Review

Digestion
Digestion 2023;105:26–33 Received: June 29, 2023
Accepted: July 18, 2023
DOI: 10.1159/000532082 Published online: August 18, 2023

Functional Dyspepsia: Current

Understanding and Future Perspective
Tadayuki Oshima
Department of Gastroenterology, Okazaki City Medical Association Public Health Center, Okazaki, Japan

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Keywords therapies, including cognitive behavioral therapy and
Hypersensitivity · Microinflammation · Delayed emptying 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
Abstract gut-brain interaction involving diverse pathophysiological
Background: Functional dyspepsia (FD) is a common dis- mechanisms. Individualized treatment based on symptoms
order characterized by chronic or recurrent upper abdom- and responses to interventions is crucial. Further research is
inal pain or discomfort without any structural abnormalities needed to improve the understanding of FD and advance
in the gastrointestinal tract. FD is categorized into two the development of effective therapies.
subgroups based on symptoms: postprandial distress syn- © 2023 S. Karger AG, Basel
drome (PDS) and epigastric pain syndrome. Summary: The
pathophysiology of FD involves several mechanisms. De-
layed gastric emptying is observed in approximately 30% of Introduction
FD patients but does not correlate with symptom patterns or
severity. Impaired gastric accommodation is important in Functional dyspepsia (FD) is a disorder of gut-brain
the pathophysiology, particularly for PDS. Visceral hyper- interaction (DGBI) with an estimated prevalence of
sensitivity, characterized by heightened sensitivity to normal 10–40% in Western countries and 5–30% in Asia [1–3].
activities, contributes to the perception of discomfort or pain Despite the apparent absence of structural gastrointes-
in FD. Alterations to the duodenal mucosa, including im- tinal tract abnormalities, patients with FD experience
paired mucosal barrier function and low-grade inflamma- declines in quality of life attributable to chronic or re-
tion, are also implicated in the pathogenesis of FD. Microbial current upper abdominal pain or discomfort [4]. The
dysbiosis and psychological factors such as stress can further diagnosis of FD necessitates the exclusion of any other
exacerbate symptoms. Treatment options include dietary organic, systemic, or metabolic diseases through routine
modifications, establishing a physician-patient relationship, investigations, including endoscopy.
acid suppressants, prokinetics, neuromodulators, and be- FD is categorized into two distinct subgroups based on
havioral therapies. Dietary recommendations include eating the pattern of symptoms. The first subgroup is post-
smaller, more frequent meals, and avoiding trigger foods. prandial distress syndrome (PDS), characterized by the
Acid suppressants are used as the first-line treatment. presence of bothersome early satiation and/or post-
Prokinetics and neuromodulators aim to improve gastric prandial fullness, occurring at least 3 times a week. The
motility and central pain processing, respectively. Behavioral second subgroup is epigastric pain syndrome (EPS),

[email protected] © 2023 S. Karger AG, Basel Correspondence to:

www.karger.com/dig Tadayuki Oshima, tadaoshima @ yahoo.co.jp
characterized by bothersome epigastric pain and/or emptying and the pattern or severity of symptoms in FD
burning occurring at least once a week. Moreover, remain inconclusive [12, 15, 16]. A comprehensive
these diagnostic criteria must be met consistently for 3 follow-up study of a substantial cohort revealed that over
months, with symptom onset occurring at least 6 months the course of 1 year, alterations in the outcomes of gastric-
prior to diagnosis [5]. emptying tests led to the reclassification of one-third of
The distribution of subtypes has been reported as 67% patients from gastroparesis to FD and vice versa. Im-
PDS, 28% EPS, and 12% with overlapping PDS/EPS portantly, these reclassifications did not coincide with
subtypes [6]. To mitigate this overlap between PDS and significant changes in the pattern or severity of the
EPS in the Rome IV classification, postprandial epigastric symptoms [17].
pain was included as a symptom of PDS, leading to an
increased prevalence of PDS under this classification as Gastric Accommodation
compared to the previous Rome III classification [7]. Symptoms of PDS occur with food intake, whereas
Although the precise pathophysiological mechanisms symptoms of EPS occur later, after meal ingestion. PDS
underlying FD are not yet fully understood, recent evi- symptoms typically manifest within 30–45 min of a meal.
dence indicates that disruptions in gastric motility, such The gastric accommodation reaction is a physiological

