Functional Dyspepsia: An Updated Review of Pathophysiology,Epidemiology,Clinical Manifestations,and International Management Guidelines

Abstract

Background

Functional dyspepsia (FD) is a prevalent yet challenging gastrointestinal disorder described as a group of upper gastrointestinal symptoms such as epigastric pain or burning, bloating, belching among many others, in the absence of an identifiable organic etiology. Its diagnosis is established according to the Rome IV criteria, which define the disorder by bothersome postprandial fullness, early satiety, epigastric pain and/or epigastric burning present for the last 3 months, with symptom onset at least 6 months before diagnosis. Despite its benign nature, functional dyspepsia can considerably affect patients’ quality of life and constitutes a significant burden on healthcare systems worldwide, as it is estimated to affect over 20% of the population. FD can be subdivided into the three following subtypes - postprandial distress syndrome (PDS), epigastric pain syndrome (EPS) and a constellation of both - based on symptoms’ pattern.

Objectives

This article provides a comprehensive overview of the epidemiology, pathophysiology, subtypes, clinical presentation as well as management strategies of functional dyspepsia. Understanding these aspects is crucial for improving diagnosis and applying effective treatment strategies for patients with functional dyspepsia.

Design

Narrative literature-based review.

Methods

We conducted a search of PubMed/MEDLINE, Embase, and Google Scholar for publications from January 2010 to March 2025, including clinical studies, reviews, and international guidelines related to functional dyspepsia.

Results

The pathophysiology of functional dyspepsia remains poorly understood, largely due to its multifactorial nature. Several factors at both the macroscopic and microscopic level have been implicated in the pathogenesis of this disorder such as altered gastrointestinal motility, impaired barrier function, altered gut-brain axis, inflammation as well as psychological factors. Several clinical guidelines, both European and American, have been developed to guide the diagnosis of functional dyspepsia and its management with the primary goal of symptom control.

Conclusion

Functional dyspepsia remains a complex disorder due its diverse clinical features and multifactorial etiology. A patient-centered approach and management based on recent guidlines are essential for effective management of this condition.

Keywords

functional dyspepsia postprandial distress epigastric pain rome IV

1. Introduction

Functional dyspepsia (FD) is a common gastrointestinal disorder characterized by persistent or recurrent epigastric pain and/or burning, postprandial fullness and early satiety in the absence of structural disease that explains the symptoms. It is classified as a disorder of gut-brain interaction, reflecting the complex interplay between the central nervous system processing and gastrointestinal function. A structured framework for diagnosing FD is established by the Rome IV criteria, supporting a positive symptom-based diagnosis strategy following relevant clinical evaluation to rule out structural disease.¹

The pathophysiology of FD is multifactorial and incompletely understood. Proposed mechanisms include psychosocial factors, altered gastric motility, low-grade inflammation and visceral hypersensitivity.²

FD considerably impairs patients’ quality of life, and is associated with increased healthcare utilization and economic burden. Studies have demonstrated that individuals with FD suffer from impairments in physical, mental and social aspects of their lives, highlighting the importance of effective management strategies.³

A systematic diagnostic approach is necessary to differentiate FD from other gastrointestinal disorders and to guide management. Various management strategies are available, ranging from lifestyle modifications and pharmacologic therapies to psychological interventions.^4,5 However, international guidelines provide differing recommendations for the treatment of FD. This comprehensive review aims to synthesize current evidence on FD, including its pathophysiology, epidemiology, clinical manifestations, diagnostic approaches and management strategies, with a focus on comparing international guidelines and emerging therapeutic options.

Specifically, this review will compare the treatment recommendations for functional dyspepsia between the North American guidelines published by the American College of Gastroenterology and the Canadian Association of Gastroenterology (ACG/CAG) in 2017,⁴ and the European guidelines developed by the United European Gastroenterology and the European Society for Neurogastroenterology and Motility (UEG/ESNM) in 2019.⁵

2. Methods

This review was conducted as a narrative literature-based review with a structured search approach to guarantee that all relevant literature is covered. A systematic search was performed using PubMed/MEDLINE, Embase, and Google Scholar databases to ensure a comprehensive search for all relevant literature published in English from January 2000 to March 2025. The search terms used included combinations of “functional dyspepsia,” “Rome IV criteria,” “epigastric pain syndrome,” “postprandial distress syndrome,” “pathophysiology,” “diagnosis,” “management,” and “clinical guidelines.” In addition, the reference lists of prominent articles and guidelines were also reviewed to identify further relevant studies.

Eligible publications included randomized controlled trials, meta-analyses, systematic and narrative reviews, observational studies, and international consensus on the epidemiology, pathophysiology, clinical expression, and management of FD. Older landmark studies were also incorporated when necessary for foundational or “historical” information. Non-peer-reviewed publications were referenced selectively when they presented authoritative, editor-reviewed, or regulatory information on functional dyspepsia.

Clinical practice guidelines were considered for comparative review based on their rigor, recency, and global clinical significance. The guidelines adopted for this study include the American College of Gastroenterology/Canadian Association of Gastroenterology (ACG/CAG) guidelines of 2017 and the consensus guidelines by the United European Gastroenterology/European Society for Neurogastroenterology and Motility (UEG/ESNM). These guidelines were chosen due to their comprehensiveness and acceptance as the most widely adopted guidelines from North America and Europe, respectively. They were devised using expert consensus and systemic evidence, based on different healthcare systems and clinical priorities, which makes them suitable for comparative analysis.

3. Pathophysiology

Functional dyspepsia (FD), a chronic condition involving dysregulation of the gut-brain axis, is characterized by recurrent epigastric pain, postprandial fullness, and early satiety without the presence of structural disease that can explain the symptoms. FD is now widely considered as a heterogeneous neuroimmune-sensorimotor disorder, rather than a single disease entity, that results from complex bidirectional interactions between gastrointestinal motor dysfunction, mucosal immune activation, epithelial barrier impairment, altered microbiota composition, visceral hypersensitivity, and dysregulated central nervous system processing. None of these mechanisms act independently, but rather interact dynamically through neural, hormonal and immunologic pathways, contributing to the pronounced heterogeneity in symptom presentation and treatment response across patients.⁶

Among the peripheral gastrointestinal mechanisms, impaired gastric accommodation and delayed gastric emptying are among the most reproducible abnormalities identified in FD. A major contributor to early satiety and postprandial fullness that is strongly associated with the postprandial distress syndrome (PDS) subtype of FD is impaired gastric accommodation, or failure of the proximal stomach to appropriately relax after meal ingestion.⁷ Delayed gastric emptying has also been reported in a subset of patients and may be a contributing factor in nausea and postprandial discomfort, although correlations between gastric emptying rates and symptom severity have remained inconsistent.⁸ Current evidence suggests that impaired accommodation may be of greater pathophysiologic relevance than delayed emptying. These motor abnormalities likely reflect altered enteric neuromuscular signalling, defective vagal regulation, abnormal gastric pacemaker activity and impaired antropyloroduodenal coordination. Notably, motor dysfunction is rarely an isolated finding and is often seen in conjunction with visceral hypersensitivity and central nervous system dysregulation.⁷

Visceral hypersensitivity is another important mechanism in FD, especially in epigastric pain syndrome (EPS) subtype. FD patients exhibit exaggerated sensory responses to physiologic gastric distension, acid exposure and duodenal stimuli. Balloon distension studies by Tack et al. (2011) have shown that pain thresholds are reduced in patients with FD, indicating altered visceral sensory processing beyond localized gastric dysfunction.⁹ This hypersensitivity is a result of sensitization of peripheral afferent neurons and central amplification of nociceptive signaling pathways. Neuroimmune interactions appear to play a crucial role in this process, as activated eosinophils and mast cells release inflammatory mediators such as histamine, tryptase, prostaglandins, and cytokines that sensitize submucosal nerve fibers and increase neuronal excitability. Recent evidence additionally indicates that dysfunction of the duodenal epithelial barrier allows increased antigen and luminal exposure to the mucosal immune system, thus perpetuating low-grade inflammation and neural sensitization.¹⁰

