Goyal MK, Goyal O, Wander P, Kaur J, Prashar G, Goyal P, Sood A. Anxiety and depression in Rome IV disorders of gut–brain interaction: Prevalence, clinical impact, and temporal association. World J Psychiatry 2026; 16(8): 119686 [DOI: 10.5498/wjp.119686]
Corresponding Author of This Article
Omesh Goyal, Department of Gastroenterology, Dayanand Medical College and Hospital, Tagore Nagar, Ludhiana 141001, Punjab, India. goyalomesh@yahoo.co.in
Research Domain of This Article
Psychiatry
Article-Type of This Article
research-article
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
Share the Article
Goyal MK, Goyal O, Wander P, Kaur J, Prashar G, Goyal P, Sood A. Anxiety and depression in Rome IV disorders of gut–brain interaction: Prevalence, clinical impact, and temporal association. World J Psychiatry 2026; 16(8): 119686 [DOI: 10.5498/wjp.119686]
Manjeet Kumar Goyal, Department of Internal Medicine, Cleveland Clinic Akron General Hospital, Akron, OH 44308, United States
Omesh Goyal, Jaskirat Kaur, Gargi Prashar, Ajit Sood, Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana 141001, Punjab, India
Praneet Wander, Division of Gastroenterology, St Mary’s Hospital, Trinity Health Of New England, Waterbury, CT 06708, United States
Prerna Goyal, Department of Medicine, R.G. Stone Super Speciality Hospital, Ludhiana 141001, Punjab, India
Co-first authors: Manjeet Kumar Goyal and Omesh Goyal
Author contributions: Goyal MK and Goyal O provided equal contributions as detailed below, meriting co-first authorship; Goyal MK, Goyal O and Sood A conceptualized the study; Goyal MK, Goyal O and Goyal P designed the methodology; Wander P, Goyal P, and Prashar G performed literature search; Goyal O, Goyal MK, Kaur J and Prashar G contributed to patient enrollment; Goyal MK, Prashar G, Kaur J, and Goyal P performed the investigation and statistical analysis; Goyal MK, Wander P, Prashar G and Kaur J generated the visualization of data and writing of the original manuscript draft; All authors performed editing of the subsequent versions of the manuscript; Goyal O, Mehta V, and Sood A provided the study supervision and data validation; All authors read and approved the final version of the manuscript.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Dayanand Medical College and Hospital, Ludhiana, No. 2018-394.
Informed consent statement: Informed consent was obtained.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Data sharing statement: Data technical appendix, statistical code, and dataset available from the corresponding author upon reasonable request.
Corresponding author: Omesh Goyal, Department of Gastroenterology, Dayanand Medical College and Hospital, Tagore Nagar, Ludhiana 141001, Punjab, India. goyalomesh@yahoo.co.in
Received: February 3, 2026 Revised: March 9, 2026 Accepted: April 8, 2026 Published online: August 19, 2026 Processing time: 177 Days and 16.8 Hours
Abstract
BACKGROUND
Patients with disorders of gut-brain interaction (DGBIs) frequently report co-existing anxiety and depression; yet data on the prevalence, clinical impact and temporal association of psychological comorbidities across the full spectrum of DGBIs, particularly regarding overlap syndromes, remain limited.
AIM
To evaluate the prevalence and temporal relationship of anxiety and depression among DGBIs, and assess the impact of overlapping DGBIs.
METHODS
In this prospective cross-sectional study conducted at a tertiary care centre in northern India, adults fulfilling Rome IV criteria for DGBIs were enrolled and compared with age- and sex-matched controls. Anxiety and depression were assessed using validated Generalized Anxiety Disorder 7-item and Patient Health Questionnaire 9-item depression scales, and health-related quality-of-life using the Patient-Reported Outcomes Measurement Information Systems (PROMIS) global questionnaire.
RESULTS
Among 1044 patients with DGBIs, anxiety and depression were present in 64.2% and 37.8%, respectively; being significantly higher in patients with overlapping DGBIs compared with single DGBI (81.2% vs 52.8%; and 51.3% vs 28.7%, respectively; both P < 0.0001). Health-related quality-of-life was significantly worse among DGBI patients, particularly those with overlap syndromes. In temporal analyses, gastrointestinal symptoms preceded the onset of anxiety in 71.0% and depression in 78.5% patients (P < 0.0001), with DGBI overlap being the strongest predictor of anxiety and depression.
CONCLUSION
DGBIs are associated with a substantial psychological burden, especially in patients with overlapping syndromes. Gastrointestinal symptom onset commonly antedates psychological distress, supporting a clinically relevant ‘gut-first’ trajectory. Early recognition and effective management of DGBIs may therefore play a role in mitigating subsequent psychological morbidity, underscoring the need for integrated management.