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as delayed gastric emptying, and impaired fundic ac- process that enables the proximal stomach to store food
commodation and sensation, including hypersensitivity, after ingestion through a reflexive reaction. Vagal cho-
may significantly contribute to the development of FD [4, linergic inputs modulate gastric tone, and the release of
8]. Moreover, recent reports have highlighted the exis- nitric oxide from intrinsic nerves has been proposed as a
tence of low-grade duodenal inflammation, including factor contributing to the mechanisms underlying gastric
intramucosal eosinophilia and elevated mast cell density accommodation response [18, 19]. Inhibition of nitric
within the duodenum. Such findings offer potential oxide synthase in healthy volunteers was shown to lead to
biomarkers and provide valuable insights into the the suppression of gastric accommodation and early
pathogenesis of FD [9–11]. Furthermore, these abnor- satiation [20]. This impaired gastric accommodation in
malities have the potential to serve as therapeutic targets response to a meal represents a key element in the
for FD. pathophysiology of FD, particularly in relation to PDS
In this review, the author aims to provide a com- symptoms, with up to 40% of patients exhibiting this
prehensive summary of the current evidence pertaining abnormality [21]. However, recent reports have suggested
to the pathophysiology and treatment options for FD, that impaired gastric accommodation is observed with
specifically focusing on the contribution of the duodenum similar prevalence in groups with PDS, EPS, and over-
to the pathophysiological mechanisms of FD and future lapping PDS-EPS [12]. Further, delayed gastric emptying
perspectives regarding potential treatment strategies or impaired gastric accommodation may not consistently
for FD. correlate with symptoms of FD [22, 23].

Gastric Hypersensitivity
Pathophysiology of FD Visceral hypersensitivity stands as a significant path-
ophysiological mechanism in various DGBIs, including
Gastric Emptying FD. Gastric sensitivity in FD patients is influenced by a
Gastric emptying has been a central focus of investi- history of sexual abuse, physical abuse, and somatization
gations into the pathophysiology of FD. Delayed gastric [24]. A history of sexual abuse is also associated with the
emptying has previously been recognized as a potential development of dyspepsia in later life [25]. This increased
mechanism underlying dyspeptic symptoms, particularly sensitivity can lead to the perception of normal gastric
in relation to PDS symptoms [12]. Extensive studies have activities, such as meal-induced gastric filling, as un-
confirmed delayed gastric emptying for solid foods in comfortable or painful, ultimately giving rise to FD
approximately 30% of FD patients [13]. Nevertheless, no symptoms. The assessment of visceral hypersensitivity
notable disparity in the prevalence of gastric emptying often involves the utilization of techniques like barostat
has been observed among Rome III subgroups of FD. measurements and intragastric acid perfusion while si-
Delayed gastric emptying was observed in only 11% of multaneously recording the intensity of the reported
Japanese PDS patients and did not demonstrate a sig- symptoms. Approximately 37% of patients exhibit hy-
nificant correlation with the symptomatic patterns ex- persensitivity to gastric distention [26]. In FD patients,
perienced [14]. Correlations between the rate of gastric the severity of dyspeptic symptoms induced by direct acid

Functional Dyspepsia Digestion 2023;105:26–33 27

DOI: 10.1159/000532082
 a

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c

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

infusion into the stomach was significantly higher than localized immune activation. The current emphasis of
that observed in healthy controls [27]. Visceral hyper- research in this field has shifted from motility to ex-
sensitivity is closely linked to the severity of symptoms in ploring low-grade inflammation, encompassing factors
FD [28]. However, FD subgroups, as defined by the Rome such as duodenal mucosal permeability and eosinophil
III criteria, did not show different associations with infiltration.
visceral hypersensitivity or disordered gastric emptying Psychological stress increases duodenal permeability
[12]. The association between visceral hypersensitivity through the activation of mast cells, mediated by a
and the subgroups defined under the Rome IV criteria for corticotropin-releasing hormone (Fig. 1) [31]. These
FD has yet to be reported. findings indicate that psychological stress disrupts the
integrity of the duodenal barrier, resulting in increased
Duodenal Mucosal Alterations permeability and microinflammation. The presence of
Recent studies have indicated that the pathogenesis modified duodenal contents, including acids, bile acids,
of FD involves impaired duodenal epithelial barrier lipids, and the microbiota, is likely to play a significant
function and low-grade inflammation (Fig. 1) [11, 29]. role in stimulating visceral sensations.
Impaired duodenal barrier integrity and immune cell In addition, duodenal eosinophil density and the de-
infiltration are clearly correlated [30], and mechanical gree of degranulation may be associated with the un-
and chemical hypersensitivities are likely to arise due to derlying pathophysiology of FD [9, 32]. Early satiety has

