Background: Functional dyspepsia (FD) is a common disorder characterized by chronic or recurrent upper abdominal pain or discomfort without any structural abnormalities in the gastrointestinal tract. FD is categorized into two subgroups based on symptoms: postprandial distress syndrome (PDS) and epigastric pain syndrome. Summary: The pathophysiology of FD involves several mechanisms. Delayed gastric emptying is observed in approximately 30% of FD patients but does not correlate with symptom patterns or severity. Impaired gastric accommodation is important in the pathophysiology, particularly for PDS. Visceral hypersensitivity, characterized by heightened sensitivity to normal activities, contributes to the perception of discomfort or pain in FD. Alterations to the duodenal mucosa, including impaired mucosal barrier function and low-grade inflammation, are also implicated in the pathogenesis of FD. Microbial dysbiosis and psychological factors such as stress can further exacerbate symptoms. Treatment options include dietary modifications, establishing a physician-patient relationship, acid suppressants, prokinetics, neuromodulators, and behavioral therapies. Dietary recommendations include eating smaller, more frequent meals, and avoiding trigger foods. Acid suppressants are used as the first-line treatment. Prokinetics and neuromodulators aim to improve gastric motility and central pain processing, respectively. Behavioral therapies, including cognitive behavioral therapy and hypnotherapy, have shown benefits for refractory FD. Severe and refractory cases may require combination therapies or experimental treatments. Key Messages: FD is a disorder of gut-brain interaction involving diverse pathophysiological mechanisms. Individualized treatment based on symptoms and responses to interventions is crucial. Further research is needed to improve the understanding of FD and advance the development of effective therapies.

Functional dyspepsia (FD) is a disorder of gut-brain interaction (DGBI) with an estimated prevalence of 10–40% in Western countries and 5–30% in Asia [1‒3]. Despite the apparent absence of structural gastrointestinal tract abnormalities, patients with FD experience declines in quality of life attributable to chronic or recurrent upper abdominal pain or discomfort [4]. The diagnosis of FD necessitates the exclusion of any other organic, systemic, or metabolic diseases through routine investigations, including endoscopy.

FD is categorized into two distinct subgroups based on the pattern of symptoms. The first subgroup is postprandial distress syndrome (PDS), characterized by the presence of bothersome early satiation and/or postprandial fullness, occurring at least 3 times a week. The second subgroup is epigastric pain syndrome (EPS), characterized by bothersome epigastric pain and/or burning occurring at least once a week. Moreover, these diagnostic criteria must be met consistently for 3 months, with symptom onset occurring at least 6 months prior to diagnosis [5].

The distribution of subtypes has been reported as 67% PDS, 28% EPS, and 12% with overlapping PDS/EPS subtypes [6]. To mitigate this overlap between PDS and EPS in the Rome IV classification, postprandial epigastric pain was included as a symptom of PDS, leading to an increased prevalence of PDS under this classification as compared to the previous Rome III classification [7].

Although the precise pathophysiological mechanisms underlying FD are not yet fully understood, recent evidence indicates that disruptions in gastric motility, such as delayed gastric emptying, and impaired fundic accommodation and sensation, including hypersensitivity, may significantly contribute to the development of FD [4, 8]. Moreover, recent reports have highlighted the existence of low-grade duodenal inflammation, including intramucosal eosinophilia and elevated mast cell density within the duodenum. Such findings offer potential biomarkers and provide valuable insights into the pathogenesis of FD [9‒11]. Furthermore, these abnormalities have the potential to serve as therapeutic targets for FD.

In this review, the author aims to provide a comprehensive summary of the current evidence pertaining to the pathophysiology and treatment options for FD, specifically focusing on the contribution of the duodenum to the pathophysiological mechanisms of FD and future perspectives regarding potential treatment strategies for FD.