Growing evidence suggests that altered central pain processing is a core component of the pathogenesis of FD, rather than solely a secondary psychological phenomenon. Functional neuroimaging studies have shown increased activation in areas related to pain perception, emotional regulation, and salience processing, including the anterior cingulate cortex, insular cortex, amygdala, and prefrontal cortex.¹¹ Dysregulation of central autonomic networks may contribute to increased stress responsiveness, increased sympathetic tone, and facilitation of visceral pain signaling. Anxiety, depression, somatization and early-life stress are highly prevalent in FD patients and may influence gastric motility, sensory processing and symptom severity via activation of the hypothalamic–pituitary–adrenal (HPA) axis and autonomic dysfunction.¹² These findings are consistent with the hypothesis that central nervous system abnormalities are likely to be both causative and perpetuating mechanisms in FD.

There is also increasing evidence implicating duodenal immune activation and impaired mucosal integrity as important contributors to the pathogenesis of FD. Histologic studies have consistently shown increased eosinophil and mast-cell infiltration of the duodenal mucosa of FD patients compared with healthy controls.¹³ In a recent systematic review and meta-analysis, duodenal eosinophils and mast cells were significantly increased in patients with FD, but there was considerable heterogeneity among the studies. Duodenal eosinophilia is among the most reproducible histopathologic findings in FD among the mechanisms currently proposed.¹⁰; however, prominent inter-study heterogeneity persists, and its precise causal role remains uncertain. Activated immune cells secrete cytokines and inflammatory mediators that can disrupt epithelial tight junctions, increase mucosal permeability and sensitize enteric neurons. This process results in visceral hypersensitivity and altered gastroduodenal motility. These anomalies are particularly striking in post-infectious FD and lend support to the hypothesis that prior infectious or environmental insults may initiate chronic neuroimmune dysregulation in susceptible individuals.¹⁴

Alterations in the intestinal microbiota may also play a role in FD by modulating immune homeostasis, epithelial permeability, and gut–brain signaling pathways. Microbial diversity has been shown to be reduced and the abundance of pro-inflammatory bacterial species increased in several studies of FD patients.¹⁵ In contrast, as compared with impaired gastric accommodation and duodenal immune activation, evidence for microbiota-related mechanisms is less consistent and causality has not yet been firmly established. Nevertheless, microbiota changes could partly explain the significant mechanistic overlap between FD and other disorders of gut–brain interaction, especially irritable bowel syndrome (IBS). Both disorders are characterized by abnormalities of visceral hypersensitivity, epithelial barrier dysfunction, mucosal immune activation, altered central pain processing and psychosocial co-morbidity, which may explain their frequent clinical coexistence.¹⁶

Importantly, these proposed mechanisms should not be seen as isolated abnormalities, but rather as interconnected components of a multidimensional gut-brain disorder. Increasing evidence supports a model in which environmental triggers, psychosocial stressors, altered composition of microbiota and mucosal immune activation interact bidirectionally with gastric sensorimotor dysfunction and central pain modulation. This integrated approach may contribute, at least in part, to the remarkable heterogeneity of FD, the overlap between PDS and EPS, and the variable therapeutic responses observed in clinical practice. It also possibly implies why symptom-based subclassification alone may not be sufficient to represent the underlying pathophysiology in many patients.

However, despite the important advances in the understanding of FD pathophysiology, many of the proposed mechanisms are supported primarily by observational studies, experimental models and neuroimaging data with relatively small sample sizes. Considerable heterogeneity among studies still exists and no validated biomarkers are available to reliably stratify patients according to dominant pathophysiological mechanisms. Thus, the exact causal relationships between these mechanisms continue to be the subject of active investigation.

4. Subtypes of FD

Dyspepsia is broadly classified into two primary categories: organic dyspepsia and functional dyspepsia, a distinction that guides both the diagnostic process and therapeutic management. Organic dyspepsia refers to cases in which the patient’s symptoms can be explained by a structural or biochemical abnormality. Peptic ulcer disease, gastroesophageal reflux disease (GERD), malignancies, and biliary disorders, are all common etiologies of organic dyspepsia.¹⁷ The prevalence of organic dyspepsia increases with age and is more frequent in individuals with alarming features such as weight loss, gastrointestinal bleeding, anemia, or dysphagia.¹⁷ These organic causes are typically identified by endoscopic evaluation especially in high-risk patients.

In contrast, FD is a Rome IV–defined disorder diagnosed according to specific symptom-based criteria. Rome IV defines FD by the presence of bothersome postprandial fullness, early satiety, epigastric pain, or epigastric burning, for at least 3 months, with symptom onset at least 6 months before diagnosis, in the absence of structural disease to explain the symptoms. Although exclusion of structural pathology through appropriate evaluation - often including upper gastrointestinal endoscopy in selected patients - remains necessary, FD should not be viewed solely as a diagnosis of exclusion, but rather a positive clinical diagnosis based on characteristic symptom patterns. This condition is considered a disorder of gut-brain interaction, with a multifactorial pathophysiology that encompasses factors such as abnormal gastric motility, increased visceral sensitivity, Helicobacter pylori infection, psychological influences, and impaired gastric accommodation.¹⁸

Functional dyspepsia frequently overlaps with other disorders of gut–brain interaction, particularly irritable bowel syndrome (IBS), and this overlap has important diagnostic and therapeutic implications. Epidemiological studies show that a substantial proportion of patients with FD, up to 40–50% in some cohorts, also meet Rome criteria for IBS, suggesting shared pathophysiological mechanisms rather than coincidental coexistence. Both conditions are associated with visceral hypersensitivity, altered gastrointestinal motility, dysregulation of the gut–brain axis, psychosocial comorbidity, and low-grade immune activation. Patients with overlapping FD–IBS tend to report more severe symptoms, greater psychological distress, and significantly impaired quality of life compared with those with either disorder alone. Clinically, this overlap challenges symptom-based classification and may explain suboptimal responses to single-mechanism therapies. As a result, management strategies should adopt a holistic, patient-centered approach that targets common underlying mechanisms, such as neuromodulation, dietary interventions, and psychological therapies, rather than treating FD and IBS as entirely separate entities.

FD is further subdivided into two major clinical subtypes based on the predominant symptom pattern: postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). PDS is characterized by bothersome postprandial fullness and/or early satiety occurring at least 3 days per week, whereas EPS is defined by bothersome epigastric pain and/or epigastric burning occurring at least 1 day per week.¹⁸

The division of functional dyspepsia based on symptoms has offered benefits not only in research but also in clinical aspects by choosing patient groups for targeted management. Oustamanolakis and Tack (2012) addressed the practical limitations of these subtypes.¹⁷ The classification into PDS and EPS has improved the treatment since it is symptom-oriented. Nevertheless, an important proportion of patients experience intersection between features in both types. Studies report that up to half of individuals with functional dyspepsia meet diagnostic criteria for both PDS and EPS, complicating the application of rigid subclassifications.¹⁷ Impaired gastric accommodation and visceral hypersensitivity often coexist in a single patient regardless of their symptom-based label. This underscores the complexity of functional dyspepsia’s clinical presentation.