28 Digestion 2023;105:26–33 Oshima

DOI: 10.1159/000532082
been found to be associated with elevated eosinophil levels of anxiety and depression. The syndrome of
levels in the duodenum [9, 33]. The number of eosino- overlapping FD and IBS exhibited the most severe gas-
phils and mast cells infiltrating the duodenum of FD trointestinal and psychological outcomes [42].
patients is correlated [10]. Moreover, accumulated data
suggest that these cells can mutually influence the via-
bility, functionality, trafficking, and activation of each Treatments for FD
other [34–36].
Although the precise causes of duodenal mucosal al- Diet
terations in FD remain elusive, a recent study identified Eating behaviors, irregular meal patterns, and
an increased number of cholinergic tuft cells in the du- moderate-to-fast eating rates are all significantly associ-
odenum of FD patients. Chemosensory tuft cells are ated with FD, so eating slowly and regularly is important.
specialized epithelial cells that express cholinergic re- Dietary recommendations for managing FD include
ceptors and are correlated with eosinophil density, sug- eating smaller, more frequent meals, avoiding high-fat
gesting that tuft cells may contribute to duodenal meals, and decreasing the intake of ultra-processed foods.
microinflammation [37]. Fatty and spicy foods, carbonated drinks, alcoholic

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beverages, and food with high citric acid content should
Microbiota be avoided. Foods and beverages containing caffeine
Helicobacter pylori (HP) infection has been established should also be reduced or avoided, as the presence of
as a factor associated with dyspepsia. However, indi- caffeine stimulates the overproduction of gastric acid
viduals who experience symptom relief following HP [43]. A preliminary study indicated that a low-
eradication therapy are now acknowledged as having HP- fermentable oligosaccharide, disaccharide, monosaccha-
associated dyspepsia, which is considered a distinct ride, and polyol (FODMAP) diet can restore the impaired
pathological entity from FD [38]. function of the duodenal mucosal barrier. However,
Duodenal microbial dysbiosis, resulting in disrupted scientific evidence on the impact of FODMAPs in FD is
motility and visceral hypersensitivity due to impaired currently insufficient. Given the frequent coexistence of
mucosal integrity and compromised immune function, FD and IBS, adopting a low-FODMAP diet may po-
could potentially contribute to the development of FD tentially alleviate certain symptoms. Dietary recom-
[39]. While small intestinal bacterial overgrowth based on mendations may vary depending on the individual and
duodenal aspirate cultures was not associated with the their specific symptoms. Multidisciplinary care, encom-
symptoms of FD, small intestinal microbial diversity and passing the expertise of gastroenterologists, dietitians,
duodenal mucosal permeability showed an inverse cor- hypnotherapists, psychologists, and behavioral physio-
relation and this relationship suggests that alterations in therapists, yielded superior outcomes when compared to
microbial diversity may influence the development or the standard care provided solely by gastroenterologists
exacerbation of symptoms in FD by affecting intestinal within the realm of DGBIs, including FD [44].
permeability [40]. Randomized controlled trials (RCTs)
are essential to validate the therapeutic efficacy of Physician-Patient Relationship and Placebo Effect
modulating microbiota in the context of FD. Since psychological distress plays a crucial role as a
risk factor for the development of DGBIs, the Rome IV
Psychological Factors criteria emphasize the importance of establishing a
Stressful stimuli delay gastric emptying, leading to strong patient-physician relationship and obtaining
increased epigastric discomfort [41]. In addition, acute psychosocial background information from the patient
psychological stress has been shown to increase intestinal right from the initial consultation stage [45]. While no
permeability, while the administration of disodium universally accepted endpoint has been devised for
cromoglycate, a mast cell stabilizer, before stress exposure evaluating symptom response in FD, previous RCTs
prevented this increase in duodenal permeability [31]. have commonly utilized measures such as patient
During the coronavirus disease 2019 pandemic, a sig- improvement, satisfactory relief, or symptom resolu-
nificant proportion of patients with either FD or irritable tion as the primary endpoints. Hence, placebo-
bowel syndrome (IBS) experienced deterioration in response rates in FD have demonstrated a wide
symptoms, with a smaller subset noting improvement. In range, spanning from 0% to 84.5%. Pooled placebo-
comparison to individuals without FD or IBS, respon- response rates in double-blinded RCTs of FD were
dents diagnosed with these conditions reported higher 32.4% in total, 44.3% in trials assessing symptom