Core Tip: Psychological comorbidities are highly prevalent in disorders of gut-brain interaction (DGBIs), particularly among patients with overlapping syndromes. In this large Rome IV-based cohort, anxiety and depression affected nearly two-thirds and one-third of patients, respectively, with substantially worse quality of life in overlap DGBIs. Notably, gastrointestinal symptoms preceded the onset of anxiety and depression in most cases, supporting a predominant gut-to-brain trajectory. These findings emphasize the need for early identification and proactive management of DGBIs, alongside integrated gut-brain care strategies, to potentially mitigate subsequent psychological morbidity.
Citation: Goyal MK, Goyal O, Wander P, Kaur J, Prashar G, Goyal P, Sood A. Anxiety and depression in Rome IV disorders of gut–brain interaction: Prevalence, clinical impact, and temporal association. World J Psychiatry 2026; 16(8): 119686
Disorders of gut-brain interaction (DGBIs) are a group of chronic gastrointestinal (GI) conditions where symptoms arise due to a complex interplay between multiple factors, such as motility disturbances, visceral hypersensitivity, altered mucosal and immune homeostasis, gut dysbiosis, altered central neural regulation, etc., in the absence of organic disease[1-3]. DGBIs affect nearly 40% of individuals worldwide, with irritable bowel syndrome (IBS), functional dyspepsia (FD), and functional constipation (FC) being the most prevalent[4,5]. DGBI patients frequently report the presence of psychological comorbidities (anxiety, depression, etc.) and significant impact on health-related quality of life (HRQoL), which leads to increased healthcare burden, work absenteeism and reduced productivity[6]. Despite the significant prevalence of DGBIs and psychological comorbidities, there is a scarcity of epidemiological data from certain parts of the world, especially South-East Asia, where distinctive diets, microbiome composition, psychosocial stressors, and healthcare access disparities may influence both the manifestation and management of DGBIs differently from Western populations[7,8].
A growing body of research highlights a strong, bidirectional link between DGBIs and psychological comorbidities, particularly anxiety and depression. Patients with DGBIs are significantly more likely to experience psychological distress, with estimates suggesting 30%-40% of individuals with IBS and FD meet criteria for either anxiety or depression[9-13]. Given the stigma surrounding mental health, variations in help-seeking behaviour, and cultural attitudes toward somatic vs psychiatric symptoms, the prevalence of psychological comorbidity in DGBI patients may differ significantly from region to region[14,15].
The gut-brain axis, a complex communication network involving the Central Nervous System, enteric nervous system, immune responses, and gut microbiota, plays a crucial role in the manifestation of both gastrointestinal and psychiatric symptoms[16]. Dysregulation of stress pathways, alterations in serotonin metabolism, autonomic dysfunction, and gut microbial imbalance have been implicated in this shared pathology. Yet, despite these well-established associations, there are limited comprehensive studies examining the psychiatric burden across different DGBI subtypes using the Rome IV criteria[17,18].
Overlap of multiple DGBIs has been reported in 30% to 80% of patients[19-22]. Emerging data have shown that patients with overlapping DGBIs experience higher rates of anxiety and depression than those with a single DGBI diagnosis[10,19,23,24]. Understanding whether psychological comorbidities differ between overlapping and non-overlapping DGBI cases could improve risk stratification, guide early intervention strategies, and enlighten targeted treatment approaches, such as the use of gut-directed psychotherapy, neuromodulators, and microbiota-based therapies.
Another major gap in current knowledge is the temporal sequence of the development of DGBIs and psychological comorbidities. Do anxiety and/or depression predispose individuals to develop a DGBI, or do chronic gut symptoms lead to the development of a psychological disorder secondarily? Prospective studies exploring this relationship are scarce. A telephone-survey-based study tried to assess the temporal relation between anxiety and FD, and found mixed results[25]. There is a lack of data assessing the temporal relationship between the development of the whole spectrum of Rome IV DGBIs and psychological disorders. This distinction is more than academic; it carries profound clinical implications. If psychological comorbidities precede DGBI onset, early mental health intervention could serve as a preventive strategy. Conversely, if DGBI symptoms drive psychological comorbidity, then timely and optimal gastrointestinal symptom control may prevent the development of psychological disorders. Without clear data on this aspect, clinicians currently lack the necessary insights to tailor biopsychosocial treatment approaches to their patients.
Beyond disorder-specific associations, growing evidence suggests that gastrointestinal symptom burden frequently co-occurs with a range of central neuropsychiatric dimensions, including mood disturbances, anxiety, attentional dysregulation, sleep disturbances, and altered stress responsivity, across multiple diagnostic categories. These observations support a broader transdiagnostic gut-brain axis framework, in which bidirectional interactions between the central nervous system, enteric nervous system, immune pathways, and gut microbiota influence both gastrointestinal and psychological symptom expression. Recent studies have further demonstrated associations between neurodevelopmental and psychiatric conditions and gastrointestinal symptom severity; for example, adults with attention-deficit/hyperactivity disorder have been shown to exhibit significantly greater IBS symptom severity compared with healthy controls, with symptom intensities correlating across domains[26].
