Abstract
Objective
To explore the potential correlation between alterations in gut microbiota and gastroesophageal reflux disease (GERD) among patients.
Methods
A case-control study was conducted, involving 50 patients diagnosed with GERD through esophageal pressure measurement and 24-hour dynamic gastric acid monitoring, as well as 53 symptom-matched controls (SCG). All participants underwent Gastrointestinal Symptom Rating Scale (GSRS), Generalized Anxiety Disorder 7-item scale (GAD-7), and Pittsburgh Sleep Quality Index (PSQI) assessments. Methane (CH4) and hydrogen (H2) breath tests were conducted to collect essential clinical data for both groups. Finally, the relationship between small intestinal bacterial overgrowth (SIBO) and GERD was analyzed using Spearman correlation analysis.
Results
In the GERD group, GSRS, anxiety rate, and PSQI were all increased (p < 0.001). The positive rate of SIBO in the GERD group is significantly higher than that in the SCG group (p < 0.05). The mean expiratory H2 abundance was significantly higher in the GERD group than in the SCG group. SIBO is positively correlated with GERD and GSRS, and positively correlated with sleep quality and anxiety. GERD is positively correlated with GSRS, and positively correlated with sleep quality and anxiety.
Conclusion
The mean expiratory H2 abundance was significantly higher in the GERD group. There may be a potential connection between SIBO and the occurrence of GERD. And SIBO may provide a new perspective on the pathogenesis of GERD.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12876-025-04291-2.
Keywords: Gastroesophageal reflux disease, DeMeester score, Intestinal bacterial overgrowth, GSRS, Anxiety, Sleep quality
Introduction
Gastroesophageal reflux disease (GERD) is a condition caused by the backward flow of stomach contents into the esophagus [1]. Despite long-term use of medications that reduce stomach acid, many patients still experience unpleasant symptoms associated with GERD. The Central American study reported the highest occurrence of GERD symptoms (19.6%) [2], while Asia, specifically Southeast Asia, had the lowest prevalence (10.0%) [3] with even lower rates observed in Southeast Asia (7.4%). The manifestation, diagnosis, and treatment approaches of GERD are influenced by a blend of chemical, mechanical, psychological, and neurological factors [4]. Alternative methods employed in the diagnosis of GERD encompass surveys evaluating symptoms, treatment outcomes, upper gastrointestinal endoscopy, esophageal manometry, and reflux monitoring [5, 6].
The disruption of the body’s homeostasis is significantly influenced by an imbalance in the intestinal flora, and when there is a disturbance in the equilibrium of microorganisms in the human gastrointestinal tract, it can lead to various pathological processes [7]. Small intestinal bacterial overgrowth (SIBO) refers to changes in the quantity, quality, and location of bacteria within the small intestine [8, 9]. In recent times, there has been growing interest in comprehending the overall impact of SIBO on human health as well as its effects on specific bodily systems. The lactulose breath test (LBT) is a non-invasive and convenient method that provides qualitative information about bacterial growth within the small intestine with a certain degree of sensitivity, accuracy, and reproducibility [10].
Henceforth, this study employed DeMeester score and 24-hour pH monitoring for diagnosing GERD, while utilizing methane(H2) hydrogen (CH4) breath test to explore the relationship between GERD and SIBO.
Methods
Participants
From June 1, 2024, to August 30, 2024, we enrolled participants aged 18–80 at the endoscopic center of Xuzhou Medical University Affiliated Hospital who had clinical suspicion of GERD and typical GERD symptoms, such as heartburn and regurgitation. All participants underwent routine esophageal manometry and 24-hour ambulatory pH monitoring.Exclusion criteria included diseases affecting gastrointestinal motility (e.g., achalasia, esophageal spasm), prior gastrointestinal surgeries, malignancies, current use of antibiotics or probiotics, pregnancy, and lactation. After strict age and sex matching, 50 patients were included in the GERD group and 53 in the symptom control group (SCG). The use of acid-suppressing drugs was not an exclusion criterion, but they were discontinued 14 days before pH monitoring (prior to this, 22 patients in the GERD group and 16 in the control group had been taking acid-suppressing drugs). This study investigated the association between the SIBO and GERD. Ethical approval was obtained from the Ethics Committee of Xuzhou Medical University Affiliated Hospital (ID: XYFY2024-KL233-01) on May 17, 2024. The study complied with the principles of the Declaration of Helsinki, and written informed consent was obtained from all participants.