It is important clinically to distinguish between organic and functional dyspepsia since it influences both prognosis and therapeutic decisions. Talley and Ford (2015)⁶ pointed out that management strategies for dyspepsia differ fundamentally depending on its classification. Direct treatment at the underlying etiology is required for organic dyspepsia — for instance, H. pylori eradication therapy for peptic ulcer disease, proton pump inhibitors for acid-related conditions, or surgical and oncological interventions for malignancies. In contrast, a multifaceted approach is typically required for functional dyspepsia while addressing both physiological and psychosocial factors. Prokinetics, acid suppressants, and antidepressants are usually used as pharmacologic treatment. On the other hand, dietary modifications, psychological therapies, and reassurance are non-pharmacological interventions.⁶

It is crucial when evaluating a patient with dyspepsia to eliminate any underlying organic disease. For example, patients with warning signs such as anemia, unexplained weight loss, evidence of gastrointestinal bleeding, or older age require prompt endoscopic examination.

5. Epidemiology and Risk Factors

The recognition of factors associated with FD contributes to enhanced clinical awareness and more effective management of FD, in addition to minimizing unnecessary treatment.¹⁹

Most epidemiological data on FD are derived from observational or cross-sectional studies. Consequently, stated associations should be interpreted cautiously, as they may be influenced by confounding variables and that they do not establish causality.

Several demographic and clinical factors have been associated with FD including older age, female sex, low body mass index (BMI), Helicobacter pylori infection, aspirin or nonsteroidal anti-inflammatory drugs use, and lower levels of education.¹⁹ These risk factors however may not be generalized to the population due to the stratification of the studies depending on cohort characteristics.¹⁹

For instance, in a study done by Kim et al. (2018),¹⁹ the risk factors of FD were studied and stratified in tertiary centers in Korea. It was found that the prevalence of functional dyspepsia (FD) in a Korean health check-up population is 10.3%, with the postprandial distress syndrome (PDS) subtype being more common (7.3%) than the epigastric pain syndrome (EPS) subtype (5.5%).¹⁹

When stratified according to age, the occurrence of FD was slightly greater in individuals aged 60 and over (11.3%) compared to those under 60 (9.9%).

When stratified according to sex, FD was more prevalent in women (12.4%) than men (7.8%).¹⁹

Low education was identified as a specific risk factor in men, whereas female sex was associated with FD in older adults.¹⁹

FD affects between 7% and 45% of people globally depending on the population.²⁰ A study done by Huang et al. (2020)²⁰ highlights certain diets and lifestyle choices found to be associated with FD.²⁰ Participants who regularly consumed spicy, hot, raw, or cold foods, as well as dairy products, were found to have an increased incidence of functional dyspepsia.²⁰ An association has also been observed with tea consumption.²⁰ The study further demonstrated a significant association between sleep disturbances and FD, potentially attributable to the upregulation of proinflammatory cytokines.²⁰ Furthermore, individuals with FD exhibited higher levels of psychological stress, anxiety, and depression.²⁰ These findings highlight the multifactorial aspect of FD.²⁰

Such associations are largely based on self-reported data on lifestyle factors and may also represent a bidirectional relationship in which the presence of dyspeptic symptoms also affects dietary habits, sleep patterns and psychological well-being.

As explained in an article written by Caballero-Mateos et al. (2022) FD was found to have multiple risk factors.²¹ FD occurs more frequently in older age groups, women, and a higher BMI.²¹ Moreover, psychological factors like anxiety and depression were more prevalent in individuals with FD as opposed to controls.²¹

Shi et al. (2022) used the Functional Dyspepsia Symptom Diary (FDSD) and the Dyspepsia Symptom Severity Index (DSSI) to show that patients with overlapping gastrointestinal disorders, such as IBD and GERD, documented more severe dyspepsic symptoms than those with only FD.²² This particularly highlights the importance of identifying subsets to target patient management and increase quality of life.

This finding likely refers to the differences in symptom burden and health-care seeking behavior rather than risk factor for FD itself.

In a large epidemiological study using Rome IV criteria, Tack et al. (2025) found that patients that have FD with overlapping subtypes (such as both PDS and EPS symptoms) were associated with seeking healthcare more frequently than patients with a single subtype or patients without FD.²³

According to the 2021 clinical practice guidelines written by Miwa et al. (2022), Helicobacter pylori infection is associated with dyspeptic symptoms, however it plays a limited role in typical FD.²⁴ In a subset of patients, treating H. pylori causes relief of symptoms, which has led to the generation of a new diagnosis: H. pylori-associated dyspepsia.²⁴ The Kyoto Global Consensus specifies that in these subsets, H. pylori is likely the underlying cause of the symptoms, whereas FD occurs without H. pylori involvement.²⁴ Most people with FD have no symptom improvement after eradication therapy, indicating that the bacterium is a causative factor only in some patients.²⁴ This distinction shows that while H. pylori may be associated with dyspepsia, a causal link exists only when eradication improves the symptoms.²⁴

Overall, the epidemiologic literature on FD is limited by substantial heterogeneity in diagnostic criteria, study populations, geographic regions, and methodology. Earlier studies have relied on Rome III or non-standardized definitions, making direct comparison with newer Rome IV-based data difficult. Furthermore, many of the reported associations, especially dietary and psychosocial factors, are based on observational studies and may reflect bidirectional associations rather than true causal mechanisms. These limitations are likely responsible for the large variability in reported prevalence of FD worldwide.

6. Clinical Presentation

Functional dyspepsia is a chronic condition that affects the upper gastrointestinal tract and manifests through a variety of distressing symptoms.²⁵ Most commonly, patients present with epigastric pain or discomfort that is often described as a burning sensation in the upper central region of the abdomen.²⁶ Another frequent symptom is early satiety which can manifest as unintentional weight loss. Patients may also complain of postprandial fullness disproportionate to the amount of food consumed. Other associated symptoms include excessive belching, nausea, and upper abdominal bloating that can significantly affect one’s quality of life²⁵ When these symptoms fulfill Rome IV criteria and no structural pathology explaining the symptoms is identified after evaluation, a diagnosis of functional dyspepsia can be established.⁶

PDS is characterized by bothersome postprandial fullness and/or bothersome early satiety occurring at least three days per week over the past three months, with symptoms starting at least six months prior to diagnosis.²⁵ The symptoms that fall in this category include early satiety, bloating, nausea, vomiting or retching, and decreased appetite.²⁵ In contrast, EPS involves epigastric pain and/or burning at least one day per week for the past three months, also with symptom onset at least six months before diagnosis. Commonly reported symptoms for patients to be classified within this category are epigastric pain and epigastric burning.²⁵ Approximately 38% of patients with functional dyspepsia are categorized into PDS, 27% into EPS, and 35% meet criteria for both.⁶

7. Diagnostic Approach

Diagnosing dyspepsia demands the identification of underlying pathology by applying a structured, evidence-based approach. Additionally, unnecessary invasive testing in low-risk individuals should be avoided. Given the symptomatic overlap between functional and organic dyspepsia, the initial workup begins with a thorough clinical assessment, focusing on symptom duration, character, and the presence of alarm features such as unintended weight loss, gastrointestinal bleeding, anemia, dysphagia, persistent vomiting, or a family history of upper gastrointestinal malignancy.²⁷ Alarm features serve as critical indicators for prompt esophagogastroduodenoscopy (EGD), as their presence significantly raises the likelihood of detecting serious organic conditions such as peptic ulcer disease (PUD), upper gastrointestinal malignancies, and erosive esophagitis.¹⁸

Current international guidelines recommend a risk-stratified, stepwise diagnostic algorithm based on patient age, symptom profile, and geographic cancer risk.²⁴ EGD is necessary when a patient is 55 years of age or older, or when a younger patient exhibits warning signs or lives in an area where stomach cancer is common.¹⁸ Given the high incidence of gastric cancer worldwide, early endoscopic examination in these populations is crucial since it can quickly discover potentially dangerous organic causes such as malignancy.²⁴

Furthermore, male sex, low body mass index, and anemia are important predictors of organic dyspepsia on endoscopic examination, based on a study in older adults with dyspepsia.²⁸

A non-invasive “test-and-treat” strategy for Helicobacter pylori is widely recommended as an initial diagnostic step in low-risk patients without alarm symptoms.^24,27 In patients who test positive for H. pylori, eradication therapy is recommended, while those who test negative are usually treated empirically with proton pump inhibitors (PPIs). This strategy is based on evidence from several studies showing that routine endoscopy in younger, symptom-free individuals rarely uncovers significant findings. Additionally, treating H. pylori not only helps relieve symptoms but also lowers the risk of peptic ulcers.²⁴

Furthermore, empirical PPI therapy serves as an effective symptom control measure in the absence of infection or alarming features.