Gastric Emptying

Gastric emptying has been a central focus of investigations into the pathophysiology of FD. Delayed gastric emptying has previously been recognized as a potential mechanism underlying dyspeptic symptoms, particularly in relation to PDS symptoms [12]. Extensive studies have confirmed delayed gastric emptying for solid foods in approximately 30% of FD patients [13]. Nevertheless, no notable disparity in the prevalence of gastric emptying has been observed among Rome III subgroups of FD. Delayed gastric emptying was observed in only 11% of Japanese PDS patients and did not demonstrate a significant correlation with the symptomatic patterns experienced [14]. Correlations between the rate of gastric emptying and the pattern or severity of symptoms in FD remain inconclusive [12, 15, 16]. A comprehensive follow-up study of a substantial cohort revealed that over the course of 1 year, alterations in the outcomes of gastric-emptying tests led to the reclassification of one-third of patients from gastroparesis to FD and vice versa. Importantly, these reclassifications did not coincide with significant changes in the pattern or severity of the symptoms [17].

Gastric Accommodation

Symptoms of PDS occur with food intake, whereas symptoms of EPS occur later, after meal ingestion. PDS symptoms typically manifest within 30–45 min of a meal. The gastric accommodation reaction is a physiological process that enables the proximal stomach to store food after ingestion through a reflexive reaction. Vagal cholinergic inputs modulate gastric tone, and the release of nitric oxide from intrinsic nerves has been proposed as a factor contributing to the mechanisms underlying gastric accommodation response [18, 19]. Inhibition of nitric oxide synthase in healthy volunteers was shown to lead to the suppression of gastric accommodation and early satiation [20]. This impaired gastric accommodation in response to a meal represents a key element in the pathophysiology of FD, particularly in relation to PDS symptoms, with up to 40% of patients exhibiting this abnormality [21]. However, recent reports have suggested that impaired gastric accommodation is observed with similar prevalence in groups with PDS, EPS, and overlapping PDS-EPS [12]. Further, delayed gastric emptying or impaired gastric accommodation may not consistently correlate with symptoms of FD [22, 23].

Gastric Hypersensitivity

Visceral hypersensitivity stands as a significant pathophysiological mechanism in various DGBIs, including FD. Gastric sensitivity in FD patients is influenced by a history of sexual abuse, physical abuse, and somatization [24]. A history of sexual abuse is also associated with the development of dyspepsia in later life [25]. This increased sensitivity can lead to the perception of normal gastric activities, such as meal-induced gastric filling, as uncomfortable or painful, ultimately giving rise to FD symptoms. The assessment of visceral hypersensitivity often involves the utilization of techniques like barostat measurements and intragastric acid perfusion while simultaneously recording the intensity of the reported symptoms. Approximately 37% of patients exhibit hypersensitivity to gastric distention [26]. In FD patients, the severity of dyspeptic symptoms induced by direct acid infusion into the stomach was significantly higher than that observed in healthy controls [27]. Visceral hypersensitivity is closely linked to the severity of symptoms in FD [28]. However, FD subgroups, as defined by the Rome III criteria, did not show different associations with visceral hypersensitivity or disordered gastric emptying [12]. The association between visceral hypersensitivity and the subgroups defined under the Rome IV criteria for FD has yet to be reported.

Duodenal Mucosal Alterations

Recent studies have indicated that the pathogenesis of FD involves impaired duodenal epithelial barrier function and low-grade inflammation (Fig. 1) [11, 29]. Impaired duodenal barrier integrity and immune cell infiltration are clearly correlated [30], and mechanical and chemical hypersensitivities are likely to arise due to localized immune activation. The current emphasis of research in this field has shifted from motility to exploring low-grade inflammation, encompassing factors such as duodenal mucosal permeability and eosinophil infiltration.

Fig. 1.

