Association between gastroesophageal reflux disease and functional dyspepsia: A systematic review and meta-analysis

Abstract

BACKGROUND

Gastroesophageal reflux disease (GERD) and functional dyspepsia (FD) have posed challenges in clinical practice. Previous studies have suggested that GERD frequently overlaps with FD. In recent years, successive observational studies have further highlighted the urgent clinical need to better characterize the association between these two conditions.

AIM

To investigate the potential link between GERD and FD by integrating the latest research evidence.

METHODS

PubMed, Web of Science, EMBASE, and the Cochrane Library were comprehensively searched using Medical Subject Headings and related keywords. The risk of bias for cohort and case-control studies was assessed using the Newcastle-Ottawa Scale, and cross-sectional studies were assessed using the Agency for Healthcare Research and Quality scale; scoring was based on the content of the original studies. When statistical heterogeneity was low (Cochran’s Q P > 0.10 and I² ≤ 50%), estimates were pooled using a fixed-effects model; otherwise (I² > 50%), a random-effects model was applied to account for between-study variability. Potential publication bias (small-study effects) was assessed by visual inspection of funnel plots and formally tested using Egger’s regression test. All analyses were conducted in Stata (version 14.0; StataCorp, College Station, TX, United States).

RESULTS

This meta-analysis included 40 studies. Of these, 19 studies (n = 99194) showed a significant association between GERD and FD [odds ratio = 4.77, 95% confidence interval (CI): 3.56-6.40, P < 0.001; I² = 96.6%]. 5 studies (n = 1655) reported a significantly higher incidence of FD in patients with non-erosive reflux disease than in those with erosive reflux disease (odds ratio = 4.50, 95%CI: 1.01-20.03, P < 0.001; I² = 97.2%). Another 10 studies (n = 2100) reported a pooled prevalence of FD symptoms of 40% among patients with GERD (95%CI: 28.0%-53.0%, P < 0.001; I² = 97.18%). 9 studies (n = 2945) reported a pooled prevalence of GERD symptoms of 41% among patients with FD (95%CI: 26.0%-58.0%, P < 0.001; I² = 98.74%).

CONCLUSION

This meta-analysis suggests that GERD and FD are associated, potentially reflecting shared pathophysiological mechanisms and/or residual confounding.

Key Words: Gastroesophageal reflux disease; Functional dyspepsia; Systematic review; Meta-analysis; Epidemiology

Core Tip: This meta-analysis integrates the most recent evidence to clarify the relationship between gastroesophageal reflux disease (GERD) and functional dyspepsia (FD). Pooled results indicate a strong association between GERD and FD, supporting the concept that these disorders frequently overlap in clinical practice. The findings suggest that shared pathophysiological pathways may contribute to co-occurrence, although residual confounding cannot be excluded. Improved recognition of GERD-FD overlap may help optimize evaluation strategies and guide more targeted, mechanism-based management.

INTRODUCTION

Gastroesophageal reflux disease (GERD) and functional dyspepsia (FD) are among the most commonly encountered upper gastrointestinal disorders in routine practice and are major contributors to symptom burden, impaired health-related quality of life, and health care utilization. GERD refers to the reflux of gastric contents into the esophagus that results in reflux-related symptoms and/or complications; in addition to typical heartburn and regurgitation, presentations may include extraesophageal symptom complexes in selected patients[1]. Although its pathogenesis remains incompletely elucidated, existing studies suggest that multiple factors contribute to the onset and progression of GERD, including lower esophageal sphincter dysfunction, abnormal gastric acid secretion, increased intragastric pressure, and esophageal mucosal acid exposure[2,3]. Epidemiologic studies further suggest that GERD has become more common in recent years, in parallel with broader changes in diet and lifestyle, highlighting its growing public health relevance[4]. FD, by contrast, is a disorder of gut-brain interaction arising from the gastroduodenal region and is characterized by postprandial fullness, early satiety, epigastric pain, and/or epigastric burning in the absence of an identifiable structural or metabolic explanation for symptoms[5]. Its core mechanisms primarily involve gastroduodenal dysfunction, including visceral hypersensitivity, impaired gastric accommodation, delayed gastric emptying, and psychological factors related to brain-gut axis interactions[6-8]. Notably, GERD and FD often overlap clinically, and their coexistence is common in practice[9]. This symptom overlap suggests a potential pathophysiological link between GERD and FD. Some studies[10] have suggested that multilayered mechanisms may contribute to the pathogenesis of both conditions, further reinforcing their overlap.

