitive behavioral therapy, and diaphragmatic breathing exercises [167]. These approaches are particularly effective when SGB presents as a bothersome, frequent belching disorder, as defined by Rome IV criteria [168].

Acid Pocket

The acid pocket is a normal physiological occurrence found in both healthy individuals and those with GERD in the postprandial period [169]. It develops when newly secreted gastric acid settles above ingested food, forming a highly acidic zone in the upper stomach [170]. In GERD patients, especially those with HH, this pocket can shift upward onto the esophageal lining, increasing acid exposure and worsening reflux symptoms [171]. Functioning as a reservoir for acid reflux, it plays a role in mucosal damage near the squamocolumnar junction [172].

Chronic exposure to these reflux episodes may contribute to mucosal inflammation and metaplasia at the EGJ and distal esophagus [173]. However, this mechanism is postprandial and does not account for reflux between meals or at night. Additionally, a bile pocket has been identified in the same region in GERD patients [174, 175].

Gastric Emptying and Accommodation

Gastric emptying represents a highly orchestrated physiological process that integrates multiple coordinated mechanisms: proximal gastric accommodation to regulate intragastric pressure and volume, rhythmic antral peristaltic contractions that propel gastric contents, and dynamic pyloric sphincter regulation that controls the rate and composition of chyme delivery into the duodenum [176]. This process is modulated by vagal input, enteric neuronal signaling, and hormonal regulators such as gastrin, motilin, and glucagon-like peptide-1 (GLP-1).

The primary mechanism through which delayed gastric emptying favors GERD symptoms involves gastric distension and prolonged retention of refluxate, which can increase TLESRs in the postprandial period [177]. Moreover, dysfunctional accommodation reflex can lead to increased reflux volume, worsening GERD symptoms [176]. However, studies have not established a direct correlation between delayed gastric emptying and esophageal acid exposure [178] and the correlation with total esophageal AET remains weak [179]. Emerenziani et al. [180] compared reflux characteristics during fasting and postprandial states in GERD patients and healthy individuals, finding that reflux is more likely to reach the proximal esophagus in the early postprandial period. This suggests that delayed gastric emptying primarily affects the proximal extent of reflux rather than total AET.

In contrast, while overall gastric emptying may not be a significant factor, delayed emptying of the proximal stomach appears to play a key role in the development of GERD, as it is associated with prolonged esophageal AET [181]. GLP-1 receptor agonists (GLP-1 RAs), such as semaglutide and liraglutide, are recently introduced drugs for diabetes and weight loss that delay gastric emptying and therefore may increase GERD risk [182]. A study by Liu et al. [183] found an 11% higher risk of GERD in diabetic patients starting GLP-1 RAs, with the incidence of EE doubling (13% vs. 6%) and a higher prevalence of strictures and BE. However, increased endoscopy rates in GLP-1 RA users may have introduced detection bias. While GERD is rarely assessed in GLP-1 RA clinical trials, data from FAERS and the adverse events reported in a clinical trial on orforglipron suggest a possible link [184, 185]. Further research is needed to clarify the risk, monitoring, and management strategies for GERD in patients taking these medications.

Central and Peripheral Neural Modulation

Visceral Hypersensitivity

Visceral hypersensitivity refers to an exaggerated perception of mechanical, chemical, thermal, or electrical stimuli [186]. It is thought to arise from a complex interplay of peripheral and central sensitization, as well as neural and immune system interactions [187, 188]. Unlike FH, which is independent of reflux events, visceral hypersensitivity plays a predominant role in RH where heightened sensory responses occur despite normal acid exposure, with a strong symptom-reflux correlation [189], making multichannel intraluminal impedance-pH monitoring an essential diagnostic tool [190]. The presence of microscopic esophagitis, impaired mucosal integrity, and defective chemical clearance further aligns RH with GERD rather than FH.

Moreover, evidence found that NERD patients are more sensitive to brief proximal acid exposure compared to those with EE [191]. Studies using the modified Bernstein test have shown that patients with erosive reflux disease and NERD exhibit heightened acid sensitivity, whereas those with BE or FH have a lower sensitivity [192–194]. One proposed peripheral mechanism for acid hypersensitivity involves transient receptor potential (TRP) ion channels, which are essential for sensory transduction and signaling pathways associated with visceral hypersensitivity. Notably, TRP vanilloid type 1 receptors, acid-sensitive receptors located in submucosal and mucosal nerve endings, are upregulated in both EE and NERD patients, contributing to their heightened acid sensitivity [195]. Other key sensory receptors involved are protease-activated receptor 2 [196]. Moreover, there are differences in the distribution of mucosal nerve fibers among NERD, EE, and BE patients. In healthy individuals and those with EE or BE, sensory nerves are located deeper in the mucosa, whereas NERD patients have more superficial sensory nerves expressing TRP vanilloid type 1 [63, 197]. Acid exposure also leads to central neural sensitization, enhancing the insula and cingulate cortex’s response to subliminal and liminal non-painful mechanical stimuli, with greater central activity observed in GERD patients compared to healthy individuals [198, 199]. Importantly, acid exposure can directly sensitize peripheral nerve endings in the esophageal mucosa [200]. Moreover, patients with NERD exhibit heightened sensitivity to thermal and mechanical stimuli, while those with refractory GERD demonstrate increased sensitivity to thermal, mechanical, and chemical stimulation of the esophagus compared to healthy controls [201–204]. Another proposed mechanism for reflux perception involves sustained esophageal contractions, which reflect a discoordination between circular and longitudinal esophageal smooth muscle activity. These contractions precede 70% of heartburn episodes detected through combined esophageal pH monitoring and ultrasonography and more recently by Endoflip^® [205], making them a potential motor correlate of heartburn [206]. While most reflux episodes do not trigger symptoms, 30% of heartburn episodes occur without sustained esophageal contractions [206]. Regarding central mechanisms, stress, anxiety, and psychological comorbidities influence central pain processing, with neurotransmitters such as endogenous opioids, endocannabinoids, and serotonin modulating anti-nociceptive pathways [207–209]. Stress has been shown to exacerbate GERD symptoms by enhancing esophageal sensitivity to acid exposure, possibly through both central modulation and peripheral effects, such as increasing mucosal permeability [210]. Sleep deprivation similarly increases esophageal sensitivity and diminishes analgesic mechanisms, further linking psychological factors to GERD symptom severity [211].