Duodenal mucosal alteration and gut-brain interactions in functional dyspepsia. Intricate bidirectional communications between the brain and gut play a significant role in the development and manifestation of symptoms in functional dyspepsia (FD). Dyspeptic symptoms are perceived in the brain, while patients with FD exhibit susceptibility to various factors present in the duodenal lumen, including the microbiota, food-derived substances, acids, bile acids, and lipids. Duodenal mucosal alterations may contribute to FD, with duodenal epithelial cells, including tuft cells, sensing the contents of the duodenal lumen (a) and leading to increased mucosal permeability (b). This increased permeability allows these contents to penetrate the mucosa, where they are recognized by immune cells, resulting in low-grade inflammation. Inflammatory cells (c) release mediators such as histamine, tryptase, and cytokines, which affect submucosal afferent nerves and disrupt gastric motility. These changes are ultimately sensed by the brain. These mediators further compromise the epithelial barrier and increase duodenal mucosal permeability. Psychological stress (d) is another important factor in the pathogenesis of FD, increasing duodenal permeability by activating mast cells through the corticotropin-releasing hormone (CRH). Duodenal contents (a), epithelial permeability (b), immune cell infiltration (c), mediators released from nerves, inflammatory cells, epithelial cells, and stress (d) interact in complex circuits, contributing to the development, intermittency, and persistence of FD symptoms. Interruption of these circuits at various steps can be considered a therapeutic target and may inform the establishment of strategies for combination therapies. CRHR1, corticotropin-releasing hormone receptor 1.

Fig. 1.

Duodenal mucosal alteration and gut-brain interactions in functional dyspepsia. Intricate bidirectional communications between the brain and gut play a significant role in the development and manifestation of symptoms in functional dyspepsia (FD). Dyspeptic symptoms are perceived in the brain, while patients with FD exhibit susceptibility to various factors present in the duodenal lumen, including the microbiota, food-derived substances, acids, bile acids, and lipids. Duodenal mucosal alterations may contribute to FD, with duodenal epithelial cells, including tuft cells, sensing the contents of the duodenal lumen (a) and leading to increased mucosal permeability (b). This increased permeability allows these contents to penetrate the mucosa, where they are recognized by immune cells, resulting in low-grade inflammation. Inflammatory cells (c) release mediators such as histamine, tryptase, and cytokines, which affect submucosal afferent nerves and disrupt gastric motility. These changes are ultimately sensed by the brain. These mediators further compromise the epithelial barrier and increase duodenal mucosal permeability. Psychological stress (d) is another important factor in the pathogenesis of FD, increasing duodenal permeability by activating mast cells through the corticotropin-releasing hormone (CRH). Duodenal contents (a), epithelial permeability (b), immune cell infiltration (c), mediators released from nerves, inflammatory cells, epithelial cells, and stress (d) interact in complex circuits, contributing to the development, intermittency, and persistence of FD symptoms. Interruption of these circuits at various steps can be considered a therapeutic target and may inform the establishment of strategies for combination therapies. CRHR1, corticotropin-releasing hormone receptor 1.

Close modal

Psychological stress increases duodenal permeability through the activation of mast cells, mediated by a corticotropin-releasing hormone (Fig. 1) [31]. These findings indicate that psychological stress disrupts the integrity of the duodenal barrier, resulting in increased permeability and microinflammation. The presence of modified duodenal contents, including acids, bile acids, lipids, and the microbiota, is likely to play a significant role in stimulating visceral sensations.

In addition, duodenal eosinophil density and the degree of degranulation may be associated with the underlying pathophysiology of FD [9, 32]. Early satiety has been found to be associated with elevated eosinophil levels in the duodenum [9, 33]. The number of eosinophils and mast cells infiltrating the duodenum of FD patients is correlated [10]. Moreover, accumulated data suggest that these cells can mutually influence the viability, functionality, trafficking, and activation of each other [34‒36].

Although the precise causes of duodenal mucosal alterations in FD remain elusive, a recent study identified an increased number of cholinergic tuft cells in the duodenum of FD patients. Chemosensory tuft cells are specialized epithelial cells that express cholinergic receptors and are correlated with eosinophil density, suggesting that tuft cells may contribute to duodenal microinflammation [37].