Although previous meta-analyses[11,12] have confirmed a significant association between GERD and FD, they largely focused on overall associations and did not systematically conduct stratified comparative analyses across population subgroups, disease subtypes, or single-group prevalence estimates. In recent years, multiple new observational studies and clinical trial data have been published, enabling a more refined evaluation of the relationship between these two conditions. Therefore, this study aims to comprehensively update and extend prior meta-analyses by integrating recent evidence and providing updated quantitative estimates of the association between GERD and FD, with particular attention to potential differences across clinical and demographic characteristics. These findings may inform individualized diagnosis and stratified management strategies, ultimately improving clinical outcomes and quality of life.

MATERIALS AND METHODS

Protocol registration

This study conducted a systematic review and meta-analysis of observational evidence to evaluate the association between GERD and FD. The review was prepared in accordance with the PRISMA statement[13]. The protocol was registered prospectively in PROSPERO (registration number: CRD420261289772).

Data sources and search strategy

A comprehensive literature search was conducted in PubMed, EMBASE, Web of Science, and the Cochrane Library from inception through December 8, 2025, to identify published studies assessing the relationship between GERD and FD. Search terms included Medical Subject Headings and free-text terms combined with Boolean operators (OR/AND). The reference lists of eligible articles and relevant reviews were also screened to identify additional records. The full search strategy is provided in Supplementary Table 1.

Eligibility criteria

Studies were eligible if they met all of the following criteria: (1) An observational design (cross-sectional, case-control, or cohort) or baseline data from randomized controlled trials; (2) Reported data enabling extraction or calculation of an association between GERD and FD; (3) Defined GERD and FD using recognized diagnostic frameworks (e.g., the Montreal consensus and Rome criteria) or clearly specified symptom-based questionnaires; and (4) Were published in English. Only English-language studies were included to ensure consistency in data extraction and methodological assessment.

Conference abstracts, protocols, duplicate reports, and studies that did not report outcomes relevant to the GERD-FD association (e.g., prevalence, incidence, or effect estimates such as risk ratios) were excluded. For studies enrolling mixed upper gastrointestinal populations, GERD-specific and FD-related outcomes were extracted when reported separately. When required information was not available in the published report, corresponding authors were contacted to request additional data; studies were excluded if valid data could not be obtained.

Study selection

In accordance with established guidance for evidence synthesis and meta-analysis[14], two reviewers independently identified and screened eligible studies. All records were imported into EndNote 2025, and duplicates were removed before screening. Titles and abstracts were screened first (including indexed keywords when available), followed by full-text assessment against prespecified eligibility criteria. Disagreements were resolved through discussion, with adjudication by a third reviewer when necessary. Reasons for exclusion at the full-text stage were recorded using a standardized template, and the selection process is summarized in the PRISMA flow diagram.

Data extraction

Data were extracted independently by two reviewers using a standardized form. The following information was collected: Study title, first author, year of publication, country or region, study design, sample size, proportion of men, age, definitions or diagnostic criteria for GERD and FD, and whether analyses accounted for potential confounders (e.g., through adjustment). Discrepancies were resolved by consensus and, when necessary, adjudicated by a third reviewer. When multiple publications arose from the same underlying participant sample, the most recent report or the report providing the most complete dataset was retained.

Risk of bias assessment

Methodological quality was assessed using tools appropriate to the study design. Cohort and case-control studies were evaluated using the Newcastle-Ottawa Scale (NOS)[15], which covers three domains across eight items and yields a total score ranging from 0 to 9, with higher scores indicating better quality. Using commonly applied thresholds, scores of 0-3, 4-6, and 7-9 were classified as low, moderate, and high quality, respectively. Cross-sectional studies were assessed using the Agency for Healthcare Research and Quality (AHRQ) checklist[16], which includes 11 items (total score 0-11); scores of 0-3, 4-7, and 8-11 were interpreted as low, moderate, and high quality, respectively. Differences in ratings were resolved by consensus, with third-reviewer adjudication when necessary.

Statistical analysis

All analyses were conducted using Stata (version 14.0; StataCorp, College Station, TX, United States). To characterize the relationship between GERD and FD from complementary perspectives, four meta-analyses were performed.

First, to estimate the association between GERD and FD, adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were extracted from each included study. Between-study heterogeneity was evaluated using Cochran’s Q test and the I² statistic. A fixed-effects model was applied when heterogeneity was limited (P > 0.10 and I² ≤ 50%); otherwise, a random-effects model was used.

Second, for phenotype-specific analyses, data on non-erosive reflux disease (NERD) and erosive reflux disease (ERD) were extracted when reported. ORs with 95%CIs for FD were calculated within each phenotype, and the estimates were compared descriptively.