This study aims to fill these crucial gaps by (1) Determining the prevalence of anxiety and depression across different DGBI subtypes using Rome IV criteria; (2) Comparing psychological comorbidities between overlapping and non-overlapping DGBI subgroups; and (3) Investigating the temporal relationship between the onset of DGBIs and psychological comorbidities. These data might refine our understanding of DGBI-psychological interactions and help to shape evidence-based care.
MATERIALS AND METHODS
Study design and setting
This observational study was conducted over a period of six months at an academic tertiary care centre in northern India. Institutional Ethics Committee approval and informed consent from participants were obtained before the start of the study and enrollment into the study, respectively.
Study population
The study cohort comprised adults (18 years to 70 years), satisfying criteria for at least one disorder of gut-brain interaction as per Rome IV criteria. Patients were recruited during routine outpatient visits, and the diagnosis of DGBI was established through the administration of the “Rome IV Diagnostic Questionnaire for Adults”. Individuals with a history of organic gastrointestinal diseases, including inflammatory bowel disease, celiac disease, peptic ulcer disease, and prior gastrointestinal surgery, etc. were excluded. Additionally, those presenting with alarm features like anemia, dysphagia, gastrointestinal bleeding, unintended weight loss exceeding 10% in three months, nocturnal symptoms, or a family history of gastrointestinal malignancies were also excluded. Other exclusion criteria included the presence of malignancy, advanced systemic comorbidities, pregnancy, history of substance abuse, or food allergies/intolerances.
To provide a comparative reference, attendants of patients visiting the hospital with no or minimal gastrointestinal symptoms (defined as abdominal discomfort occurring less than two days per month and altered bowel movements in less than 25% of total defecations) were taken as controls. They were also required to have no or well-controlled comorbidities and no history of substance abuse. This approach ensured a representative baseline population for comparison with DGBI patients, who often have associated comorbid conditions. This strategy also allowed recruitment of individuals from the same catchment population and healthcare environment as the cases, thereby reducing potential differences in socio-demographic background, healthcare access, and environmental exposures. Anxiety and depression in controls were assessed using the same validated instruments [Generalized Anxiety Disorder 7-item (GAD-7) and Patient Health Questionnaire 9-item depression (PHQ-9)] administered to the DGBI cohort.
Study outline
To ensure diagnostic accuracy and rule out organic diseases, all study participants and controls were required to have normal baseline investigations performed within the past 6 months, including hemogram, fasting blood glucose, serum creatinine, alanine transaminase, and thyroid-stimulating hormone levels. For individuals with diabetes, glycated haemoglobin levels were assessed to confirm a well-controlled status.
Data collection instruments
The “Rome IV Diagnostic Questionnaire for Adults” was used to analyze the presence of DGBIs. The questionnaire in both English and Hindi versions were utilized to ensure inclusivity. Social, demographic, medical history, comorbidities, history of gastrointestinal infections, food habits, and addictions were all recorded using a 65-item questionnaire. This questionnaire also included the following scales: (1) Anxiety and depression were evaluated using GAD-7 and PHQ-9, respectively[27,28]; and (2) HRQoL was assessed using Patient-Reported Outcomes Measurement Information Systems (PROMIS) Global-10 questionnaire[29].
Data collection procedure
Participants were screened using the inclusion and exclusion criteria during visits to the outpatient department. After obtaining written informed consent, trained personnel (blinded from the study) administered the diagnostic questionnaires, ensuring that participants understood the items and clarifying any uncertainties to minimize missing data. Questionnaires were reviewed for completeness and accuracy before being finalized for analysis. To further minimize bias, trained personnel conducted interviews in a standardized manner, ensuring consistency across all participants. The collected data were systematically entered into a pre-designed database for statistical analysis.
Assessment of the temporal relationship between gastrointestinal and psychological symptoms
To evaluate the temporal relationship between DGBI symptoms and psychological comorbidities, participants with anxiety and/or depression were asked during the structured interview to recall the approximate onset of their gastrointestinal symptoms and psychological symptoms. Based on patient-reported chronology, cases were categorized as gut-first when gastrointestinal symptoms preceded psychological symptoms, brain-first when anxiety or depressive symptoms occurred before gastrointestinal symptoms, and concurrent onset when both symptom groups were reported to have begun within the same general time period. Participants who were unable to provide a reasonably clear estimate of symptom chronology were excluded from the temporal sequencing analysis to minimize potential misclassification.