As previously stated, the Rome IV criteria support a positive diagnosis of FD based on characteristic symptom patterns, after appropriate evaluation has excluded structural disease that could explain these symptoms. This diagnosis requires the presence of characteristic symptoms for at least three months, with symptom onset at least six months before diagnosis.¹⁸

When symptoms persist despite standard therapy or when unusual symptoms indicate alternative diagnosis, additional diagnostic tools should be performed. These modalities include high-resolution esophageal manometry, pH impedance testing, and gastric emptying studies.¹⁸ The purpose of dyspepsia diagnosis is the identification of treatable or life-threatening organic pathology, without undue delay, with the cautious use of healthcare resources in order to minimize invasive procedures and reserve them for those at high risk.

8. Treatment Guidelines and Pharmacologic Management

8.1. Management of FD According to American and Canadian Guidelines

The joint clinical guideline on dyspepsia published in July 2017, by The American College of Gastroenterology (ACG) and Canadian Association of Gastroenterology (CAG), remains the most recent reliable source for functional dyspepsia management in the United States. In this guideline, the recommendations follow a stepwise, symptom-driven algorithm with the goal to improve patient quality of life and attain significant symptom alleviation by customising therapies to each patient’s unique symptom patterns and therapeutic response.⁴

Based on this guideline, once the diagnosis of functional dyspepsia (FD) is made in a patient, the first line of management would be to test and treat for Helicobacter Pylori if positive, whether confirmed by endoscopic gastric biopsies or non-invasive testing.⁴ In this latest update, a 2022 meta-analysis of 29 randomized controlled trials in H. pylori-positive patients compared eradication therapy to placebo controls. The analysis demonstrated that eradication therapy had a statistically significant impact on curing dyspepsia symptoms (RR for dyspepsia not being cured = 0.91; 95% CI = 0.88–0.94; P < 0.0001) and on symptom improvement (RR for symptoms not improving = 0.84; 95% CI = 0.78–0.91).²⁹

However, in patients who test negative or continue to have persistent symptoms of dyspepsia despite eradication of the infection with quadruple therapy, it is recommended to begin a PPI therapy trial. This consensus was formed on the fact that an increased sensitivity to acid may be associated with a subset of FD.³⁰ Moreover, a 2017 Cochrane systematic review including 25 RCTs from 27 papers (with 8453 participants) compared PPIs versus placebo, H2RAs or prokinetics for symptom relief in FD. The analysis demonstrated no statistically significant difference between the PPI and H2RA therapy (RR 0.88, 95% CI 0.74-1.04), although the evidence is estimated as low quality due to heterogeneity and risk of bias in the included studies.³¹ However, if the patient’s symptoms do not improve after an eight week PPI trial of a daily regular dose, there is no benefit in doubling the dosage according to data.⁴ As per the US FDA guidelines, it is not recommended for patients to chronically receive PPI therapy without attempting at withdrawal periods every six to twelve months.³²

Hence the next step in management would be to initiate antidepressant therapy. Since antidepressants have proven to be beneficial in treating irritable bowel syndrome (IBS) symptoms³³ and there is a commonality among FD and IBS,³⁴ it is plausible that antidepressant therapy can also improve symptoms of dyspepsia.⁴ When comparing RCTs between a placebo and tricyclic antidepressants (TCA) or selective serotonin reuptake inhibitor (SSRI) respectively, only TCAs have shown a statistically meaningful improvement on dyspepsia symptoms,^4,35 hence are the drug of choice.

If all previous measures are unsuccessful, prokinetic drugs may show some benefit as they accelerate gastric emptying³⁶ that may be delayed in patients with FD.^4,9 Despite having studies on 26 RCTs on prokinetics in regards to FD showing a slight yet statistically significant decrease in overall dyspeptic symptoms, none of the drugs under evaluation are presently marketed in the US, Canada, or Europe. Among known prokinetics, metoclopramide was not assessed since there have been no clinical trials examining its effectiveness in FD and data on domperidone was tainted with bias and unclear.⁴

When all drug therapy options are exhausted, psychological therapy should be offered to FD patients. Similarly to TCA therapy, research depicting psychological therapy has shown promise in IBS cases,³⁷ but the evidence base remains limited by poor study quality. Among the RCTs studied, cognitive behavioral therapy and other various forms of psychotherapy were the most common interventions implemented showing an exceeding benefit when compared to the control, being the conventional treatment. This recommendation is still conditional because the underlying evidence is limited, the intervention can be expensive, and it requires a lot of patient effort and involvement.⁴

On another note, many patients choose complementary and alternative medicine (CAM) to treat their gastrointestinal issues. However, the routine use of CAM is not recommended by the ACG and CAG since it is challenging to draw definitive results due to the large range of herbal therapies and other techniques, poor research quality hinders the overall evidence, even if some individual trials, such as those of acupuncture, Chinese herbal medicine, and the herbal product STW 5, suggest potential symptom improvement.⁴ Interested patients who are aware that the hazards and benefits of CAM are still unknown may be offered it.

Functional dyspepsia is a multifactorial condition with diverse pathophysiologic mechanisms that make the diagnosis and management of this condition complex.⁴ Some subsets of FD– abnormal gastric accommodation and delayed gastric emptying– require invasive, expensive and uncomfortable measures, specialized motility studies (gastric barostat or single-photon emission computed tomography),³⁸ to form a diagnosis as they are challenging to evaluate using standard diagnostic methods. Other influencing elements may include a history of infections, visceral hypersensitivity, duodenal eosinophilia, and the use of certain drugs.⁹ Regardless of these discoveries, pinpointing specific pathways hasn’t had a significant impact on treatment choices, and routine motility testing isn’t advised in FD due to its limited availability and poor symptom association.⁴However, in specific individuals with FD where there is a high suspicion of gastroparesis due to persistent, severe nausea and vomiting unresponsive to standard treatment, 4-hour solid phase gastric-emptying scan may be warranted.^4,39 The latter may confirm an alternate diagnosis to FD, gastroparesis, explaining resistance to treatment as they exhibit similar symptom profiles and are likely part of a broader spectrum of gastric sensorimotor dysfunction.⁴⁰

The ACG and CAG joint guidelines, in summary, provide a systematic, symptom-driven methodology for the treatment of functional dyspepsia in the US and Canada. In order to maximize therapeutic success and customize treatment to each patient’s unique symptom profile, these guidelines emphasize a sequential strategy, starting with H. pylori eradication followed by acid suppression, neuromodulation, prokinetic drugs, and psychological therapies. Following this guideline-based paradigm is still the most practical and evidence-based approach accessible in clinical practice, even though the underlying pathophysiologic mechanisms vary widely.