Esophageal Hypervigilance

Research on refractory reflux patients shows that most reported symptoms are not directly linked to reflux events or acid exposure [212, 213], prompting investigations into the mechanisms underlying symptom perception in GERD. Esophageal hypervigilance, characterized by heightened awareness and amplification of esophageal sensations, is prevalent across various GERD phenotypes and contributes to symptom severity, independent of acid exposure [214]. This heightened sensitivity leads to an exaggerated perception of threat, negatively impacting psychosocial well-being and quality of life in GERD patients [215]. Heightened symptom awareness can lead to a conditioned fear response, setting off a cycle of autonomic nervous system activation and involuntary behaviors aimed at avoiding symptoms [214].

Much of the research on hypervigilance has focused on FH [216–218], a disorder entirely independent of reflux events and primarily driven by central pain modulation and brain-gut axis dysfunction. Unlike RH, FH patients do not exhibit microscopic esophageal abnormalities [219]. These pathophysiological differences [220] also lead to distinct treatment responses: RH patients often benefit from anti-reflux surgery [221–224] and high-dose PPIs, whereas FH patients respond better to neuromodulators and psychological interventions rather than acid suppression or surgical treatments [225, 226]. Although hypervigilance has been extensively studied in FH, it also contributes to symptom perception in refractory GERD, complicating both diagnosis and treatment [227].

Conclusion

GERD symptoms result from a complex interplay between protective and disruptive mechanisms, with multiple contributing factors rather than a single cause. The balance between esophageal defenses, such as mucosal integrity, clearance, and LES function, and disruptive factors like acid exposure, bile reflux, TLESRs, and esophageal hypersensitivity determines symptom severity and persistence. Neural sensitization, both peripheral and central, and psychological influences, including hypervigilance and autonomic responses, further amplify symptom perception, making GERD a condition that extends beyond the esophagus. Given this multifaceted pathophysiology, both diagnosis and effective management of GERD require a comprehensive approach that addresses structural and functional abnormalities, as well as patient-specific factors influencing symptom perception and response to therapy.

Conflict of Interest Statement

Edoardo Vincenzo Savarino has served as speaker for AbbVie, Agave, AGPharma, Alfasigma, Aurora Pharma, Cadigroup, Celltrion, Dr. Falk, EG Stada Group, Fenix Pharma, Fresenius Kabi, Galapagos, Janssen, JB Pharmaceuticals, Innovamedica/Adacyte, Malesci, MayolyBiohealth, Omega Pharma, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Tillots, and Unifarco; he has also served as a consultant for AbbVie, Agave, Alfasigma, Biogen, Bristol Myers Squibb, Celltrion, Diadema Farmaceutici, Dr. Falk, Fenix Pharma, Fresenius Kabi, Janssen, JB Pharmaceuticals, Merck & Co, Nestlè, Reckitt Benckiser, Regeneron, Sanofi, SILA, Sofar, SYNformulas GmbH, Takeda, and Unifarco, and he has received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco, and Zeta Farmaceutici. Vincenzo Savarino, Elisa Marabotto, Matteo Ghisa, and Luisa Bertin have no conflict to declare. Nicola de Bortoli has served as an advisory board member for Alfasigma, Sanofi Genzyme, and Dr. Falk and received lecture grants from Reckitt Benckiser, Malesci, Dr. Flak, Sofar, Alfasigma, and Pharma Line.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

Luisa Bertin, Vincenzo Savarino, Elisa Marabotto, Matteo Ghisa, Nicola de Bortoli, and Edoardo Vincenzo Savarino contributed to the conception and design of the review. Luisa Bertin and Matteo Ghisa drafted the initial manuscript, while Vincenzo Savarino, Elisa Marabotto, Nicola de Bortoli, and Edoardo Vincenzo Savarino provided critical revisions for important intellectual content. All authors were involved in the literature search, critical analysis, and interpretation of relevant studies, approved the final version of the manuscript, and agreed to be accountable for all aspects of the work.

Funding Statement

This study was not supported by any sponsor or funder.