Functional Dyspepsia Digestion 2023;105:26–33 29

DOI: 10.1159/000532082
improvement, and 15.6% in trials assessing complete Neuromodulators
relief [46]. The definition of efficacy significantly in- The intricate bidirectional communication between
fluences the placebo response and the interpretation of the brain and gut plays a significant role in the devel-
efficacy for the target drug. opment and manifestation of symptoms in FD. Dysre-
gulation in central pain processing, involving altered
Acid Suppressants perception and modulation of pain signals, contributes to
Although no evidence suggesting overproduction of hypersensitivity and increased perception of pain. Neu-
gastric acid has been recognized in FD patients, impaired romodulators, including low-dose antidepressants, could
duodenal acid clearance and duodenal hypersensitivity to therefore be recommended as second-line therapy. Tri-
infused gastric acid have been reported in studies related cyclic antidepressants (TCAs) such as amitriptyline,
to FD. Acid suppression by H2 receptor antagonists imipramine, and nortriptyline at low doses offer effective
(H2RAs) or proton pump inhibitors (PPIs) has thus been second-line treatment of FD. However, side effects should
applied as a treatment of FD. However, no difference in be carefully considered. Antipsychotics, such as sulpiride
efficacy has been seen between different doses of PPI. or levosulpiride, a 5-hydroxytryptamine-1A agonist,
Furthermore, no RCT has provided conclusive evidence tandospirone [53], and gabapentinoid, pregabalin, are

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demonstrating any efficacy of potassium-competitive also effective as second-line treatments [54]. Mirtazapine
acid blockers compared to placebo. might be effective in FD patients with weight loss [55].
In addition to acid suppression, PPIs could improve
increased duodenal permeability and infiltration of mast Behavioral Therapies
cells and eosinophils. Indeed, one study showed that Gut-brain behavioral interventions have demonstrated
pantoprazole effectively alleviated symptoms in patients potential benefits for FD patients who have not re-
with FD while concurrently reducing duodenal mast cell sponded to conventional therapies. These interventions
and eosinophil counts, as well as improving duodenal improved both psychological and physiological aspects
permeability [47]. and show potential for improving gastrointestinal
symptoms and quality of life. Psychodynamic interper-
Prokinetics sonal therapy [56], cognitive behavioral therapy, stress
As one subgroup of patients diagnosed with FD exhibits management approaches, and hypnotherapy have all
abnormalities in gastric motility, impaired gastric accom- shown some efficacy in the treatment of refractory FD
modation, and gastric hypersensitivity, pharmacological [57]. Nevertheless, RCTs to date have exhibited hetero-
agents that enhance gastroduodenal motility and gastric geneity, encompassing variations in therapeutic modality,
accommodation appear to hold potential efficacy in the duration, symptom focus, and delivery intensity. While
treatment of FD. A clinical trial conducted on Japanese these studies have consistently indicated the benefits for
subjects as well as a systematic review have reported that patients, methodological discrepancies and divergent
acotiamide, an acetylcholinesterase inhibitor, exhibited forms of gut-brain behavioral therapy hinder the en-
superior efficacy compared to the control group in the dorsement of any specific approach over another. Further
treatment of overall symptoms associated with FD, espe- RCTs investigating gut-brain behavioral therapies are
cially for PDS [48, 49]. Acotiamide accelerated meal- necessary to determine optimal utilization and patient-
induced gastric accommodation [50] and restored meal- selection criteria for these treatments.
induced gastric accommodation impaired by stress.
A placebo-controlled trial investigating the effects of Challenges for Treatment of Severe and
itopride, a dopamine 2 receptor antagonist and cholin- Refractory Symptoms
esterase inhibitor, evaluated symptoms associated with No specific treatments targeting severe FD have been
FD. The trial demonstrated a significant decrease in elucidated. However, several studies targeting severe or
various symptoms, including early satiety, postprandial refractory FD have been performed in small-sized
fullness, and upper abdominal bloating [51]. RCTs. Clidinium/chlordiazepoxide, a combination of
Rikkunshito, a traditional Japanese herbal medicine, antispasmodic and anxiolytic drugs, improved dys-
has also been found to be effective in improving the peptic symptoms and quality of life as an adjunct
symptoms of FD and is well tolerated. As a result, rik- treatment to PPIs in patients with FD that failed to
kunshito is now recommended as first-line therapy in respond to PPIs [58]. A combination of the anxiolytic
Japanese evidence-based clinical practice guidelines for flupenthixol and the antidepressant melitracen was
FD [52]. effective for patients with refractory FD [59]. Such