8.2. Management of FD According to European Guidelines

The United European Gastroenterology (UEG) is a leading non-profit organization founded in 1992 aiming to improve the care of digestive health in Europe. Similarly, the European Society for Neurogastroenterology and Motility (ESNM) is a leading European scientific society with a focus on neurogastroenterology and motility and all diseases related to the field. Both societies have hundreds of members who are professionals in the fields and other leading affiliated organizations and participate in occasional national and international meetings that help improve the world of gastroenterology.

In October 2019, following several meetings that have preceded that, both the UEG and ESNM had voted on several statements in aims to reach consensus regarding FD. The voted upon included statements regarding the definition of FD, epidemiology and risk factors, impact, pathophysiology, diagnosis, treatment, and recommendations.⁵ All the statements pertaining to the treatment and management in section 6 of the statements are summarized in Table 1, alongside their endorsement status, and the quality of evidence to support or oppose the statement. While the endorsement is based on whether 80% or more of the consensus group agreed with the statement, the quality of evidence falls into one of four groups: A, being high quality of evidence which represents high quality studies with consistent results, B, being a moderate quality of evidence which represents a high quality one time study with limitations, C, being a low quality of evidence which represents a study with severe limitations, and D, being a very low quality of evidence which represents data with no research evidence.⁵

Table 1.

Summary of ACG and CAG Guidelines for the Management of Functional Dyspepsia

Step	Clinical recommendation	Strength & evidence quality
1	Offer TCA therapy to dyspepsia patients under 60 not responding to PPI or H. pylori eradication.	Conditional, Low-quality evidence
2	Treat H. pylori-positive FD patients with eradication therapy.	Strong, High-quality evidence
3	Treat H. pylori-negative or post-eradication symptomatic FD patients with PPI therapy.	Strong, Moderate-quality evidence
4	Offer TCA therapy to FD patients unresponsive to PPI or H. pylori treatment.	Conditional, Moderate-quality evidence
5	Offer prokinetic therapy if PPI, H. pylori treatment, and TCAs fail.	Conditional, Very low-quality evidence
6	Offer psychological therapies to FD patients unresponsive to medications.	Conditional, Very low-quality evidence
7	Do not routinely recommend complementary and alternative medicine (CAM).	Conditional, Very low-quality evidence
8	Do not routinely perform motility studies in FD patients.	Conditional, Very low-quality evidence
9	Consider motility studies in selected patients when gastroparesis is strongly suspected.	Conditional, Very low-quality evidence

This table outlines the key treatment steps recommended by the American College of Gastroenterology (ACG) and Canadian Association of Gastroenterology (CAG) for functional dyspepsia, including the strength of each recommendation and the quality of supporting evidence.

FD management remains challenging due to limited high-quality evidence, particularly for dietary interventions, though frequent small meals and low-fat diets are commonly advised despite insufficient supporting data. H. pylori eradication provides only minimal symptom improvement and reduces ulcer/cancer risk, with greater efficacy in epigastric pain syndrome (EPS). Proton pump inhibitors (PPIs) are first-line for H. pylori-negative FD, though Rome IV notes inefficacy for postprandial distress (PDS), while prokinetics show contradictory benefits but are limited by safety concerns, for example the effect of domperidone on QT prolongation. Tricyclic antidepressants (TCAs) like amitriptyline outperform placebos for EPS, most likely via pain modulation, whereas SSRIs/SNRIs fail to demonstrate efficacy. Additionally, Mirtazapine aids weight gain and early satiety. Herbal therapies on the other hand such as STW-5 and peppermint oil show promise in meta-analyses, while rifaximin may help in the reduction of bloating. Psychological interventions (CBT, hypnotherapy) and acupuncture offer short-term relief, though studies related to them suffer from bias making them unreliable. For weight loss, enteral feeding may address the issue despite some non-life threatening complications faced.

Unfortunately, the largest area of lack of consensus in the UEG and ESNM meeting is the section on treatment approaches for FD.⁵ There is consensus to eradicate every H. pylori positive FD patient, and PPI therapy is considered an effective therapy for FD, although there is no consensus that it is the preferred initial therapy. Moreover, there is no consensus on the potential use and efficacy of prokinetics or antidepressants, but, although not endorsed, there was an almost‐agreement (78%) on the use of TCA in EPS specifically. There is also no consensus on the use of other psychological or herbal therapies in FD. There is agreement on the use of nutritional support in case of severe weight loss.⁵

More recently, updated European guidance has further refined the management framework for FD. The 2022 British Society of Gastroenterology (BSG) guidelines emphasized a biopsychosocial and multidisciplinary approach to FD, recognizing the disorder as a disease of gut–brain interaction rather than an isolated gastric disorder. Similar to the UEG/ESNM consensus, the BSG guidelines support H. pylori eradication and PPI therapy as core initial treatments; however, they additionally place stronger emphasis on integrating dietary modification, psychological therapies, and gut–brain neuromodulators into routine management. The BSG recommendations also acknowledge the substantial overlap between FD, irritable bowel syndrome, anxiety, and other disorders of gut–brain interaction, advocating for individualized treatment strategies tailored to symptom subtype and comorbidities.⁴¹

Furthermore, the recently published 2025 Italian joint consensus guidelines provided additional updates concerning FD pathophysiology. In contrast to earlier symptom-focused approaches, the Italian guidelines highlighted the role of duodenal low-grade inflammation, impaired mucosal permeability, altered microbiota composition, and gut–brain axis dysfunction in FD pathogenesis. These guidelines reinforced the importance of tailoring treatment according to the predominant symptom pattern, particularly distinguishing PDS from EPS, while also emphasizing lifestyle modification, nutritional counseling, and psychogastroenterological support as integral components of long-term management.⁴²

8.3. Comparing and Contrasting North American and European Guidelines

Although the American/Canadian and European guidelines differ in emphasis and interpretation of evidence, recent updates demonstrate overlap in the overall management strategy for FD. The ACG/CAG guideline, the UEG/ESNM consensus, the 2022 BSG guideline, and the 2025 Italian consensus all adopt the Rome IV framework for defining FD and distinguishing its major clinical subtypes, EPS and PDS. Similarly, all guidelines recommend a “test-and-treat” strategy for H. pylori infection followed by PPI therapy in patients who remain symptomatic or are H. pylori-negative. Across both North American and European recommendations, prokinetics maintain a limited role because of inconsistent efficacy, restricted availability, and safety concerns. Likewise, escalation to neuromodulators and psychological therapies is generally reserved for refractory disease.^4,5,41,42

Despite these similarities, important differences remain. The ACG/CAG guideline primarily follows a symptom-driven and sequential pharmacologic algorithm beginning with H. pylori eradication, followed by PPIs, tricyclic antidepressants, prokinetics, and psychological therapies.⁴ In contrast, more recent European guidelines frame FD more explicitly as a disorder of gut–brain interaction and place greater emphasis on biopsychosocial factors, overlapping gastrointestinal disorders, and individualized multidisciplinary care.^41,42 European recommendations also discuss psychological therapies more prominently, particularly in patients with refractory symptoms or significant psychosocial burden.^5,41

Another distinction lies in the interpretation and application of evidence supporting specific therapies. The ACG/CAG guideline provides clearer therapeutic sequencing and stronger recommendations favoring PPIs and tricyclic antidepressants,⁴ whereas the original UEG/ESNM consensus demonstrated less agreement regarding antidepressants, prokinetics, and psychological therapies despite moderate-quality evidence.⁵ More recent European updates, however, increasingly advocate subtype-directed and mechanism-oriented therapy. The BSG guideline incorporated updated network meta-analyses and formal GRADE methodology to evaluate available interventions and identify future therapeutic priorities,⁴¹ while the Italian consensus emphasized emerging mechanistic concepts such as duodenal microinflammation, impaired epithelial barrier integrity, microbiota-related alterations, and visceral hypersensitivity.⁴²

Overall, while North American and European guidelines share many core therapeutic principles, European updates increasingly support a biopsychosocial and pathophysiology-oriented approach that recognizes the heterogeneity of FD. Nevertheless, both management sequences remain constrained by the absence of reliable biomarkers and validated mechanism-targeted therapies, resulting in continued reliance on empiric strategies (Tables 2 and 3).