Microbiota

Helicobacter pylori (HP) infection has been established as a factor associated with dyspepsia. However, individuals who experience symptom relief following HP eradication therapy are now acknowledged as having HP-associated dyspepsia, which is considered a distinct pathological entity from FD [38].

Duodenal microbial dysbiosis, resulting in disrupted motility and visceral hypersensitivity due to impaired mucosal integrity and compromised immune function, could potentially contribute to the development of FD [39]. While small intestinal bacterial overgrowth based on duodenal aspirate cultures was not associated with the symptoms of FD, small intestinal microbial diversity and duodenal mucosal permeability showed an inverse correlation and this relationship suggests that alterations in microbial diversity may influence the development or exacerbation of symptoms in FD by affecting intestinal permeability [40]. Randomized controlled trials (RCTs) are essential to validate the therapeutic efficacy of modulating microbiota in the context of FD.

Psychological Factors

Stressful stimuli delay gastric emptying, leading to increased epigastric discomfort [41]. In addition, acute psychological stress has been shown to increase intestinal permeability, while the administration of disodium cromoglycate, a mast cell stabilizer, before stress exposure prevented this increase in duodenal permeability [31]. During the coronavirus disease 2019 pandemic, a significant proportion of patients with either FD or irritable bowel syndrome (IBS) experienced deterioration in symptoms, with a smaller subset noting improvement. In comparison to individuals without FD or IBS, respondents diagnosed with these conditions reported higher levels of anxiety and depression. The syndrome of overlapping FD and IBS exhibited the most severe gastrointestinal and psychological outcomes [42].

Diet

Eating behaviors, irregular meal patterns, and moderate-to-fast eating rates are all significantly associated with FD, so eating slowly and regularly is important. Dietary recommendations for managing FD include eating smaller, more frequent meals, avoiding high-fat meals, and decreasing the intake of ultra-processed foods. Fatty and spicy foods, carbonated drinks, alcoholic beverages, and food with high citric acid content should be avoided. Foods and beverages containing caffeine should also be reduced or avoided, as the presence of caffeine stimulates the overproduction of gastric acid [43]. A preliminary study indicated that a low-fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) diet can restore the impaired function of the duodenal mucosal barrier. However, scientific evidence on the impact of FODMAPs in FD is currently insufficient. Given the frequent coexistence of FD and IBS, adopting a low-FODMAP diet may potentially alleviate certain symptoms. Dietary recommendations may vary depending on the individual and their specific symptoms. Multidisciplinary care, encompassing the expertise of gastroenterologists, dietitians, hypnotherapists, psychologists, and behavioral physiotherapists, yielded superior outcomes when compared to the standard care provided solely by gastroenterologists within the realm of DGBIs, including FD [44].

Physician-Patient Relationship and Placebo Effect

Since psychological distress plays a crucial role as a risk factor for the development of DGBIs, the Rome IV criteria emphasize the importance of establishing a strong patient-physician relationship and obtaining psychosocial background information from the patient right from the initial consultation stage [45]. While no universally accepted endpoint has been devised for evaluating symptom response in FD, previous RCTs have commonly utilized measures such as patient improvement, satisfactory relief, or symptom resolution as the primary endpoints. Hence, placebo-response rates in FD have demonstrated a wide range, spanning from 0% to 84.5%. Pooled placebo-response rates in double-blinded RCTs of FD were 32.4% in total, 44.3% in trials assessing symptom improvement, and 15.6% in trials assessing complete relief [46]. The definition of efficacy significantly influences the placebo response and the interpretation of efficacy for the target drug.