GERD
Participants were categorized according to the DeMeester score acquired from 24-hour pH monitoring [11, 12]. The DeMeester score is a comprehensive metric used to assess acid exposure during extended dynamic pH monitoring. It is commonly employed for classifying patients diagnosed with GERD. Individuals who fall below the threshold of 14.72 for the DeMeester score and have less than 4% acid exposure time are categorized as normal in terms of their acid reflux levels. Conversely, individuals who exceed a DeMeester score of 14.72 and exhibit an acid exposure time equal to or greater than 4% are identified as having GERD.
Methane hydrogen breath test [13] & diagnostic methods for SIBO [14, 15]
To minimize the possibility of false positive results, it is recommended to avoid consuming foods that produce gas, such as dairy products, legumes, artificial sweetened foods and beverages, alcoholic beverages, wheat products, and high-fiber vegetables, within 24 h before the test. However, rice, beef, skinless roasted chicken, eggs, and sugar-free water are allowed. Participants should consume only a small amount of water 12 h before the test. It is important to avoid smoking (including exposure to second-hand smoke), maintain good oral hygiene, stay calm and avoid strenuous activities on the test day. When using the BreathTracker SC (QuinTron) for breath testing, the levels of hydrogen and methane in the breath samples will be measured. The baseline level is determined after standard gas calibration in a fasting state. Participants should consume 10 g of lactulose syrup dissolved in warm water provided by Beijing Hanmei Pharmaceutical Co., Ltd., and undergo a breath test every 30 min for a total duration of 150 min. The hydrogen and methane concentrations at each time point are determined using gas chromatography and recorded. Time-activity curves of hydrogen and methane are generated based on these results. The following criteria are used to diagnose SIBO based on the results of the breath test: (1) If the H2 concentration increases by ≥ 20 ppm from the baseline within 90 min, the SIBO test result is considered positive; and/or (2) If the CH4)concentration exceeds 10 ppm or more 150 min after the breath test, the SIBO test result is considered positive.
Severity of Gastrointestinal symptoms (GSRS)
The severity of gastrointestinal symptoms was quantified using the GSRS [16]. The GSRS is a specialized questionnaire designed to evaluate and track gastrointestinal (GI) symptoms, encompassing different aspects related to the digestive system. It employs a scale ranging from 0 (indicating absence of symptoms) to 6 (representing extremely severe symptoms). The cumulative score for the GSRS is determined by summing up the individual scores of all items, with higher scores indicating more pronounced GI symptom severity. Extensive research has demonstrated that the GSRS exhibits favorable reliability and validity, making it suitable for both clinical practice and scientific investigations in diverse GI disorders. In this research, the GSRS demonstrates a cronbach α coefficient of 0.949.
Anxiety symptoms
The Generalized Anxiety Disorder 7-item scale (GAD-7) was used to assess participants’ anxiety symptoms [17]. Respondents evaluate each statement using a scale from 0 (not present) to 3 (frequent), reflecting their experiences in the past two weeks. The cumulative score of GAD-7 is calculated by adding up individual item scores, ranging from 0 (no sign of anxiety) to 21 (significant display of anxiety). Due to its simplicity and strong psychometric characteristics, the GAD-7 scale is widely utilized in both clinical and research settings. In this research, the GAD-7 demonstrates a cronbach α coefficient of 0.898.
Sleep quality assessment
The participants were requested to fulfill the Pittsburgh Sleep Quality Index (PSQI), a self-assessment tool created by Buysse et al. [18]. This tool assesses the quality of sleep for a duration of one month and provides an overall score as well as scores for seven different aspects. These aspects include personal perception of sleep quality, time taken to fall asleep, duration of sleep, efficiency of sleep, disturbances during sleep, use of sleeping aids, and daytime impairment. Each aspect is rated on a scale from 0 to 3, resulting in a total score ranging from 0 to 21. A higher score indicates lower quality of sleep. Previous studies have demonstrated that a total PSQI score above 5 accurately distinguishes between individuals with good and poor sleep across diverse populations, including older adults [19, 20]. In this research, the PSQI demonstrates a cronbach α coefficient of 0.859.