Table 2.

A Table Summarizing all the Statements With Endorsements Made Regarding the Treatment and Management of FD

Statement	Endorsement	Quality of evidence
6.1. Dietary adjustment improves symptoms in FD	No	C
6.2. H. pylori positive FD patients should receive eradication therapy	Yes	A
6.3. PPI therapy is the most appropriate initial therapy for FD	No	B
6.4. PPI therapy is an effective therapy for FD.	Yes	A
6.5 PPI therapy is most effective for EPS	No	C
6.6 Prokinetic therapy is the most appropriate initial therapy for FD	No	C
6.7. Prokinetic therapy is an effective therapy	No	B
6.8. Prokinetic therapy is most effective for PDS.	No	B
6.9. Efficacy of prokinetics is not related to their enhancement of gastric emptying rate.	No	B
6.10. Itopride is effective for FD patients.	No	C
6.12. Tricyclic antidepressants are effective for post‐prandial distress syndrome (PDS).	No	B
6.13. Tricyclic antidepressants are not effective for post‐prandial distress syndrome (PDS).	No	B
6.14. Serotonin reuptake inhibitors are effective for FD.	No	B
6.15. Serotonin reuptake inhibitors are not effective for FD.	No	B
6.16. Serotonin noradrenaline reuptake inhibitors are effective for FD.	No	C
6.17. Serotonin noradrenaline reuptake inhibitors are not effective for FD.	No	C
6.18. Mirtazapine is effective for post‐prandial distress syndrome patients with weight loss.	No	B
6.19. 5‐HT1A agonists (tandospirone, buspirone, …) are effective for PDS.	No	B
6.20. Herbal therapies are effective for FD patients.	No	B
6.21. Iberogast (STW‐5) is effective for FD patients.	No	B
6.22. Rifaximin is effective for FD patients.	No	C
6.23. Hypnotherapy is effective for FD patients.	No	B
6.24. Cognitive–behavioral therapy (CBT) is effective for FD patients.	No	B
6.25. Acupuncture is effective for FD patients.	No	B
6.26. Mindfulness is effective for FD patients.	No	B
6.27. In case of severe weight loss in FD, nutritional support may be needed.	Yes	B

Table 3.

Comparison of ACG/CAG and UEG/ESNM Guidelines for Functional Dyspepsia Management

Management aspect	ACG/CAG guidelines (2017)	UEG/ESNM guidelines (2019)
Approach Style	Stepwise, symptom-driven algorithm	Consensus-based statements, not always treatment-focused
H. pylori Eradication	Strongly recommended for H. pylori-positive patients	Endorsed; high-quality evidence (Grade A)
Initial Therapy	PPI therapy after H. pylori eradication failure	PPI therapy effective, but not endorsed as first-line
PPI Efficacy by Subtype	General FD: recommended; EPS may respond better	PPI effective overall; not endorsed specifically for EPS (Grade C)
PPI vs H2RA	No significant difference shown in RCTs	Not specifically addressed
TCA Use	Recommended after failure of PPI/H. pylori eradication	No consensus; almost endorsed for EPS (78% agreement); low-to-moderate evidence (Grade B)
SSRI/SNRI Use	Not recommended (no benefit over placebo)	Not endorsed; both effective and ineffective claims not supported (Grade B/C)
Mirtazapine	Mentioned as possibly useful in weight loss and satiety	Not endorsed; weak evidence (Grade B)
Prokinetics	Suggested after failure of TCA; low-quality evidence; limited availability	Not endorsed; effectiveness inconsistent; safety concerns noted (Grades B/C)
Psychological Therapies	Suggested after drug therapy fails; CBT and hypnotherapy considered	Not endorsed due to study bias; moderate evidence (Grade B)
CAM (e.g., STW-5, acupuncture)	Not routinely recommended; lack of strong evidence	Not endorsed; no strong evidence; inconsistent findings (Grade B)
Motility Studies	Not routinely recommended; consider only if gastroparesis strongly suspected	Not specifically addressed; gastroparesis not a focus
Dietary Advice	Not emphasized	No endorsement; low-quality evidence (Grade C)
Nutritional Support (for weight loss)	Not specifically addressed	Endorsed for severe weight loss (Grade B)

This table compares the treatment recommendations for functional dyspepsia between North American (ACG/CAG) and European (UEG/ESNM) guidelines, highlighting areas of agreement, disagreement, and evidence strength.

8.4. Commentary on Guidelines and a Pathophysiology-Based Approach to Diagnosis and Management

Recent European updates, particularly the 2022 BSG and 2025 Italian consensus guidelines, reflect an important shift in FD management from a predominantly symptom-based modeltoward a more integrated biopsychosocial and pathophysiology-oriented model. These guidelines increasingly acknowledge the contribution of gut–brain interaction abnormalities, duodenal microinflammation, altered epithelial permeability, visceral hypersensitivity, and psychosocial comorbidity to symptom generation. Nevertheless, despite these advances, current therapeutic recommendations remain largely empirical because most proposed pathophysiologic mechanisms cannot yet be reliably identified or targeted in routine clinical practice. Consequently, management strategies continue to rely heavily on sequential therapeutic trials^41,42

Despite the availability of international guidelines for the management of functional dyspepsia, several limitations remain evident. Both the ACG/CAG and UEG/ESNM recommendations rely largely on symptom-based algorithms and consensus statements rather than direct stratification according to underlying pathophysiologic mechanisms. This reflects the inherent heterogeneity of FD and the absence of reliable, clinically accessible biomarkers that can guide targeted therapy. As a result, current guideline-based management often follows a trial-and-error approach, which may contribute to variable treatment responses and patient dissatisfaction.

A key area of divergence between North American and European guidelines lies in the prioritization of initial therapy and the interpretation of evidence supporting specific pharmacologic classes. While both guidelines agree on the importance of Helicobacter pylori eradication and the exclusion of organic disease, there is limited consensus regarding the optimal sequencing of acid suppression, neuromodulators, and prokinetic agents. Notably, European guidelines demonstrate a more conservative stance, with fewer endorsed statements despite moderate-quality evidence for several interventions, underscoring the ongoing uncertainty in FD management.

Given these limitations, an approach that integrates symptom subtypes with dominant pathophysiologic mechanisms may provide a more rational and individualized framework for diagnosis and treatment. Functional dyspepsia is increasingly recognized as a spectrum of gastric sensorimotor and gut–brain axis dysfunction rather than a single disease entity. Accordingly, therapeutic strategies may be optimized by aligning treatment selection with the predominant FD subtype, postprandial distress syndrome (PDS) or epigastric pain syndrome (EPS) and their associated mechanisms.

In patients with PDS, impaired gastric accommodation, delayed gastric emptying, and postprandial hypersensitivity appear to play a central role. Therefore, management in this subgroup should emphasize therapies targeting gastric motor function and accommodation. Initial strategies may include dietary modifications such as smaller, low-fat meals, followed by pharmacologic agents with effects on gastric motility or fundic relaxation. In selected patients with significant early satiety or weight loss, agents such as mirtazapine may offer dual benefits through appetite stimulation and central neuromodulation. Nutritional support should be considered when clinically indicated.