Acid Suppressants

Although no evidence suggesting overproduction of gastric acid has been recognized in FD patients, impaired duodenal acid clearance and duodenal hypersensitivity to infused gastric acid have been reported in studies related to FD. Acid suppression by H2 receptor antagonists (H2RAs) or proton pump inhibitors (PPIs) has thus been applied as a treatment of FD. However, no difference in efficacy has been seen between different doses of PPI. Furthermore, no RCT has provided conclusive evidence demonstrating any efficacy of potassium-competitive acid blockers compared to placebo.

In addition to acid suppression, PPIs could improve increased duodenal permeability and infiltration of mast cells and eosinophils. Indeed, one study showed that pantoprazole effectively alleviated symptoms in patients with FD while concurrently reducing duodenal mast cell and eosinophil counts, as well as improving duodenal permeability [47].

Prokinetics

As one subgroup of patients diagnosed with FD exhibits abnormalities in gastric motility, impaired gastric accommodation, and gastric hypersensitivity, pharmacological agents that enhance gastroduodenal motility and gastric accommodation appear to hold potential efficacy in the treatment of FD. A clinical trial conducted on Japanese subjects as well as a systematic review have reported that acotiamide, an acetylcholinesterase inhibitor, exhibited superior efficacy compared to the control group in the treatment of overall symptoms associated with FD, especially for PDS [48, 49]. Acotiamide accelerated meal-induced gastric accommodation [50] and restored meal-induced gastric accommodation impaired by stress.

A placebo-controlled trial investigating the effects of itopride, a dopamine 2 receptor antagonist and cholinesterase inhibitor, evaluated symptoms associated with FD. The trial demonstrated a significant decrease in various symptoms, including early satiety, postprandial fullness, and upper abdominal bloating [51].

Rikkunshito, a traditional Japanese herbal medicine, has also been found to be effective in improving the symptoms of FD and is well tolerated. As a result, rikkunshito is now recommended as first-line therapy in Japanese evidence-based clinical practice guidelines for FD [52].

Neuromodulators

The intricate bidirectional communication between the brain and gut plays a significant role in the development and manifestation of symptoms in FD. Dysregulation in central pain processing, involving altered perception and modulation of pain signals, contributes to hypersensitivity and increased perception of pain. Neuromodulators, including low-dose antidepressants, could therefore be recommended as second-line therapy. Tricyclic antidepressants (TCAs) such as amitriptyline, imipramine, and nortriptyline at low doses offer effective second-line treatment of FD. However, side effects should be carefully considered. Antipsychotics, such as sulpiride or levosulpiride, a 5-hydroxytryptamine-1A agonist, tandospirone [53], and gabapentinoid, pregabalin, are also effective as second-line treatments [54]. Mirtazapine might be effective in FD patients with weight loss [55].

Behavioral Therapies

Gut-brain behavioral interventions have demonstrated potential benefits for FD patients who have not responded to conventional therapies. These interventions improved both psychological and physiological aspects and show potential for improving gastrointestinal symptoms and quality of life. Psychodynamic interpersonal therapy [56], cognitive behavioral therapy, stress management approaches, and hypnotherapy have all shown some efficacy in the treatment of refractory FD [57]. Nevertheless, RCTs to date have exhibited heterogeneity, encompassing variations in therapeutic modality, duration, symptom focus, and delivery intensity. While these studies have consistently indicated the benefits for patients, methodological discrepancies and divergent forms of gut-brain behavioral therapy hinder the endorsement of any specific approach over another. Further RCTs investigating gut-brain behavioral therapies are necessary to determine optimal utilization and patient-selection criteria for these treatments.

Challenges for Treatment of Severe and Refractory Symptoms

No specific treatments targeting severe FD have been elucidated. However, several studies targeting severe or refractory FD have been performed in small-sized RCTs. Clidinium/chlordiazepoxide, a combination of antispasmodic and anxiolytic drugs, improved dyspeptic symptoms and quality of life as an adjunct treatment to PPIs in patients with FD that failed to respond to PPIs [58]. A combination of the anxiolytic flupenthixol and the antidepressant melitracen was effective for patients with refractory FD [59]. Such findings imply that combinations of drugs with distinct effects could serve as promising strategies for treatment of severe or refractory FD.