Statistical analysis
Statistical analysis was performed utilizing SPSS 27.0 software. The data’s normality was assessed through the utilization of the Kolmogorov-Smirnov test. For measurement data conforming to a normal distribution, mean ± standard deviation (x̄ ± s) is used for representation. For non-normal distribution data, median [M(Q25, Q75)] is adopted as the descriptive statistical indicator. Count data are presented in the form of frequency (n) and percentage (%). The t-test is used for comparison of means of continuous variables, while the Mann-Whitney U test is applied for comparison of means of categorical variables. The χ2 test is used for comparison of percentages of categorical variables. Spearman correlation analysis is utilized to analyze correlations. In this study, Cronbach’s α coefficient is adopted as the assessment index to evaluate the internal consistency of the measurement scale. A p-value < 0.05 indicates statistical significance.
Results
General clinical data
The research involved a total of 103 participants, with 50 individuals in the GERD group and 53 in the SCG group. The general clinical characteristics of both groups are presented in Table 1. There were no significant disparities observed in terms of gender, age, and BMI between the two groups. However, notable variations were found regarding GSRS scores, anxiety levels, and sleep quality (p < 0.001 for all) when comparing the two groups.
Table 1.
Comparison of general clinical data between the GERD group and the SCG group
| Item | GERD(50) | SCG (53) | χ2/t | p |
|---|---|---|---|---|
| Gender, male (%) | 22(44.00%) | 27(50.94%) | 0.497 | 0.481 |
| Age, year | 47.38 ± 17.00 | 44.85 ± 18.36 | −0.713 | 0.477 |
| BMI | 22.59 ± 4.62 | 23.41 ± 3.38 | 1.033 | 0.304 |
| GSRS | 38.00(31.00, 48.00) | 22.00(18.00, 24.00) | −8.272 | < 0.001 |
| Anxiety | 34(68.00%) | 5(9.43%) | 37.509 | < 0.001 |
| Sleep quality | 13.36 ± 6.47 | 9.05 ± 6.38 | −3.397 | < 0.001 |
Results of methane hydrogen breath test
Table 2 shows that the positive rate of SIBO in the GERD group is significantly higher than that in the SCG group (p < 0.05). The mean expiratory H2 abundance (Fig. 1A) was significantly higher in the experimental group than in the SCG group; however, the mean expiratory CH4 abundance (Fig. 1B) was not higher in the GERD group.
Table 2.
The rate of SIBO positive, pure hydrogen-positive, pure methane-positive, and hydrogen-methane positive between the GERD group and the SCG group
| SIBO | H2 | CH4 | |
|---|---|---|---|
| GERD | 32(64.00%) | 28(56.00%) | 18(36.00%) |
| SCG | 23(43.39%) | 17(32.08%) | 11(20.75%) |
| χ2 | 4.389 | 5.986 | 2.956 |
| p | 0.036 | 0.014 | 0.086 |
Fig. 1.
The time-abundance curve for hydrogen and methane. A The time-abundance curve for H2; B The time-abundance curve for CH4
Analysis of the correlation between SIBO and clinical data
The results of the correlation analysis can be observed in Table 3, indicating a potential positive association between SIBO and GERD as well as GSRS. However, the correlation coefficient between SIBO and GERD is 0.300, indicating a small effect. There is a positive relationship between SIBO and both sleep quality and anxiety. Similarly, GERD exhibits a potential positive correlation with GSRS and displays potential positive associations with sleep quality and anxiety.
Table 3.