Third and fourth, to quantify symptom overlap, two single-arm proportion meta-analyses were conducted: (1) The prevalence of FD symptoms among patients with GERD; and (2) The prevalence of GERD symptoms among patients with FD. For each study, the total number of participants and the number reporting the symptom(s) of interest were extracted. Because proportions may exhibit non-constant variance, study-specific proportions were log-transformed before pooling. A random-effects model was applied to the transformed values, and the pooled estimates were then back-transformed to report prevalence (%) with 95%CIs.

To evaluate robustness, leave-one-out sensitivity analyses were performed for association outcomes by iteratively excluding each study and recalculating the pooled effect. Publication bias was assessed visually using funnel plots and tested using Egger’s regression. Potential sources of heterogeneity were explored using prespecified subgroup analyses or meta-regression according to survey source, regional income, sample size, and endoscopic classification.

RESULTS

Literature search

During the literature search, a total of 9623 records were identified from the databases listed above. First, 2420 duplicate records were removed. Second, after screening titles and abstracts, 7057 records were excluded. Subsequently, meta-analyses and systematic reviews were excluded. Finally, 40 studies[17-56] were included in the meta-analysis after excluding studies with irrelevant outcomes, conference abstracts, and studies from which data could not be extracted. The study selection process is shown in Figure 1.

Figure 1 Studies screening process.

Study characteristics

This study aimed to comprehensively evaluate the association between GERD and FD using multiple meta-analyses. In total, 40 studies met the inclusion criteria. These studies provided the data for the subsequent analyses. Of these, 19 studies reported sufficient data to estimate the overall association between GERD and FD (99194 participants); 5 studies reported data on the association between NERD, ERD, and FD (1655 participants); 10 studies reported the prevalence of FD among patients with GERD (2100 participants); and 9 studies reported the prevalence of GERD among patients with FD (2945 participants). The main characteristics of the included studies are summarized in Table 1[17-56].

Table 1 Basic characteristics of the included studies.

