doi:10.1111/j.1440-1746.2011.06633.

GASTROENTEROLOGY _6633 53..60

Current understanding of pathogenesis of

functional dyspepsia
Hiroto Miwa,* Jiro Watari,† Hirokazu Fukui,† Tadayuki Oshima,† Toshihiko Tomita,† Jun Sakurai,†
Takashi Kondo† and Takayuki Matsumoto†
Division of *Upper and †Lower Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan

Key words Abstract

chronic gastritis, dysmotility, dyspepsia,
gastric acid, placebo, Rome classification,
visceral hypersensitivity.
Accepted for publication 28 January 2011.
Correspondence
Professor and Chairman, Hiroto Miwa,
Division of Upper Gastroenterology,
Department of Internal Medicine, Hyogo
College of Medicine, 1-1, Mukogawa-cho,
Nishinomiya, Hyogo 663-8501, Japan. Email:
miwahgi@hyo-med.ac.jp
Functional dyspepsia (FD) is a disorder in which upper abdominal symptoms occur in the
absence of organic disease that explains them. Many pathogenic factors have been pro-
posed for FD, including motility abnormalities, visceral hypersensitivity, psychosocial
factors, excessive gastric acid secretion, Helicobacter pylori, genetics, environment, diet,
lifestyle, and post-infectious FD. Many of those pathogenic factors are also common to
irritable bowel syndrome and other functional gastrointestinal disorders, so understanding
FD offers a glimpse into the nature of functional gastrointestinal disorders in general.
Motility abnormalities and visceral hypersensitivity are thought to be important in the
manifestation of FD symptoms, but the other factors are also thought to contribute by
interacting and modifying motility and visceral hypersensitivity.

Functional dyspepsia: definition and
current status
Dyspepsia refers to symptoms centered in the upper abdominal
region, such as stomachache, heartburn, feeling bad after eating,
and heavy feeling in the stomach. Many patients complain of
dyspepsia despite the absence of an obvious organic cause such as
ulcer, esophagitis, or cancer. Dyspepsia in a patient with no
organic disease that explains the symptoms is known as functional
dyspepsia (FD). FD is one of a number of functional gastrointes-
tinal disorders.
The scientific investigation of the pathophysiology of FD began
not so long ago, and research on FD from many different angles
remains active. The first definition of FD was developed in 1998 by
a working party of the American Gastroenterological Association1
and a committee of the International Congress of Gastroenterology
in Rome.2 Subsequently, the Rome II classification system was
developed in 1999,3 followed by the Rome III system in 2006.4
According to the Rome III system, which is currently in use, FD is
defined as the presence of at least one of the following symptoms
in the absence of organic disease that is likely to explain the
symptoms, with the symptoms being present for the three months
preceding diagnosis and having their onset at least six months
before diagnosis: bothersome postprandial fullness, early satia-
tion, epigastric pain, and epigastric burning. The Rome III system
further subdivides FD into postprandial distress syndrome (PDS),
which is the presence of bothersome postprandial fullness and/or
early satiation, and epigastric pain syndrome (EPS), which is the
presence of epigastric pain and/or epigastric burning.4
Dyspepsia is one of the most common disorders in medicine,
with dyspeptic patients seen on a daily basis not only by gastro-
enterologists, but also by physicians in a variety of other fields.
According to the Domestic/International Gastroenterology Sur-
veillance Study (DIGEST) published in 1999, 9% of Japanese
adults experienced moderate or more severe dyspeptic symptoms
at least once per week,5 and 34% of those persons were seen by a
healthcare provider.6 In recent years, as health awareness has
increased, medical checkups and comprehensive medical exami-
nations (so-called “ningen [human] dock”) have become more
common, and the prevalence of Helicobacter pylori infection has
decreased,7 the proportion of dyspepsia patients with organic
disease that explains their symptoms seems to be decreasing.
Indeed, in a study of consecutive outpatients who visited a univer-
sity hospital, about 40% of those with abdominal symptoms as
their chief complaint were diagnosed with functional gastrointes-
tinal disorders.8 Unfortunately, despite the large number of FD
patients, there are almost no treatments for FD that have shown
superiority to placebo in rigorous clinical studies.9 We hope that
study of the pathophysiology of FD will lead to the development of
effective evidence-based treatments for FD patients.
Factors related to the pathophysiology
of FD
Why do FD patients experience symptoms despite the apparent
absence of organic disease? Symptoms are normally perceived
mainly in the brain, and one would expect dyspeptic symptoms
to result from the perception of stimuli from the stomach and