Correlation analysis of SIBO and clinical data
| Factor 1 | Factor 2 | r | p |
|---|---|---|---|
| SIBO | GERD | 0.300 | 0.002 |
| SIBO | GSRS | 0.423 | < 0.001 |
| SIBO | Sleep quality | 0.257 | 0.009 |
| SIBO | Anixty | 0.203 | 0.040 |
| GERD | GSRS | 0.650 | < 0.001 |
| GERD | Sleep quality | 0.246 | 0.012 |
| GERD | Anixty | 0.603 | < 0.001 |
Discussion
The microbial composition of the human gastrointestinal tract is pivotal in determining health outcomes and disease susceptibility [21]. In this study, we investigated whether there were changes in the small intestinal microbiota of GERD patients. GERD is believed to result from excessive gastric acid secretion [22], and therefore, acid-suppressing medications are commonly used to alleviate symptoms by inhibiting gastric acid production [23]. However, it has been observed that the incidence of GERD increases with age despite a decrease in gastric acid secretion [24], suggesting that gastric acid secretion cannot account for all the causes of GERD. When food is not easily digested due to various factors, it can promote colonic fermentation, thereby impacting the function of the lower esophageal sphincter (LES) in GERD [25]. That is to say, the dysfunction of the LES may also serve as a significant etiology for GERD [26]. When food is not easily digested due to various factors, it can promote colonic fermentation, thereby impacting the function of the LES in GERD [27]. LES dysfunction can lead to the backflow of stomach contents and result in symptoms of gastroesophageal reflux. The alteration of bacterial microbiota in the small intestine plays a pivotal role in hindering proper digestion [28]. Consequently, changes in the bacterial microbiota within the small intestine may subsequently influence GERD development.
In this study, the GSRS, anxiety rate, PSQI, and SIBO positive scores of patients in the GERD group were found to be significantly higher compared to those in the SCG group. This suggests that GERD has a profound impact on patients’ quality of life and contributes to the development of intestinal bacterial overgrowth. Similar studies have also reported an increased likelihood of comorbid conditions such as feeding difficulties, sleep problems, and excessive crying among infants with GERD [29]. When SIBO occurs, abnormal bacteria in the small intestine metabolize carbohydrates, resulting in the production of H2, CH4, and carbon dioxide. These gases are then passively diffused into the pulmonary capillaries for excretion. However, our research found that only the increase in H2 content has a potential connection with SIBO. Therefore, emphasis should be placed on evaluating H2 levels to assess the occurrence of GERD. It is worth noting that the elevated incidence of SIBO associated with hydrogen may be attributed to excessive hydrogen production within the gut environment. In our experimental line chart, we observed higher levels of exhaled H2 in the experimental group compared to the SCG group, which indicates that the composition of bacteria in the small intestine of GERD patients has become disordered.
Furthermore, the presence of SIBO leads to disturbances in both the gut microbiota and Intestinal epithelial cells (IECs), consequently affecting the individual’s ability to absorb carbohydrates, proteins, and lipids [30]. Moreover, this condition exacerbates nutrient competition as a result of the bacterial population [31]. SIBO is positively correlated with both GERD and GSRS, and also has a positive correlation with patients’ anxiety and sleep quality, suggesting that SIBO may have a potential connection with the occurrence of GERD and has an impact on patients’ general health status.
The exploration of small intestinal bacteria’s characteristics has been limited in previous research, which predominantly concentrated on utilizing sequencing techniques to evaluate the attributes of gut microbiota. In this study, the methane and hydrogen breath test were utilized to assess the small intestinal flora of patients with GERD, while analyzing the correlation between SIBO occurrence and GERD in both methane and hydrogen breath tests. The aim was to investigate the association between GERD and intestinal bacteria, providing insights into studying the specific mechanisms underlying GERD and intestinal bacteria metabolism. One advantage of this study lies in the use of patients with positive symptoms but negative physiological tests as controls. This design can effectively distinguish functional symptoms from pathological reflux. Additionally, previous research has been relatively limited in exploring the simple bacterial characteristics of the intestine, mainly focusing on using sequencing techniques to assess the features of the intestinal microbiota. In this study, CH4 and H2 breath tests were used to evaluate the small intestinal flora in GERD patients, providing new insights into the specific mechanisms of GERD and intestinal bacterial metabolism.