Definition of overlap across DGBI regions
DGBIs were categorized according to the Rome IV anatomical classification into six major groups: Esophageal disorders, gastroduodenal disorders, bowel disorders, centrally mediated disorders of gastrointestinal pain, gallbladder and sphincter of Oddi disorders, and anorectal disorders. Individual participants could meet diagnostic criteria for more than one DGBI. Overlap was defined as the presence of two or more DGBI diagnoses involving different anatomical regions. For the purpose of regional overlap analysis, multiple diagnoses within the same anatomical region were counted as a single regional category. The number of regions involved per patient was therefore determined by the distinct Rome IV anatomical categories represented.
Outcomes
The primary objective was to determine the prevalence of anxiety and depression among patients with DGBIs. The secondary objectives were to (1) Compare the prevalence of these psychological comorbidities between overlapping and non-overlapping DGBI groups; and (2) Assess the temporal relationship between the onset of psychological comorbidities and DGBIs (categorizing whether anxiety/depression preceded, followed, or occurred concurrently with gastrointestinal symptoms).
Statistical analysis
Categorical variables were expressed as proportions, while continuous variables were presented as means with standard deviations if normally distributed or as medians with interquartile ranges if non-normally distributed. Between-group comparisons were performed using the χ2 test or Fisher’s exact test for categorical variables and independent t-tests or Mann-Whitney U tests for continuous variables, depending on distribution characteristics. To determine whether overlapping DGBIs were independently associated with psychological comorbidities, multivariate logistic regression analyses were performed with depression and anxiety as separate dependent variables. Variables included in the models were selected based on clinical relevance and univariate analysis and included age, sex, disease duration, overlap status, and the presence of major Rome IV DGBI categories. Adjusted odds ratios (aORs) with 95% confidence interval (CI) were reported.
To explore the temporal association between anxiety, depression, and the onset of DGBI symptoms, a histogram was considered, assessing whether psychological comorbidities preceded or followed the development of gastrointestinal symptoms. Data analysis was performed using SPSS software version 21 (Chicago, IL, United States). Statistical significance was set at a P-value of less than 0.05. This study adhered to ethical guidelines, including the principles of the Declaration of Helsinki and Good Clinical Practice and STROBE guidelines. Confidentiality of participant data was ensured through anonymization and secure data storage.
RESULTS
DGBIs were diagnosed in 1079 of the 2538 individuals who visited the outpatient department throughout the study period. Of them, 1044 (41.1%) DGBI patients were included for additional study after 35 patients were eliminated. Of 1021 controls who were matched for age and gender were enrolled. Table 1 compares the clinical and demographic characteristics of the patients and controls. The age distribution was comparable between the groups, with most participants aged 31-50 years. Females comprised 48.1% of the DGBI cohort. Among DGBI patients, 40.7% were overweight, and 19.9% were obese. Symptom duration exceeded two years in 42% of the patients. Comorbidities such as diabetes and hypertension were similar across groups.
Table 1 Baseline characteristics of patients with disorders of gut-brain interaction and controls, n (%).
The prevalence of anxiety (671; 64.2%) and depression (395; 37.8%) among DGBI patients was significantly higher compared to the prevalence of anxiety (47; 4.6%) and depression (26; 2.5%) among controls (P < 0.001). The median scores of the GAD-7 and PHQ-9 questionnaires among major DGBI subgroups, and among common DGBIs, are shown in Figure 1. A comparison of patients with and without anxiety is depicted in Table 2. Compared with patients without anxiety, those with anxiety demonstrated a higher proportion of female gender, lower body mass index, longer duration of symptoms, presence of overlapping DGBIs, higher prevalence of co-existing depression, and lower physical and mental HRQoL scores (Table 2). Similar trends were observed when comparing the characteristics of DGBI patients with or without depression (Table 3). Furthermore, the HRQoL physical and mental scores were markedly lower in the DGBI patients (physical 13.8 ± 3.4; mental 13.2 ± 3.8) compared with controls (physical 19.5 ± 0.3; mental 19.4 ± 0.4).
Figure 1 Box and whisker plots.
A: Comparison of Generalized Anxiety Disorder 7-item scale between overlapping and non-overlapping disorder of gut-brain interactions (DGBI) groups; B: Comparison of the Patient Health Questionnaire 9-item between overlapping and non-overlapping DGBI groups; C: Comparison of Generalized Anxiety Disorder 7-item scale between overlapping and non-overlapping individual DGBIs; D: Comparison of the Patient Health Questionnaire 9-item between overlapping and non-overlapping individual DGBIs. GAD-7: Generalized Anxiety Disorder 7-item; PHQ-9: Patient Health Questionnaire 9-item; DGBI: Disorder of gut-brain interaction; FC: Functional constipation; FD: Functional dyspepsia; FEsD: Functional esophageal disorders; IBS: Irritable bowel syndrome; GD: Gastroduodenal; AD: Anorectal disorder.
Table 2 Comparison of clinical characteristics of “disorders of gut-brain interaction” patient groups with and without anxiety.