Ref.	Countries	Study type	Sample size	Men (%)	Age, mean, median or range	GERD diagnosis criteria	FD diagnosis criteria	Confounders adjusted	Quality scores
Locke et al[17], 2000	United States	Cross-sectional study	643	47.6%	48	Modified BDQ	Modified BDQ	Age, sex, and somatic symptom score	AHRQ scores 8
Noh et al[18], 2010	South Korea	Cross-sectional study	2388/360	44.1%/80.0%	43.2 ± 8.4/43.0	Modified Korean BDQ, Endoscopy	Modified Korean BDQ, Rome III	Age, sex, BMI, SSC, smoking status, alcohol use, marital status, and education	AHRQ scores 8
Fujiwara et al[19], 2011	Japan	Cross-sectional study	2680	65.7%	40.0	Self-report questionnaire, GERD symptoms	Self-report questionnaire, Rome III	Age, sex, BMI, smoking habits, drinking habits	AHRQ scores 7
Choi et al[20], 2013	South Korea	Cross-sectional study	4565/678	51.9%	46.3 ± 10.3	Modified Korean BDQ, endoscopy	Modified Korean BDQ, Rome III	Age, sex, BMI, hiatal hernia, SSC score	AHRQ scores 8
Jarbøl et al[21], 2017	Denmark	Cross-sectional study	47090	47.7%	51.7 ± 15.5	Comprehensive questionnaire-extracted from RIIIAQ, Montreal definition	Comprehensive questionnaire-extracted from RIIIAQ, Rome III	Age and sex	AHRQ scores 9
Lee et al[22], 2009	South Korea	Cross-sectional study	1443	46.6%	48.6	Questionnaire, GERD symptoms	Questionnaire, Rome II	Age	AHRQ scores 7
Nakov et al[23], 2023	Bulgaria	Cross-sectional study	1896	26.9%	35.5 ± 11.7	Questionnaire on general and GI health, modified Montreal definition	Questionnaire on general and GI health, Rome IV	—	AHRQ scores 7
Hu et al[24], 2002	China (Hong Kong)	Cross-sectional study	1649	47.0%	37.9 ± 15.0	Validated bowel symptom questionnaire, GERD symptoms	Validated bowel symptom questionnaire, Rome I	Age, sex, occupation, educational level, frequency and severity of symptoms and the degree of depression score	AHRQ scores 8
Choung et al[25], 2012	United States	Cross-sectional study	3527	48.0%	61 ± 15	Modified BDQ, GERD symptoms	Modified BDQ, Rome III	Age, sex, SSC score, constipation, diarrhea, IBS	AHRQ scores 8
Shaib and El-Serag[26], 2004	15 low- and middle-income countries	Cross-sectional study	5506	41.8%	32.7 ± 14.3	Questionnaire, GERD symptoms	Questionnaire, FD symptoms	-	AHRQ scores 6
Hongo[27], 2011	Japan	Cross-sectional study	Electronic survey (n = 2125); postal survey (n = 11020)	-	-	Questionnaires on GI symptoms, all items were evaluated in 3 to 5 Likert scales, GERD symptoms	Questionnaires on GI symptoms, all items were evaluated in 3 to 5 Likert scales, FD symptoms	-	AHRQ scores 5
Pleyer et al[28], 2014	United States	Cohort study	382	-	-	The international classification of diseases, 2nd edition (HICDA-2) coding system codes	The international classification of diseases, 2nd edition (HICDA-2) coding system codes	Age, sex, calendar year	NOS scores 7
Ohara et al[29], 2011	Japan	Cross-sectional study	1076	44.1%	55.8 ± 3.3	Questionnaire based on symptoms defined according to the Montreal definition, endoscopy	Questionnaire based on symptoms defined according to the Rome III criteria	—	AHRQ scores 7
Chirila et al[30], 2016	Romania	Cross-sectional study	184	42.4%	49.4	Questionnaire, Montreal definition	Questionnaire, Rome III	Age, sex, educational level, smoking status, physical activity level, BMI, perceived stress level, general wellbeing, frequency of other food items	AHRQ scores 8
Jones et al[31], 2022	Australia	Cohort study	1312	51.0%	62 ± 14	A single question as the Montreal definition	Questionnaire, Rome III	Age, sex	NOS scores 6
Caballero-Mateos et al[32], 2023	Spain	Cross-sectional study	338	38.5%	47.9	GERDQ, endoscopy	Rome IV	Age, sex, BMI, alcohol consumption, use of calcium channel blockers, use of inhalers, HADS score	AHRQ scores 8
Fujita et al[33], 2024	Japan	Cross-sectional study	3085	53.5%	48.8 ± 9.1	Questionnaire, endoscopy	Questionnaire, Rome III	Age, sex, BMI, current smoking, alcohol consumption, anxiety (high STAI score), hiatal hernia, FD subtype, frequency of acid reflux symptoms	AHRQ scores 10
Lee et al[34], 2022	South Korea	Cohort study	733	41.3%	52.7 ± 13.1	Korean BDQ, GERDQ, endoscopy	Korean BDQ, GERDQ, Rome III	Age, sex, BMI, smoking, alcohol, marital status, education, HADS score	NOS scores 5
Mochizuki et al[35], 2018	Japan	Cohort study	7552	63.1%	52.4 ± 10.0	Questionnaire, GERD symptoms, endoscopy	Questionnaire, Rome III	Age, sex, BMI, smoking, alcohol consumption, hiatal hernia, atrophic gastritis, Barrett’s mucosa, anxiety (STAI), stress, overlapping FD, LA grade, and medication use	NOS scores 7
Wu et al[36], 2007	China (Hong Kong)	Cross-sectional study	224	46.9%	50.6	Symptom assessment, endoscopy, esophageal manometry, esophageal pH monitoring	Symptom assessment, Rome II	Age, sex, severity of heartburn, disease duration, obesity, smoking, alcohol, FD, IBS, psychological disorders, hiatal hernia, Helicobacter pylori infection, esophageal dysmotility, positive acid perfusion test result, abnormal esophageal pH study	AHRQ scores 9
Lee et al[37], 2015	China (Taiwan)	Cross-sectional study	222	49.6%	46.7	Modified Chinese GERDQ, Montreal definition, endoscopy	Rome III	Age, sex	AHRQ scores 6
Lee et al[38], 2014	China (Taiwan)	Cross-sectional study	171	49.6%	46.7	modified Chinese GERDQ, Montreal definition, endoscopy	Rome III	-	AHRQ scores 5
Saberi-Firoozi et al[39], 2007	Shiraz, southern Iran	Cross-sectional study	304	29.4%	49.9 ± 11.1	Questionnaire, GERD symptoms	-	-	AHRQ scores 6
Locke et al[40], 1997	United States	Cross-sectional study	303	-	25-74	Questionnaire, GERD symptoms	-	Age, sex, PSC score, other atypical symptoms	AHRQ scores 9
Yi et al[41], 2012	China (Taiwan)	Cross-sectional study	210	35.7%	45.9	Questionnaire, GERD symptoms, endoscopy	-	-	AHRQ scores 6
Mwandri et al[42], 2014	Northern Tanzania	Cross-sectional study	92	53%	47.3 ± 17.0	Questionnaire, GERD symptoms, endoscopy	-	-	AHRQ scores 5
Bor et al[43], 2016	Moscow	Cross-sectional study	251	-	-	modified Mayo Clinic GERD questionnaire, GERD symptoms	-	-	AHRQ scores 7
Alsulobi et al[44], 2017	Arar city, Northern Saudi Arabia	Cross-sectional study	186	29.0%	-	Questionnaire, GERD symptoms	-	-	AHRQ scores 4
Savarino et al[45], 2009	Switzerland and Italy	Cross-sectional study	200	47.5%	48	Symptom questionnaire, oesophageal multichannel intraluminal impedance and pH monitoring, endoscopy	-	-	AHRQ scores 7
Sarwar et al[46], 2021	Pakistan	Cross-sectional study	218	0	30	GERDQ, Montreal definition	-	-	AHRQ scores 7
Kitapçioğlu et al[47], 2007	Turkey	Cross-sectional study	126	-	43.7	Reflux questionnaire derived from Locke	-	-	AHRQ scores 8
Nagami et al[48], 2011	Japan	Cross-sectional study	GERD: 210/FD: 378	33.6%	60	Self-reporting type of questionnaire, GERD symptoms, endoscopy	Self-reporting type of questionnaire, Rome III	-	AHRQ scores 5
Bytzer et al[49], 2000	Denmark	Cross-sectional study	217	5%	43	-	Questionnaire on dyspeptic symptoms, Endoscopy	-	AHRQ scores 7
Bolling-Sternevald et al[50], 2002	Denmark and Sweden	Cross-sectional study	404	41%	42.8 ± 14.1	-	GSRS, the Carlsson-Dent Questionnaire, PGWB, Endoscopy, Rome I	Age, sex, GSRS, PGWB, Carlsson-Dent index total score	AHRQ scores 8
Peura et al[51], 2004	United States	Randomized controlled trial	921	37.8%	43	-	A dyspepsia symptom questionnaire, endoscopy, Rome criteria	Age, sex, race, Helicobacter pylori status, baseline endoscopic findings, weight, alcohol use, tobacco use, caffeine use	AHRQ scores 10
Tack et al[52], 2018	Belgium	Cross-sectional study	247	32.8%	44	-	Symptom questionnaire, ambulatory pH monitoring, gastric emptying studies, sensitivity to gastric distention and gastric accommodation, Rome II criteria	Age, sex, BMI, Helicobacter pylori infection status, delayed gastric emptying, hypersensitivity to gastric distention, impaired gastric accommodation	AHRQ scores 7
Xiao et al[53], 2010	China	Cross-sectional study	186	38.7%	39 ± 12	-	Questionnaire based on the Rome III, abdominal ultrasound, endoscopy, Ambulatory 24-hour esophageal-gastric dual pH monitoring	-	AHRQ scores 8
Aro et al[54], 2011	Sweden	Cross-sectional study	157	49%	54	-	Extended ASQ, Rome III, endoscopy	Anxiety, depression, use of proton pump inhibitors, age, sex	AHRQ scores 9
Aro et al[55], 2015	Sweden	Cohort study	110/93	48.1%	53/63.2	-	ASQ, Rome III, esophagogastroduodenoscopy	Age, sex, BMI, smoking, high alcohol consumption, Helicobacter pylori infection, use of NSAIDs and/or aspirin, use of PPIs, anxiety, depression	NOS scores 9
Rahman et al[56], 2021	Bangladesh	Cross-sectional study	232	32.8%	41.1	-	Enhanced Asian Rome III questionnaire, endoscopy, including Helicobacter pylori tests from gastric biopsies	Age, sex, marital status, family income, use of NSAIDs and aspirin, psychological distress, history of acute gastroenteritis, education	AHRQ scores 8