30 Digestion 2023;105:26–33 Oshima

DOI: 10.1159/000532082
findings imply that combinations of drugs with distinct and aprepitant and tradipitant, both neurokinin 1 re-
effects could serve as promising strategies for treatment ceptor antagonists. These medications show potential in
of severe or refractory FD. enhancing gastroduodenal motility and alleviating
Gabapentin, a neuropathic analgesic as an adjunctive symptoms associated with both FD and gastroparesis.
drug for PPIs, relieved gastrointestinal symptoms in However, further research is necessary, particularly
patients with refractory FD [60]. A duodenal-release through well-designed RCTs, to ascertain the efficacy and
formulation of a combination of caraway oil and safety of these agents.
L-menthol alongside standard therapy achieved im-
provements in dyspeptic symptoms among severely af-
fected patients with FD [61]. In uncontrolled studies, a 5- Conclusions
HT1A agonist, buspirone, improved early satiation and
gastric emptying, while amitriptyline demonstrated im- FD is a prevalent DGBI. Despite extensive research, the
provement in postprandial fullness among patients who pathophysiology underlying FD remains only incom-
did not respond to first-line therapy [62]. Additional pletely understood. Correlations between gastric emp-
RCTs involving a substantial sample size are necessary to tying, visceral hypersensitivity, and accommodation with

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more comprehensively evaluate the efficacy of these gastrointestinal symptoms in FD have yielded incon-
approaches. clusive results. Recent research has brought to light the
crucial role of the duodenum in FD, serving as both a
Drugs in Development generator of symptoms and a potential target for ther-
Since histamine is released by mast cells, concurrent apeutic interventions. Accordingly, FD may indeed be a
administration of H1 receptor antagonists and H2RAs gastroduodenal disorder originating from duodenal
can be considered a potential approach. An uncon- mucosal alterations. Disruptions in the duodenal mucosa
trolled study demonstrated that the administration of and associated duodeno-gastric feedback mechanisms
loratadine and ranitidine resulted in subsequent im- may contribute to the development and persistence of FD
provement in symptoms of FD [63]. However, RCTs symptoms. Clinical trials exploring the efficacy of drugs
are needed to establish the efficacy and safety of this that specifically target low-grade duodenal inflammation
method. and mast cell degranulation are warranted. The devel-
Alterations to the duodenal microbiota may play a role opment of therapies addressing impaired duodenal
in the pathophysiology of FD. A clinical trial utilizing the mucosal barrier function is expected. Furthermore, ex-
minimally absorbed antibiotic rifaximin revealed signif- ploration of non-pharmacological therapies, including
icantly higher rates of substantial relief in global symp- dietary modifications, behavioral interventions, and
toms and postprandial fullness [64]. Furthermore, Ba- psychological therapies, is warranted in future studies
cillus coagulans MY01 and B. subtilis MY02 exhibited into the management of FD.
superior efficacy compared to placebo in improving
symptoms of FD. Efficacy was found to be associated with
an elevated relative abundance of Faecalibacterium [65].
Conflict of Interest Statement
Duodenal eosinophilia may be a target of the therapy.
PPI showed reduced eosinophils and normalized duo- The author has received lecture fees from Takeda Pharmaceutical
denal permeability in FD. Both α4β7 integrin and SI- Company, Ltd., and Otsuka Pharmaceutical Company, Ltd.
GLEC-8 are expressed on eosinophils. Monoclonal
antibodies such as vedolizumab, targeting α4β7 integrin,
and lirentelimab, targeting SIGLEC-8, have been de- Funding Sources
veloped for the treatment of inflammatory bowel dis-
eases and are currently undergoing trials for use in the This study was supported by a Grant-in-Aid for Scientific
treatment of eosinophilic gastrointestinal diseases [66, Research (C) from the Japan Society for the Promotion of Science
(JSPS) (22K08066).
67], with potential for the treatment of FD.
Given the similar nature of FD and gastroparesis,
drugs currently being developed for the treatment of
Author Contributions
gastroparesis may also hold promise for the management
of FD. Candidates of note include relamorelin, a ghrelin Tadayuki Oshima wrote the draft and reviewed and edited the
agonist; prucalopride and velusetrag, as 5-HT4 agonists; manuscript.

Functional Dyspepsia Digestion 2023;105:26–33 31

DOI: 10.1159/000532082
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DOI: 10.1159/000532082