Effect of DGBI overlap on psychological comorbidities
Overlapping DGBIs were present in 421 (40.3%) of the patients, while the rest were diagnosed with a single DGBI. The proportion of individual DGBIs and their overlap patterns are depicted in Figure 2. Patients with overlapping DGBIs reported a substantially higher prevalence of anxiety and depression, compared to those with a single DGBI (81.2% vs 52.8%; and 51.3% vs 28.7%, respectively; P < 0.0001) (Table 4). This pattern was consistent across the three major subgroups, i.e. esophageal disorders, gastroduodenal disorders, and bowel disorders. Furthermore, patients with overlapping FD, IBS, or FC had significantly higher prevalence of anxiety compared to those with non-overlapping disorders; while depression was significantly more frequent in overlapping FD, and non-significantly higher in overlapping IBS and FC (Table 5). Furthermore, there was a marked prevalence of anxiety and depression in common overlap conditions (Supplementary Table 1).
Figure 2 Venn diagrams.
A: Venn diagrams illustrating the overlap of specific disorders of gut-brain interaction; B: Venn diagrams illustrating the overlap of specific disorders of gut-brain interaction. FC: Functional constipation; FD: Functional dyspepsia; FEsD: Functional esophageal disorders; IBS: Irritable bowel syndrome; FDD: Functional defecation disorder.
Table 4 Prevalence of psychological comorbidities in various “disorders of gut-brain interaction” subgroups with stratification according to overlap status, n (%).
DGBI groups
Anxiety prevalence
Depression prevalence
All patients
Patients with a single DGBI
Patients with overlapping DGBIs
P value (single vs overlapping DGBIs)
All patients
Patients with a single DGBI
Patients with overlapping DGBIs
P value (single vs overlapping DGBIs)
All DGBIs
671/1044 (64.2)
329/623 (52.8)
342/421 (81.2)
0.0001
395/1044 (37.8)
179/623 (28.7)
216/421 (51.3)
0.0001
Esophageal Disorders (n = 348)
248/348 (71.2)
79/143 (55.2)
169/205 (82.4)
0.0001
138/348 (39.6)
35/143 (24.5)
103/205 (50.2)
0.0001
Gastroduodenal disorders (n = 521)
362/521 (69.5)
85/177 (32.8)
8277/344 (80.5)
0.0001
227/521 (43.6)
49/177 (27.7)
178/344 (51.7)
0.0001
Bowel disorders (n = 415)
273/415 (65.8)
122/221 (55.2)
151/194 (78.4)
0.0001
173/415 (41.7)
72/221 (32.6)
101/194 (52.6)
0.0001
Centrally mediated disorders of gastrointestinal pain (n = 48)
36/48 (75)
15/24 (62.5)
21/24 (87.5)
0.0933
23/48 (47.9)
8/24 (33.3)
15/24 (62.5)
0.0820
Gall bladder and sphincter of Oddi disorders (n = 14)
Table 5 Prevalence of psychological comorbidities in functional dyspepsia, irritable bowel syndrome and functional constipation patients with stratification according to overlap status1.
Beyond overall prevalence, we evaluated the distribution of symptom severity using established PHQ-9 and GAD-7 cut-offs. Among the 1044 patients with DGBIs, depression severity based on PHQ-9 scores was categorized as absent in 649 patients (62.2%), mild in 354 (33.9%), moderate in 32 (3.1%), and moderately severe in 10 (1.0%) (Table 6 and Figure 3A). Similarly, anxiety severity based on GAD-7 scores was absent in 373 patients (35.7%), mild in 546 (52.3%), moderate in 83 (8.0%), and severe in 32 (3.1%) (Figure 3B).
Figure 3 Distribution of depression severity and anxiety severity.
A: Distribution of depression severity in the study cohort. Pie chart illustrating the distribution of depression severity assessed using the Patient Health Questionnaire-9. Categories represent absent, mild, moderate, and moderately severe depression, based on the standard Patient Health Questionnaire-9 score thresholds. Values indicate the number of patients in each severity category; B: Distribution of anxiety severity in the study cohort. Pie chart illustrating the distribution of anxiety severity assessed using the Generalized Anxiety Disorder-7 scale. Categories represent absent, mild, moderate, and severe anxiety based on standard Generalized Anxiety Disorder-7 score thresholds. Values indicate the number of patients in each severity category.
Table 6 Distribution of anxiety and depression severity among patients with single vs overlapping disorders of gut-brain interaction.
Predictors of factors associated with depression and anxiety
In univariate analyses, male sex was associated with lower odds of both depression and anxiety, whereas longer disease duration and the presence of overlapping DGBIs were associated with higher odds of psychological symptoms (Table 7). In multivariable logistic regression analyses, overlap of DGBIs remained independently associated with both depression and anxiety after adjustment for age, sex, disease duration, and DGBI subtype. Patients with overlapping DGBIs had significantly higher odds of depression (aOR = 2.37, 95%CI: 1.20-4.68, P = 0.013) and anxiety (aOR = 3.21, 95%CI: 1.59-6.49, P = 0.001) compared with those with a single DGBI. Male sex remained independently associated with lower odds of depression (aOR = 0.43, 95%CI: 0.32-0.58, P < 0.001) and anxiety (aOR = 0.41, 95%CI: 0.30-0.56, P < 0.001), while longer disease duration was associated with increased odds of both outcomes.