GERD: Gastroesophageal reflux disease; FD: Functional dyspepsia; BDQ: Bowel disease questionnaire; AHRQ: Agency for healthcare research and quality; BMI: Body mass index; SSC: Somatization symptom checklist; IBS: Irritable bowel syndrome; RIIIAQ: ROME III questionnaires; GI: Gastrointestinal; HICDA-2: Hospital international classification of diseases adaptation, second edition; NOS: Newcastle-Ottawa Scale; HADS: Hospital Anxiety and Depression Scale; STAI: State-Trait Anxiety Inventory; GERDQ: Gastroesophageal reflux disease questionnaire; PSC: Psychosomatic symptom checklist; GSRS: Gastrointestinal Symptom Rating Scale; PGWB: Psychological General Well-Being Questionnaire; ASQ: Abdominal Symptom Questionnaire; NSAIDs: Non-steroidal anti-inflammatory drugs; PPIs: Proton pump inhibitors; NSAIDs: Non-steroidal anti-inflammatory drugs.

Risk of bias assessment

After quality assessment using the NOS for cohort and case-control studies and the AHRQ criteria for cross-sectional studies, the mean NOS score across the included studies was 6.8. Similarly, the mean AHRQ score for cross-sectional studies was 7.3. Overall, these scores indicated that the observational studies included in this meta-analysis were of high quality. Table 1 presents the item-level quality ratings and total scores for each study according to the prespecified criteria. The consistently high scores across studies support the robustness and reliability of the synthesized evidence.