In contrast, EPS is more closely associated with visceral hypersensitivity and altered central pain processing. Acid suppression with proton pump inhibitors may provide benefit in a subset of patients, particularly those with acid sensitivity. However, neuromodulatory therapies, especially tricyclic antidepressants, appear to play a more prominent role in EPS by modulating pain perception along the gut–brain axis. This aligns with evidence suggesting greater efficacy of TCAs in pain-predominant dyspepsia compared with postprandial symptoms.

Psychological comorbidity is prevalent across both FD subtypes and may exacerbate symptom severity and chronicity. Consequently, psychological interventions such as cognitive behavioral therapy and hypnotherapy may be considered in refractory cases, particularly when psychosocial stressors are prominent. Although guideline endorsement remains limited due to methodological concerns, these therapies may offer meaningful benefit in carefully selected patients.

From a diagnostic standpoint, routine physiologic testing is not recommended in most patients with FD; however, targeted investigations may be justified in refractory or atypical cases. For example, gastric emptying studies may be appropriate when severe nausea and vomiting raise concern for gastroparesis, while esophageal pH or motility testing may be useful when overlapping gastroesophageal reflux or esophageal disorders are suspected.

However, different distinct mechanistic contributors, such as impaired gastric accommodation, duodenal immune activation, visceral hypersensitivity, and altered gut-brain signaling, are yet to be reliably identified in routine practice. Consequently, current management strategies remain limited by the absence of reliable biomarkers capable of anticipating treatment response or defining further clinically meaningful FD subgroups.

In summary, while current guidelines provide a valuable framework for the management of functional dyspepsia, integrating symptom-based classification with pathophysiologic principles may allow for a more individualized and mechanism-driven approach. Such a strategy has the potential to improve treatment efficacy, reduce unnecessary therapeutic trials, and better address the heterogeneity inherent to FD.

9. Conclusion

Functional dyspepsia is increasingly recognized to be a disorder of gut–brain interaction that is heterogeneous rather than a purely gastric or symptom-defined disorder. The evolution of Rome IV criteria has refined the diagnostic framework of FD by supporting a positive symptom-based diagnosis following appropriate evaluation to exclude structural disease. Important advances have led to greater understanding of the neuroimmune, sensorimotor and psychosocial mechanisms involved in FD but there are major gaps in translating these mechanistic insights into precision-based clinical care. Moreover, the substantial overlap between FD subtypes, particularly between PDS and EPS, and the frequent co-occurrence of FD with other disorders of gut-brain interaction such as irritable bowel syndrome, demonstrate the clinical and biological heterogeneity of this disorder. Current management strategies are therefore still largely empirical and symptom-driven despite growing recognition of distinct pathophysiologic subgroups and an increasing shift toward biopsychosocial and mechanism-oriented models of care. This review highlights both convergence and divergence between North American and European management guidelines. Given its complexity, an individualized and multidisciplinary treatment approach remains necessary. In addition to pharmacologic therapy, effective care should typically include lifestyle and dietary modifications, as well as psychological support when indicated. The comparison between international guidelines displays both similarities and differences in terms of treatment prioritization, diagnostic thresholds and the integration of dietary, psychosocial and multidisciplinary interventions. While all guidelines highlight the necessity of ruling out structural causes and adopting a symptom-based approach, differences arise in the timing and selection of empiric treatments, the role of H. pylori eradication, and the importance of psychosocial and nutritional therapy. This underlines the necessity for physicians to employ a context-specific, evidence-based approach, adopting recommendations that best match their patients’ social setting and healthcare environment. Further research should aim for better characterization of pathophysiological subtypes, identification of reliable biomarkers for diagnosis and treatment response and validation of emerging therapies including neuromodulators, microbiome interventions, and gut-brain axis-targeted management strategies. Multinational clinical trials and comparative effectiveness studies may also help harmonize guideline recommendations and address areas of divergence. Reliable data on non-pharmacological treatments, long-term outcomes and underrepresented populations—such as children and the elderly— are also necessary. Recent guideline updates increasingly support a personalized and multidisciplinary approach to FD management, reflecting the evolving recognition of FD as a complex disorder of gut–brain interaction rather than a single uniform clinical entity.

Footnotes

Acknowledgements

The author(s) have no acknowledgements to declare.

ORCID iD

Karam Karam

Ethical Considerations

Not applicable. This research involved secondary analysis of existing literature and did not require ethical approval.

Consent to Participate

A signed written informed consent was obtained prior to manuscript submission.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

Drossman

Hasler

. Rome IV—Functional GI Disorders: Disorders of Gut-Brain Interaction. Gastroenterology. 2016;150(6):1257-1261. doi:10.1053/j.gastro.2016.03.035.

Vanheel

Farré

. Changes in gastrointestinal tract function and structure in functional dyspepsia. Nat Rev Gastroenterol Hepatol. 2013;10(3):142-149. doi:10.1038/nrgastro.2012.255.

Van Oudenhove

Vandenberghe

Vos

Holvoet

Demyttenaere

Tack

. Risk factors for impaired health-related quality of life in functional dyspepsia: Quality of life in functional dyspepsia. Aliment Pharmacol Ther. 2011;33(2):261-274. doi:10.1111/j.1365-2036.2010.04510.x.

Moayyedi

Lacy

Andrews

Enns

Howden

Vakil

. ACG and CAG Clinical Guideline: Management of Dyspepsia. Am J Gastroenterol. 2017;112(7):988-1013. doi:10.1038/ajg.2017.154.

Wauters

Dickman

Drug

, et al. United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on functional dyspepsia. United Eur Gastroenterol J. 2021;9(3):307-331. doi:10.1002/ueg2.12061.

Talley

Ford

. Functional Dyspepsia. Longo DL, ed. N Engl J Med. 2015;373(19):1853-1863. doi:10.1056/NEJMra1501505.

Broeders

BWLCM

Carbone

Balsiger

, et al.

Review article: Functional dyspepsia—a gastric disorder, a duodenal disorder or a combination of both?

Aliment Pharmacol Ther. 2023;57(8):851-860. doi:10.1111/apt.17414.

Oshima

. Functional Dyspepsia: Current Understanding and Future Perspective. Digestion. 2024;105(1):26-33. doi:10.1159/000532082.

Tack

Masaoka

Janssen

. Functional dyspepsia. Curr Opin Gastroenterol. 2011;27(6):549-557. doi:10.1097/MOG.0b013e32834b7ca8.

10.

Shah

Fairlie

Brown

, et al. Duodenal Eosinophils and Mast Cells in Functional Dyspepsia: A Systematic Review and Meta-Analysis of Case-Control Studies. Clin Gastroenterol Hepatol. 2022;20(10):2229-2242.e29. doi:10.1016/j.cgh.2022.01.014.

11.

Van Oudenhove

Vandenberghe

Dupont

, et al. Abnormal Regional Brain Activity During Rest and (Anticipated) Gastric Distension in Functional Dyspepsia and the Role of Anxiety: A H2 15O-PET Study. Am J Gastroenterol. 2010;105(4):913-924. doi:10.1038/ajg.2010.39.

12.

. Psychological Co-morbidity in Functional Gastrointestinal Disorders: Epidemiology, Mechanisms and Management. J Neurogastroenterol Motil. 2012;18(1):13-18. doi:10.5056/jnm.2012.18.1.13.

13.

Walker

Aggarwal

Shim

, et al. Duodenal eosinophilia and early satiety in functional dyspepsia: Confirmation of a positive association in an A ustralian cohort. J Gastroenterol Hepatol. 2014;29(3):474-479. doi:10.1111/jgh.12419.

14.