However, this study has some limitations. First, the sample of this study was derived from hospital patients, which may limit the generalizability of the research results. Compared with the general community population, the hospital sample may have systematic differences in terms of age structure, gender distribution, educational background, and socioeconomic status. Additionally, as a study conducted in a regional tertiary hospital, the clinical record characteristics of the included subjects (such as disease severity and medical-seeking behavior) may further affect the representativeness of the sample. To minimize such biases, the research team implemented standardized calibration procedures during the data collection stage and selected control participants through strict matching criteria to enhance comparability between groups. Second, the sample size of this study was relatively small and the recruitment of GERD patients was geographically limited. The differences in their dietary and lifestyle habits may have affected the experimental results. However, this study controlled for known confounding factors (such as gender/age) through methods such as matching the control group. Therefore, for regions with similar lifestyles, the study’s explanation of the relationship between SIBO occurrence and GERD still has significant reference value. Moreover, the control group for GERD consisted of patients with GERD symptoms, and their esophageal pH monitoring results showed no pathological reflux. Therefore, they were merely symptom control groups. Thus, symptom control groups can control for known symptom covariates, but this also avoids the potential issue of negative control groups being too strict in their inclusion criteria and thus being less representative of real clinical scenarios. Finally, the exclusion criteria in this study were relatively numerous, making the research sample targeted and reducing the general applicability of the research results. Future studies will validate our findings in a broader population. Additionally, although a 14-day drug withdrawal period may partially eliminate the influence of PPIs, the residual effects of long-term medication use should be interpreted with caution.
In brief, this study aimed to explore the association between GERD and gut microbiota by comparing the incidence of SIBO in individuals with GERD versus those without. The research results show that individuals diagnosed with GERD exhibit higher GSRS, anxiety, sleep disorders, and a higher positive rate of SIBO. These findings suggest that intestinal bacteria may be involved in the development process of GERD. Specifically, SIBO can lead to elevated H2 levels, which may have a potential connection with the occurrence of GERD. However, this requires further validation through large-sample longitudinal studies in the future. Therefore, considering SIBO as a potential factor in the study of the pathogenesis of GERD may provide new insights into the treatment of this disease.
Supplementary Information
Acknowledgements
We extend our heartfelt appreciation to all the individuals who participated in this research. Additionally, we would like to acknowledge Xuzhou Medical University Affiliated Hospital for their effective management of this study.
Authors’ contributions
Study conception and design was performed by Xunlei Pang and Yanhong Wang, Material preparation, data collection, and analysis were performed by Zhiwei Hu, Baodong Shan, Yizhou Wang, Jun Yang and Lili Lu. The manuscript was written by Zhiwei Hu and Baodong Shan. The writing, review, and editing was performed by Xunlei Pang and Yanhong Wang. All authors read and approved the final manuscript.
Funding
This work was supported by the Key Development Project of Science and Technology Bureau in Xuzhou (Social development) [grant number KC22233], the Project supported by the Affiliated Hospital of Xuzhou Medical University [grant number 2023ZL19], Postgraduate Research & Practice Innovation Program of Jiangsu Province [grant number KYCX25_3282], Paired Assistance Scientifc Research Project by The Affiliated Hospital of Xuzhou Medical University [grant number SHJDBF2024203] and The guiding science and technology project of Suqian [grant number Z2024060].
Data availability
Data is provided within the manuscript or supplementary information files.
Declarations
Ethics approval and consent to participate
Approval for this study was granted by the Ethics Committee of Xuzhou Medical University Affiliated Hospital (ID: XYFY2024-KL233-01) on May 17th in the year 2024. The study adhered to the principles outlined in the Helsinki Declaration with informed consent obtained from all participants.
Consent for publication
The research paper has received unanimous agreement from all authors for publication.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Zhiwei Hu and Baodong Shan contributed equally to this work.
Contributor Information
Yanhong Wang, Email: 316987724@qq.com.
Xunlei Pang, Email: pangxunlei@163.com.
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Supplementary Materials
Data Availability Statement
Data is provided within the manuscript or supplementary information files.