Relationship between GERD and FD

Association between GERD and FD: A total of 19 studies were included in the analysis[17-35]. A random-effects meta-analysis showed that the odds of FD among patients with GERD were 4.77 times those in the control group (OR = 4.77, 95%CI: 3.56-6.40, P < 0.001; Figure 2A). Substantial heterogeneity was observed across studies (I² = 96.6%).

Figure 2 Forest plots of the meta-analysis. A: Meta-analysis of the association of gastroesophageal reflux disease (GERD) and functional dyspepsia (FD); B: Meta-analysis of the association of non-erosive reflux disease/erosive reflux disease and FD; C: Meta-analysis of the association of FD symptoms among GERD patients; D: Meta-analysis of the association of GERD symptoms among FD patients. CI: Confidence interval.

Association between NERD/ERD and FD: A pooled analysis of 5 studies examined the relationship between NERD/ERD and FD[18,20,36-38]. The combined results showed that, compared with patients with ERD, those with NERD had significantly higher odds of FD (OR = 4.50, 95%CI: 1.01-20.03, P < 0.001; I² = 97.2%; Figure 2B).

Prevalence of FD symptoms among GERD patients: A total of 10 studies reported the prevalence of FD symptoms among GERD patients[39-48]. A single-arm proportion meta-analysis showed a pooled prevalence of 40% (95%CI: 28.0%-53.0%, P < 0.001; Figure 2C), with substantial heterogeneity (I² = 97.18%).

Prevalence of GERD symptoms among FD patients: A total of 9 studies reported the prevalence of GERD symptoms among FD patients[48-56]. A single-arm proportion meta-analysis showed a pooled prevalence of 41% (95%CI: 26.0%-58.0%, P < 0.001; Figure 2D). Heterogeneity was high (I² = 98.74%).

Subgroup analysis

To further explore the association between GERD and FD and potential effect modifiers, subgroup analyses were conducted for the first meta-analysis (19 studies) according to population, regional income, and sample size.

By population (Figure 3A), community-based populations with GERD had higher odds of FD (OR = 5.17, 95%CI: 3.77-7.08, P < 0.001; I² = 95.8%) than hospital-based populations with GERD (OR = 4.11, 95%CI: 1.99-8.47, P < 0.001; I² = 97.6%). However, the between-group difference was not significant (P = 0.568).

Figure 3 Subgroup analyses of the gastroesophageal reflux disease-functional dyspepsia association. A: Subgroup for population; B: Subgroup for economic-income; C: Subgroup for sample size. CI: Confidence interval.

By regional income (Figure 3B), the pooled OR was 4.85 in high-income regions (95%CI: 3.56-6.60, P < 0.001; I² = 96.2%) and 3.66 in low- and middle-income regions (95%CI: 3.23-4.15, P < 0.001; I² = 0%). Both subgroups showed a significant association between GERD and FD, and the between-group difference was not significant (P = 0.097).

For sample size (Figure 3C), the median sample size (1000 participants) was used as the cutoff, and studies were classified as large (≥ 1000 participants) or small (< 1000 participants). The large-sample subgroup showed higher odds of FD (OR = 5.26, 95%CI: 3.84-7.22, P < 0.001; I² = 97.0%) than the small-sample subgroup (OR = 3.43, 95%CI: 1.73-6.80, P < 0.001; I² = 88.3%); however, the between-group difference was not significant (P = 0.266).

Sensitivity analysis

To assess the influence of individual studies on the pooled estimates, leave-one-out sensitivity analyses were performed for each of the four meta-analyses by sequentially removing one study at a time and re-estimating the summary effect.

The phenotype-stratified associations of NERD/ERD with FD (Figure 4A) and the pooled prevalence of FD symptoms among patients with GERD (Figure 4B) remained stable across iterations; no single study materially changed the direction of the pooled effect. In contrast, the meta-analysis of the association between GERD and FD (Figure 4C) and the pooled prevalence of GERD symptoms among patients with FD (Figure 4D) showed substantial fluctuations in the pooled estimates when certain studies were excluded, suggesting limited stability of these results. Because all studies met the predefined inclusion criteria, and to avoid introducing selective bias through post hoc exclusions, these studies were retained in the final analyses.

Figure 4 Sensitivity analysis for pooled estimates. A: Sensitivity analysis of non-erosive reflux disease/erosive reflux disease and functional dyspepsia (FD); B: Sensitivity analysis of FD symptoms among gastroesophageal reflux disease (GERD) patients; C: Sensitivity analysis of GERD and FD; D: Sensitivity analysis of GERD symptoms among FD patients. CI: Confidence interval.