Gabapentin, a neuropathic analgesic as an adjunctive drug for PPIs, relieved gastrointestinal symptoms in patients with refractory FD [60]. A duodenal-release formulation of a combination of caraway oil and L-menthol alongside standard therapy achieved improvements in dyspeptic symptoms among severely affected patients with FD [61]. In uncontrolled studies, a 5-HT1A agonist, buspirone, improved early satiation and gastric emptying, while amitriptyline demonstrated improvement in postprandial fullness among patients who did not respond to first-line therapy [62]. Additional RCTs involving a substantial sample size are necessary to more comprehensively evaluate the efficacy of these approaches.

Drugs in Development

Since histamine is released by mast cells, concurrent administration of H1 receptor antagonists and H2RAs can be considered a potential approach. An uncontrolled study demonstrated that the administration of loratadine and ranitidine resulted in subsequent improvement in symptoms of FD [63]. However, RCTs are needed to establish the efficacy and safety of this method.

Alterations to the duodenal microbiota may play a role in the pathophysiology of FD. A clinical trial utilizing the minimally absorbed antibiotic rifaximin revealed significantly higher rates of substantial relief in global symptoms and postprandial fullness [64]. Furthermore, Bacillus coagulans MY01 and B. subtilis MY02 exhibited superior efficacy compared to placebo in improving symptoms of FD. Efficacy was found to be associated with an elevated relative abundance of Faecalibacterium [65].

Duodenal eosinophilia may be a target of the therapy. PPI showed reduced eosinophils and normalized duodenal permeability in FD. Both α4β7 integrin and SIGLEC-8 are expressed on eosinophils. Monoclonal antibodies such as vedolizumab, targeting α4β7 integrin, and lirentelimab, targeting SIGLEC-8, have been developed for the treatment of inflammatory bowel diseases and are currently undergoing trials for use in the treatment of eosinophilic gastrointestinal diseases [66, 67], with potential for the treatment of FD.

Given the similar nature of FD and gastroparesis, drugs currently being developed for the treatment of gastroparesis may also hold promise for the management of FD. Candidates of note include relamorelin, a ghrelin agonist; prucalopride and velusetrag, as 5-HT4 agonists; and aprepitant and tradipitant, both neurokinin 1 receptor antagonists. These medications show potential in enhancing gastroduodenal motility and alleviating symptoms associated with both FD and gastroparesis. However, further research is necessary, particularly through well-designed RCTs, to ascertain the efficacy and safety of these agents.

FD is a prevalent DGBI. Despite extensive research, the pathophysiology underlying FD remains only incompletely understood. Correlations between gastric emptying, visceral hypersensitivity, and accommodation with gastrointestinal symptoms in FD have yielded inconclusive results. Recent research has brought to light the crucial role of the duodenum in FD, serving as both a generator of symptoms and a potential target for therapeutic interventions. Accordingly, FD may indeed be a gastroduodenal disorder originating from duodenal mucosal alterations. Disruptions in the duodenal mucosa and associated duodeno-gastric feedback mechanisms may contribute to the development and persistence of FD symptoms. Clinical trials exploring the efficacy of drugs that specifically target low-grade duodenal inflammation and mast cell degranulation are warranted. The development of therapies addressing impaired duodenal mucosal barrier function is expected. Furthermore, exploration of non-pharmacological therapies, including dietary modifications, behavioral interventions, and psychological therapies, is warranted in future studies into the management of FD.

The author has received lecture fees from Takeda Pharmaceutical Company, Ltd., and Otsuka Pharmaceutical Company, Ltd.

This study was supported by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (JSPS) (22K08066).

Tadayuki Oshima wrote the draft and reviewed and edited the manuscript.

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