Table 7 Univariate and multivariate logistic regression analysis of factors associated with depression and anxiety in patients with disorders of gut-brain interactions.
Temporal association between DGBIs and psychological comorbidities
In a comprehensive evaluation of the temporal association between DGBIs and psychological comorbidities, distinct patterns emerged. Among the 671 patients with anxiety, 477 (71.0%) reported that DGBI symptoms preceded the onset of anxiety, 98 (14.6%) experienced anxiety prior to developing gastrointestinal symptoms, and 96 (14.3%) noted a simultaneous onset of both conditions (Figure 4A). A χ2 analysis confirmed that these differences in temporal sequence were highly significant (P < 0.0001), indicating that, in the majority of cases, the onset of DGBI appears to act as a precipitating factor for the development of anxiety. A parallel analysis of depression in this cohort further reinforced the significance of the temporal relationship between DGBI and psychological distress. Of the 395 patients with depression, 310 (78.5%) reported that DGBI symptoms occurred before the emergence of depressive symptoms, 35 (8.9%) indicated that depression preceded DGBI, and 50 (12.7%) experienced both conditions concurrently (Figure 4B). The distribution of these three categories was also statistically significant (P < 0.0001).
Figure 4 Temporal sequencing of disorder of gut-brain interaction and psychological comorbidity.
A: Difference between duration of disorder of gut-brain interaction and anxiety symptoms; negative values indicate gut-first onset, positive values indicate anxiety-first onset, and zero indicates concurrent onset; B: Difference between duration of disorder of gut-brain interaction and depressive symptoms using the same convention, demonstrating a predominance of gut-first sequencing. DGBI: Disorder of gut-brain interaction.
DISCUSSION
The present cross-sectional study evaluated the prevalence, temporal association, and clinical impact of psychological comorbidities in DGBI patients. Among the cohort of 1044 patients, anxiety and depression were diagnosed in 64.3% and 37.8% of patients, respectively. Notably, patients with overlapping DGBIs (presence of ≥ 1 DGBI) had a higher prevalence of anxiety and depression compared to those with a single DGBI. Furthermore, in a novel temporal analysis, more than two-thirds of patients with anxiety and/or depression reported that the onset of gastrointestinal symptoms preceded the development of psychological symptoms, implying a predominantly gut-to-brain sequence.
The prevalence rates for anxiety and depression among DGBI patients have varied considerably across the globe due to multiple factors such as the geographical distribution, type of DGBI studied (most data are on IBS and FD only), the criteria for diagnosis of DGBI (Rome III vs Rome IV), criteria for anxiety/depression diagnosis, etc.[30-32]. A meta-analysis by Zamani et al[31] reported a pooled prevalence of anxiety and depression of 39.1% and 28.8%, respectively, in IBS patients. Another meta-analysis by Ghoshal et al[12] reported approximately 8-fold higher odds of anxiety and 7-fold higher odds of depression in comparison to controls in Indian IBS patients. A recent study in a Vietnamese IBS cohort reported 55.9% anxiety and 40.8% depression[33,34]. Importantly, this psychological burden is not limited to IBS alone. FD patients report similar patterns. A meta-analysis of FD found pooled anxiety and depression rates of roughly 29%-32%[35]. One Indian study of FD found that over half the FD patients had significant anxiety or depression[36]. Only a few studies have evaluated the prevalence of anxiety and depression across all DGBI subtypes. A recent Rome Foundation global study in Australia found that among adults with any DGBI, 26.6% met the criteria for anxiety and 28.96% for depression[37]. Our study observed higher rates of anxiety and depression, possibly due to the tertiary-care setting, and the use of sensitive diagnostic scales (GAD-7/PHQ-9).
Overlaps of two or more DGBIs have been reported among 30% to 80% of the DGBI patients[4,20,24,38]. DGBI overlap has been found to drive worse outcomes[21,37,39]. In a multi-country internet survey, the number of affected gastrointestinal regions was linearly associated with higher anxiety and depression scores (P < 0.0001)[19]. Overlap syndromes in particular carry the greatest burden: A Korean psychiatric clinic study showed DGBI overlap patients had the highest anxiety, depression, and somatization scores of any DGBI subgroup[40]. Thus, our finding that overlapping DGBIs yield worse psychological outcomes is consistent with global evidence that multiple gut-brain disorders amplify anxiety, depression and somatization[4,21].