Publication bias assessment

For the four meta-analyses, publication bias was evaluated using funnel plots for visual inspection and Egger’s regression test for statistical assessment. The four funnel plots (Figure 5) were approximately symmetrical, suggesting that the effect sizes were distributed evenly around the pooled estimate and that there were no obvious signs of publication bias. Consistent with this finding, Egger’s test did not show a statistically significant intercept for any analysis (P = 0.090, 0.362, 0.861, and 0.235, respectively; Figure 6). Taken together, these results do not indicate a material risk of publication bias in this meta-analysis.

Figure 5 Funnel plots for publication bias assessment. A: Funnel plots of gastroesophageal reflux disease (GERD) and functional dyspepsia (FD); B: Funnel plots of non-erosive reflux disease/erosive reflux disease and FD; C: Funnel plots of FD symptoms among GERD patients; D: Funnel plots of GERD symptoms among FD patients. ES: Effect size.

Figure 6 Egger’s regression analyses for publication bias. A: Egger’s regression of gastroesophageal reflux disease (GERD) and functional dyspepsia (FD); B: Egger’s regression of non-erosive reflux disease/erosive reflux disease and FD; C: Egger’s regression of FD symptoms among GERD patients; D: Egger’s regression of GERD symptoms among FD patients. CI: Confidence interval.

DISCUSSION

Main findings

This meta-analysis systematically evaluated the association between GERD and FD across 40 observational studies. The pooled results indicate that GERD and FD frequently co-occur in clinical practice, suggesting a trend toward comorbidity. Overall, patients with GERD had nearly fivefold higher odds of FD than individuals without GERD, and patients with NERD had approximately 4.5-fold higher odds of FD than those with ERD. Approximately 40% of patients with GERD reported FD symptoms, whereas about 41% of patients with FD reported concomitant GERD symptoms. Considered alongside recent clinical evidence[57,58], these findings provide epidemiologic support for a potential role of GERD in the pathogenesis of FD.

Interpretation

Compared with previous meta-analyses that focused solely on comorbidity, this study provides more comprehensive evidence by also evaluating the prevalence of overlapping symptoms. These multidimensional findings are unlikely to be explained entirely by chance or diagnostic bias and instead suggest that GERD and FD may share core pathophysiological mechanisms. From a motility perspective, delayed gastric emptying and impaired fundic accommodation are considered key links between the two disorders. Prior studies have reported that approximately 50% of patients with GERD, FD, or overlap of both have delayed gastric emptying[57,59]. According to the literature[60], impaired fundic relaxation is also common in both patient groups. Abnormal signaling related to gastric distension and a rapid increase in postprandial intragastric pressure can directly provoke FD symptoms (e.g., early satiety and postprandial fullness). It may also increase reflux events by triggering more transient lower esophageal sphincter relaxations[61,62]. At the level of sensory afferents, visceral hypersensitivity may act as a shared symptom amplifier. Central and peripheral sensitization related to brain-gut axis dysfunction can increase the sensitivity of visceral afferent nerves in the esophageal and gastroduodenal regions, leading to physiological reflux to be perceived as pathological heartburn and normal postprandial gastric accommodation to produce early satiety and pain[63]. Overlap between GERD and FD, particularly the PDS subtype, has also been associated with increased duodenal eosinophils[64].

The subgroup analyses revealed several clinically meaningful patterns. First, at the population level, the odds of FD among community-based GERD populations (OR = 5.17) were higher than those among hospital-based GERD populations (OR = 4.11), although the between-group difference was not statistically significant (P = 0.568). This pattern suggests that community-based samples may better capture the full spectrum of GERD, including milder or atypical presentations that may share greater pathophysiological overlap with FD. Notably, in community settings, many individuals with concurrent GERD and FD symptoms do not seek medical care, and this subgroup may contribute to a stronger observed association between GERD and FD.

In contrast, hospital-based samples may overrepresent patients with more typical or severe GERD, in whom the association with FD could be attenuated by coexisting organic lesions or other comorbid conditions. Therefore, from a primary care and public health perspective, early screening and appropriate intervention may be warranted for individuals in the community who report GERD and FD symptoms, even if they do not yet meet criteria for specialist referral, with important clinical and preventive implications.