Porcari

Ingrosso

Maida

, et al. Prevalence of irritable bowel syndrome and functional dyspepsia after acute gastroenteritis: systematic review and meta-analysis. Gut. 2024;73(9):1431-1440. doi:10.1136/gutjnl-2023-331835.

15.

Kwon

Yeom

Lee

Kim

. Role of the Small Intestinal Microbiota in Gastrointestinal Disorders. Korean J Helicobacter Up Gastrointest Res. 2024;24(4):339-345. doi:10.7704/kjhugr.2024.0059.

16.

Tkach

Dorofeev

Kharchenko

. Modern views on the mechanisms of pathogenesis and tactics of management of patients with overlap of irritable bowel syndrome and functional dyspepsia. Review. Mod Gastroenterol. 2022(1—2):63-72. doi:10.30978/MG-2022-1-63.

17.

Oustamanolakis

Tack

. Dyspepsia: Organic Versus Functional. J Clin Gastroenterol. 2012;46(3):175-190. doi:10.1097/MCG.0b013e318241b335.

18.

Stanghellini

Chan

FKL

Hasler

, et al. Gastroduodenal Disorders. Gastroenterology. 2016;150(6):1380-1392. doi:10.1053/j.gastro.2016.02.011.

19.

Kim

Lee

, et al. Prevalence and Risk Factors of Functional Dyspepsia in Health Check-up Population: A Nationwide Multicenter Prospective Study. J Neurogastroenterol Motil. 2018;24(4):603-613. doi:10.5056/jnm18068.

20.

Huang

Wang

Duan

Yang

. Correlation between lifestyle and social factors in functional dyspepsia among college freshmen. J Int Med Res. 2020;48(8):0300060520939702. doi:10.1177/0300060520939702.

21.

Caballero-Mateos

López-Hidalgo

Torres-Parejo

, et al. Risk factors for functional dyspepsia, erosive and non-erosive gastroesophageal reflux disease: A cross-sectional study. Gastroenterol Hepatol. 2023;46(7):542-552. doi:10.1016/j.gastrohep.2022.12.005.

22.

Shi

Luo

Wang

, et al. Functional dyspepsia symptom diary is correlated with other questionnaires and associated with severity in patients with functional dyspepsia: a multicenter, prospective observational study. J Gastroenterol Hepatol. 2022;37(7):1298-1306. doi:10.1111/jgh.15854.

23.

Tack

Palsson

Bangdiwala

, et al. Functional Dyspepsia and Its Subgroups: Prevalence and Impact in the Rome IV Global Epidemiology Study. Aliment Pharmacol Ther. 2025;62(3):330-339. doi:10.1111/apt.70189.

24.

Miwa

Nagahara

Asakawa

, et al. Evidence-based clinical practice guidelines for functional dyspepsia 2021. J Gastroenterol. 2022;57(2):47-61. doi:10.1007/s00535-021-01843-7.

25.

Harer

Hasler

. Functional Dyspepsia: A Review of the Symptoms, Evaluation, and Treatment Options. Gastroenterol Hepatol. 2020;16(2):66-74.

26.

Francis

Zavala

. Functional Dyspepsia. In: StatPearls. StatPearls Publishing; 2025. https://www.ncbi.nlm.nih.gov/books/NBK554563/. Accessed May 25, 2025.

27.

Harmon

Peura

. Review: Evaluation and management of dyspepsia. Ther Adv Gastroenterol. 2010;3(2):87-98. doi:10.1177/1756283X09356590.

28.

Simngam

Pinyopornpanish

Kulkheereerattana

Chuaiad

Arayakulsakol

Pinyopornpanish

. Prevalence and factors associated with organic dyspepsia in older adults with dyspepsia. Sci Rep. 2025;15(1):15250. doi:10.1038/s41598-025-00097-0.

29.

Ford

Tsipotis

Yuan

Leontiadis

Moayyedi

. Efficacy of Helicobacter pylori eradication therapy for functional dyspepsia: updated systematic review and meta-analysis. Gut. 2022;71(10):1967-1975. doi:10.1136/gutjnl-2021-326583.

30.

Haruma

Hata

Shiotani

, et al. Evaluation of duodenal hypersensitivity induced by duodenal acidification using transnasal endoscopy - PubMed. 2010; Accessed May 15, 2025. https://pubmed-ncbi-nlm-nih-gov.uobezsecureaccess.idm.oclc.org/20546445/.

31.

Pinto-Sanchez

Yuan

Hassan

Bercik

Moayyedi

. Proton pump inhibitors for functional dyspepsia. Cochrane Upper GI and Pancreatic Diseases Group, ed. Cochrane Database Syst Rev. 2017;2018(3):CD011194. doi:10.1002/14651858.CD011194.pub3.

32.

Research C for DE and FDA Drug Safety Communication: Clostridium difficile associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs). FDA. Published online June 26, 2019. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-clostridium-difficile-associated-diarrhea-can-be-associated-stomach. Accessed May 15, 2025.

33.

Ford

Quigley

EMM

Lacy

, et al. Effect of antidepressants and psychological therapies, including hypnotherapy, in irritable bowel syndrome: systematic review and meta-analysis. Am J Gastroenterol. 2014;109(9):1350-1365. doi:10.1038/ajg.2014.148. quiz 1366.

34.

Ford

Marwaha

Lim

Moayyedi

. Systematic review and meta-analysis of the prevalence of irritable bowel syndrome in individuals with dyspepsia. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2010;8(5):401-409. doi:10.1016/j.cgh.2009.07.020.

35.

Ford

Luthra

Tack

Boeckxstaens

Moayyedi

Talley

. Efficacy of psychotropic drugs in functional dyspepsia: systematic review and meta-analysis. Gut. 2017;66(3):411-420. doi:10.1136/gutjnl-2015-310721.

36.

Lacy

Talley

Locke

, et al. Review article: current treatment options and management of functional dyspepsia. Aliment Pharmacol Ther. 2012;36(1):3-15. doi:10.1111/j.1365-2036.2012.05128.x.

37.

Ford

Quigley

Lacy

, et al. Effect of antidepressants and psychological therapies, including hypnotherapy, in irritable bowel syndrome: systematic review and meta-analysis - PubMed. Accessed May 15, 2025. https://pubmed-ncbi-nlm-nih-gov.uobezsecureaccess.idm.oclc.org/24935275/

38.

Ang

. Measurement of gastric accommodation: a reappraisal of conventional and emerging modalities - PubMed. Accessed May 16, 2025. https://pubmed-ncbi-nlm-nih-gov.uobezsecureaccess.idm.oclc.org/21624107/

39.

Camilleri

Parkman

Shafi

Abell

Gerson

. American College of Gastroenterology. Clinical guideline: management of gastroparesis. Am J Gastroenterol. 2013;108(1):18-37. doi:10.1038/ajg.2012.373. quiz 38.

40.

Lacy

. Functional dyspepsia and gastroparesis: one disease or two? Am J Gastroenterol. 2012;107(11):1615-1620. doi:10.1038/ajg.2012.104.

41.

Black

Paine

Agrawal

, et al. British Society of Gastroenterology guidelines on the management of functional dyspepsia. Gut. 2022;71(9):1697-1723. - Google Search. https://gut.bmj.com/content/71/9/1697. Accessed May 14, 2026.

42.

Sarnelli

Pesce

Barbara

, et al. Italian guidelines for the diagnosis and treatment of functional dyspepsia - joint consensus from the Italian societies of gastroenterology and endoscopy (SIGE), Neurogastroenterology and motility (SINGEM), hospital gastroenterologists and endoscopists (AIGO), digestive endoscopy (SIED) and general medicine (SIMG). Dig Liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver. 2025;57(9):1730-1747. doi:10.1016/j.dld.2025.06.012.