Only a few large studies have evaluated the temporal relationship between the onset of gut symptoms and psychological comorbidities. Prospective work by Koloski et al[39] found that in the community, roughly two-thirds of IBS or FD patients reported gastrointestinal symptoms first, with only one-third reporting mood disorder onset first[41]. A large UK biobank study even found that baseline constipation was linked to approximately 50% higher risk of developing depression later, consistent with gut dysfunction contributing to later mood changes[42]. Our study is probably the first to evaluate the temporal relationship between psychological comorbidities and DGBIs diagnosed by Rome IV criteria in an Asian population. Our cross-sectional data indicate a predominance of gut-to-brain direction, with most of the patients reporting the onset of psychological comorbidity after the onset of DGBI.
Taken together, these data suggest that DGBI symptoms frequently precede psychological distress in patient-reported chronology; however, the cross-sectional design prevents the determination of causal directionality. Our results highlight the potential importance of early identification of gastrointestinal symptoms in attenuating subsequent psychological burden. Overall, these findings reinforce the view that DGBIs are complex, multifactorial disorders with substantial phenotypic overlap and tightly interwoven associations with anxiety and depression. Across heterogeneous populations and healthcare settings, the existing literature consistently indicates that psychological distress is not only highly prevalent among individuals with DGBIs but also clinically relevant to symptom severity and disease impact.
At a mechanistic level, our findings and the literature point to common pathways linking gut and psycho-somatic symptoms. Chronic visceral pain and discomfort in IBS/FD engage stress axes, leading to sustained sympathetic output and hypothalamic-pituitary-adrenal activation[43]. This, in turn, perpetuates intestinal hyperpermeability, mucosal immune activation, and eosinophil and mast cell degranulation in the gut wall, which can sensitise afferent nerves and elicit pain[44-46]. Concurrently, stress-related neurotransmitter imbalances (e.g., elevated norepinephrine, altered GABA/glutamate ratios) support anxiety and mood symptoms[47,48]. The gut microbiota adds another dimension: Dysbiosis associated with DGBIs can promote systemic inflammation and alter tryptophan metabolism, reducing central serotonin availability[45]. Indeed, the fact that modulating the microbiome can impact both gut and brain outcomes is illustrated by studies using dietary modification, probiotics or fecal microbiota transplant in patients with DGBIs[49,50]. For example, in an IBS trial, patients whose bowel symptoms improved after fecal microbiota transplantation also showed significant reductions in depressive scores, whereas placebo recipients did not[50]. Thus, it may be plausible that targeted microbiome therapies might simultaneously benefit gastrointestinal and psychological dimensions of DGBIs.
Our study has several strengths. Firstly, we enrolled a relatively large cohort of patients (n = 1044) and used a standardized Rome-IV diagnostic questionnaire across diverse DGBI subtypes. Secondly, we assessed both overlapping and single DGBI syndromes, which adds depth beyond IBS/FD-only analyses. Thirdly, our novel temporal analysis of DGBI-psychological comorbidity offers unique insight into gut-brain interplay, supporting the hypothesis that gastrointestinal dysfunction may act as an initiating factor for subsequent psychological distress in a substantial proportion of patients. However, certain limitations merit consideration. Its cross-sectional design cannot definitively prove causality or exact temporal sequence; recall bias may affect patients’ reporting of symptom chronology. Our sample was drawn from tertiary gastrointestinal clinics and likely enriched for complex cases, limiting generalizability to community settings. Additionally, cultural factors or stigma might have influenced the reporting of anxiety/depression. Nevertheless, given consistency with other Indian and global findings, these results appear robust. Future prospective cohort studies enrolling individuals with newly diagnosed Rome IV DGBIs and longitudinally tracking gastrointestinal symptoms and psychological status would allow more precise characterization of symptom trajectories and clarify whether a gut-first or brain-first pathway predominates.
The present findings also have practical implications for routine clinical care. Given the high prevalence of anxiety and depression observed in patients with DGBIs, particularly those with overlapping syndromes, a structured, stepwise approach to psychological assessment may be beneficial in clinical practice. First, routine screening for anxiety and depressive symptoms using validated instruments such as the GAD-7 and PHQ-9 may be considered for all patients meeting Rome IV criteria for DGBIs during initial clinical evaluation. Second, clinicians should maintain a heightened index of suspicion for psychological comorbidities in patients with overlapping DGBIs, who appear to represent a higher-risk subgroup with greater disease burden and poorer quality of life. Third, patients demonstrating moderate to severe psychological distress, persistent symptoms despite optimized gastrointestinal therapy, or significant impairment in quality of life may benefit from early referral for psychological or behavioural interventions, including gut-directed psychotherapy or multidisciplinary care. Such an integrated gut–brain approach may facilitate more comprehensive management of DGBIs and potentially mitigate downstream psychological morbidity.