Second, in the subgroup analysis stratified by regional economic status and geography, studies from both high-income regions and low- and middle-income regions showed a significant positive association between GERD and FD, and the between-group difference was not statistically significant (P = 0.097). This finding suggests that the association between GERD and FD is broadly consistent across levels of economic development, rather than being primarily driven by regional cultural factors or differences in healthcare accessibility. Although the point estimate was higher in high-income regions, this is more likely attributable to non-biological, systemic differences between regions: On the one hand, more developed healthcare systems, higher endoscopy utilization, and greater health awareness in high-income settings can substantially increase the likelihood of identifying and diagnosing comorbidity between the two disorders; on the other hand, differences in dietary patterns (e.g., higher intake of high-fat, high-sugar, and ultra-processed foods), patterns of psychological stress, and medication use (such as non-steroidal anti-inflammatory drugs) may also, to some extent, amplify the comorbid presentation of GERD and FD.

In addition, from a methodological perspective, our analysis showed that studies with larger sample sizes tended to report ORs for FD that were closer to the overall estimate than did smaller studies, suggesting that larger studies may yield more stable and reliable effect estimates.

Importantly, when GERD was categorized endoscopically, the meta-analysis showed that patients with NERD had approximately 4.5-fold higher odds of FD than those with ERD. This finding is particularly important because it supports the hypothesis that NERD and FD share a common functional-disorder substrate involving visceral hypersensitivity, dysregulation of the brain-gut axis, and disordered gastrointestinal motility[65,66]. In contrast, ERD is characterized by overt mucosal injury, and symptoms in these patients may be more strongly driven by acid-related chemical stimulation[67].

Implications and limitations

Compared with previously published meta-analyses, this study differs in that it qualitatively describes the association. It not only determined the pooled prevalence of FD among GERD patients and the pooled prevalence of GERD among FD patients, but also quantitatively compared the odds of FD between patients with NERD and those with ERD, thereby providing more precise epidemiologic evidence to support clinical differentiation and comorbidity management of the two conditions.

The pooled OR in this study was nearly 5, which was significantly lower than that reported in two previous meta-analyses[11,12]. This difference likely reflects substantial variation in diagnostic criteria and in the definitions of the study populations. The literature included in prior analyses largely diagnosed dyspepsia and GERD based on symptoms, without clearly distinguishing organic from functional disease, and included many cases of “uninvestigated dyspepsia”[68,69]. Studies that carried relatively high weights in the pooled analyses may therefore have inflated the overall effect size. In contrast, this study applied stricter inclusion criteria, including only studies with a clear diagnosis of FD or those in which organic diseases were ruled out by endoscopy. By excluding studies with ambiguous or unverified diagnoses, this approach reduced clinical heterogeneity and yielded a more conservative and reliable pooled effect estimate.

The results suggest that clinicians should proactively inquire about and assess symptoms of the other condition when diagnosing and managing either disease. Among patients with GERD who respond poorly to treatment, the possibility of concomitant, unrecognized FD should be considered, and vice versa. This comprehensive assessment may facilitate the development of more thorough and targeted management strategies, thereby potentially improving patient outcomes.

This study also has several limitations. First, heterogeneity across the included studies was high (I² values generally > 95%). Despite careful evaluation, the sources of this heterogeneity could not be identified; it may reflect unmeasured confounders or subtle methodological differences across studies. Second, most studies were cross-sectional, which limits causal inference. Whether GERD - particularly NERD - contributes to FD, or whether other factors account for the sequential or simultaneous occurrence of both conditions, remains to be confirmed in prospective cohort studies. Third, only English-language publications were included, potentially excluding relevant studies published in other languages and introducing language bias. Consequently, the generalizability of the findings may be limited. Fourth, adjustment for potentially important confounders, such as Helicobacter pylori infection status and medication history (particularly proton pump inhibitors and anxiolytics), was inconsistent across studies, which may have influenced the result. To reduce heterogeneity and strengthen the evidence base, future research should prioritize large-scale, prospective, multicenter cohort studies; adopt unified international diagnostic standards; standardize population selection and exclusion criteria; and, where feasible, incorporate objective physiologic assessments, such as endoscopy and esophageal pH monitoring. This would help address the limitation that questionnaire-based, symptom-only diagnoses may not reliably distinguish comorbidity. Future studies should, where feasible, prospectively collect objective measures of psychological status, lifestyle exposures, and relevant biomarkers using validated instruments and standardized assays. This richer set of covariates would support more informative risk-prediction models and provide a firmer basis for evaluating plausible causal pathways.

CONCLUSION

This meta-analysis indicates that GERD and FD are associated to a certain extent. However, a more precise explanation of this relationship requires further research. The findings may inform strategies for the clinical diagnosis and treatment of GERD and FD. Given the substantial heterogeneity observed, rigorously designed prospective studies with standardized diagnostic criteria are warranted to further elucidate the complex relationship between GERD and FD and to support more definitive conclusions.

ACKNOWLEDGEMENTS

Thanks to all the authors for the efforts and good teamwork.