CONCLUSION
In summary, DGBI patients in our tertiary care cohort had a very high prevalence of anxiety and depression, particularly among those with overlapping syndromes, reinforcing the fact that the disorders of gut-brain interaction profoundly affect mental health. Importantly, our data indicate that gastrointestinal symptoms often antedate psychological comorbidities in patient-reported timelines. However, this observation should be interpreted cautiously, as the cross-sectional design and reliance on retrospective recall preclude establishing whether gastrointestinal dysfunction causally contributes to the development of anxiety or depression. Future work should prospectively track DGBI and psychological comorbidities over time to confirm this temporal relationship. Mechanistic studies evaluating gut microbiome and/or visceral hypersensitivity could explore how gut pathology leads to the development of a psychological illness. Clinically, our findings underscore the need for screening for anxiety and depression in all DGBI patients - especially those with overlapping disorders - and for addressing gastrointestinal symptoms promptly to possibly prevent the development of a psychological morbidity. Holistic management of DGBIs will therefore require integrated care approaches that attend to both gut and brain.
Sperber AD, Bangdiwala SI, Drossman DA, Ghoshal UC, Simren M, Tack J, Whitehead WE, Dumitrascu DL, Fang X, Fukudo S, Kellow J, Okeke E, Quigley EMM, Schmulson M, Whorwell P, Archampong T, Adibi P, Andresen V, Benninga MA, Bonaz B, Bor S, Fernandez LB, Choi SC, Corazziari ES, Francisconi C, Hani A, Lazebnik L, Lee YY, Mulak A, Rahman MM, Santos J, Setshedi M, Syam AF, Vanner S, Wong RK, Lopez-Colombo A, Costa V, Dickman R, Kanazawa M, Keshteli AH, Khatun R, Maleki I, Poitras P, Pratap N, Stefanyuk O, Thomson S, Zeevenhooven J, Palsson OS. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study.Gastroenterology. 2021;160:99-114.e3.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 1768][Cited by in RCA: 1519][Article Influence: 303.8][Reference Citation Analysis (13)]
Sperber AD, Dumitrascu D, Fukudo S, Gerson C, Ghoshal UC, Gwee KA, Hungin APS, Kang JY, Minhu C, Schmulson M, Bolotin A, Friger M, Freud T, Whitehead W. The global prevalence of IBS in adults remains elusive due to the heterogeneity of studies: a Rome Foundation working team literature review.Gut. 2017;66:1075-1082.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 416][Cited by in RCA: 387][Article Influence: 43.0][Reference Citation Analysis (0)]
Knowles SR, Skvarc D, Ford AC, Palsson OS, Bangdiwala SI, Sperber AD, Mikocka-Walus A. Negative Impact of Disorders of Gut-Brain Interaction on Health-Related Quality of Life: Results From the Rome Foundation Global Epidemiology Survey.Gastroenterology. 2023;164:655-668.e10.
[RCA] [PubMed] [DOI] [Full Text][Cited by in RCA: 39][Reference Citation Analysis (0)]
Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems.Ann Gastroenterol. 2015;28:203-209.
[PubMed] [DOI]
Sperber AD, Freud T, Aziz I, Palsson OS, Drossman DA, Dumitrascu DL, Fang X, Fukudo S, Ghoshal UC, Kellow J, Khatun R, Okeke E, Quigley EMM, Schmulson M, Simren M, Tack J, Whitehead WE, Whorwell P, Bangdiwala SI. Greater Overlap of Rome IV Disorders of Gut-Brain Interactions Leads to Increased Disease Severity and Poorer Quality of Life.Clin Gastroenterol Hepatol. 2022;20:e945-e956.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 78][Cited by in RCA: 93][Article Influence: 23.3][Reference Citation Analysis (0)]
Gwee KA, Lee YY, Suzuki H, Ghoshal UC, Holtmann G, Bai T, Barbara G, Chen MH, Chua ASB, Gibson PR, Hou X, Liu J, Nakajima A, Pratap N, Sachdeva S, Siah KTH, Soh AYS, Sugano K, Tack J, Tan VPY, Tang X, Walker M, Wu DC, Xiao YL, Zulkifli KK, Toh C. Asia-Pacific guidelines for managing functional dyspepsia overlapping with other gastrointestinal symptoms.J Gastroenterol Hepatol. 2023;38:197-209.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 21][Cited by in RCA: 29][Article Influence: 9.7][Reference Citation Analysis (0)]
Goyal O, Goyal MK, Gupta A, Bharadwaj A, Mehta A, Kumar P, Goyal P, Sood A. Prevalence and predictors of nonceliac wheat sensitivity in refractory irritable bowel syndrome and functional dyspepsia: results from a randomized double-blind placebo-controlled study.Eur J Gastroenterol Hepatol. 2025;37:1238-1248.
[RCA] [PubMed] [DOI] [Full Text][Cited by in RCA: 4][Reference Citation Analysis (0)]