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© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
Pathogenesis of functional dyspepsia
duodenum; yet in FD, those organs do not show organic abnor-
malities. Are there functional abnormalities? Or are there micro-
scopic abnormalities that cannot be seen macroscopically? Or is
the brain perceiving symptoms despite the absence of any cause?
Generally, the pathophysiology of FD is thought to involve factors
including gastric motility abnormalities, visceral hypersensitivity,
and gastric acid secretion abnormalities.
Motility abnormalities
The possibility of a relationship between motility abnormalities
and dyspeptic symptoms has been investigated for a comparatively
long period of time, but the results have not been particularly
clear.10 Recently, however, it has been learned that postprandial
gastric motility has two phases—a phase when an accommodation
reflex occurs in the proximal stomach (fundus) after food con-
sumption, and a subsequent phase when distal gastric distension
occurs after a delay—and it is becoming clear that the proximal
gastric distension that occurs in the first phase correlates fairly
well with dyspeptic symptoms.11,12 By using a barostat connected
to a polyethylene-vinyl balloon, the gastric accommodation reflex
was found to occur in the gastric fundus when a nutrient was
consumed. This reflex, which is also known as the “reservoir
function of the stomach,” is thought to serve the biological purpose
of food storage. However, 40% to 50% of FD patients show
impaired gastric accommodation, and this impairment is thought
to cause early satiation.13 Thinking that it might be possible to
evaluate gastric accommodation with gastric scintigraphy, a
method normally used to evaluate of gastric emptying, our group
prepared the scintigrams in shown in Figure 1. These scintigrams
show gastric food distribution in a healthy subject and an FD
patient after the subjects had consumed solid food. Even though
the subjects were in the upright position, most of the food was
retained in the fundus of the healthy subject, indicating that the
accommodation reflex occurred. In the FD patient, most of the
food was transferred to the distal stomach soon after ingestion,
suggesting that the accommodation reflex may have been
impaired.
54
© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
H Miwa et al.
Figure 1 Postprandial gastric food distribu-
tion in a healthy subject and an FD patient. The
scintigrams show food distribution in the
stomach after ingestion of solid food by a
healthy subject (A) and an FD patient (B). Even
though the experiment was performed with
the subjects in the upright position, most of the
solid food was retained in the fundus of the
healthy subject, indicating that the accommo-
dation reflex occurred. In the FD patient, most
of the food was transferred to the distal
stomach soon after ingestion, suggesting that
the accommodation reflex may have been
impaired.
Delayed gastric emptying, experienced by the patient as a heavy
feeling in the stomach, has been known to be a feature of FD for
some time. Gastric scintigraphy with radioisotopes is the standard
method used for direct evaluation of gastric emptying. Although
presently there does not seem to be a strong direct relationship
between gastric emptying and dyspeptic symptoms,10 the relation-
ship between gastric emptying time and dyspeptic symptoms had
previously attracted substantial interest.10 About 40% of FD
patients show delayed gastric emptying after ingestion of solid
food.14
Visceral hypersensitivity
Visceral hypersensitivity has been shown to be involved functional
disorders throughout the gastrointestinal system, including non-
erosive gastroesophageal reflux disease (NERD) in the esopha-
gus,15 irritable bowel syndrome (IBS),16 and FD. The above-
mentioned balloon technique is commonly used to determine the
distension volume at which pain is experienced in the stomach,
and that volume was found to be significantly lower in FD patients
than in healthy subjects.17 Indeed, 35% to 50% of FD patients are
said to be hypersensitive to gastric distension stimuli.17,18 The
result of the balloon distension experiment shown in Figure 2
demonstrates the gastric hypersensitivity of FD patients.17 This
result suggests that FD patients may experience as symptoms an
increase in stomach contents of a size that normally would not be
perceived (allodynia). Such gastric hypersensitivity is said to be
related to symptoms including postprandial pain, belching, and
weight loss.18 In addition to hypersensitivity to gastric distension,
FD patient also seems to have hypersensitivity in the stomach and
duodenum to acid, bile acid, and some nutrients.19
Progress is also being made in basic research on the mechanism
of visceral hypersensitivity. Studies conducted so far have shown
that central sensitization at the junctions of primary sensory
neurons (nerve fibers from the gastrointestinal organs to the dorsal
spinal roots) and secondary neurons (nerve fibers from the dorsal
spinal roots to the brainstem) play an important role in hypersen-
sitivity.20 In addition, the role of NMDA (N-methyl-D-aspartate)
Journal of Gastroenterology and Hepatology 26 (2011) Suppl. 3; 53–60
H Miwa et al.
100
Percenta
P
80
age of patients with
60
40
w pain
20
n
100 200 300 400 500 600 700 800
Intragastric
I i volume
l ((mL)
L)
Figure 2 Pain threshold in FD patients and healthy subjects examined
by balloon distension. A balloon was placed in the stomach of FD
patients and healthy subjects, and the pain threshold was determined
as the balloon was inflated. No healthy subjects experienced pain until
the balloon had been inflated to a volume of 400 mL, but at that volume,
about one half of the FD patients experienced pain. This showed that
the FD patients were hypersensitive to the distension stimulus.
Adapted from Lemann et al.17 with modifications. , FD (n = 24);
, Healthy control (n = 24).
receptors for the excitatory neurotransmitter glutamic acid at those
junctions has attracted particular attention.21,22
Psychosocial factors
Psychosocial factors are deeply involved in the pathophysiology of
FD. The strong effect of psychological factors on gastrointestinal
function has been well known for a long time. A famous paper
published in 1949 reported an experiment in which 22-year-old
medical student had marked intestinal contractions immediately
after being informed of the disease name rectal cancer,23 and
everyone has probably experienced diarrhea or abdominal pain
when under stress. In a recent large-scale epidemiological study,
persons with FD symptoms did not show differences in depression
scores from persons without FD symptoms, but did show signifi-
cantly higher anxiety scores.24 We suspect that many physicians
who interact with FD patients may have the impression that such
patients are prone to psychological abnormalities. There also have
been many reports concerning psychological symptoms in FD
patients.25,26 The involvement of psychosocial factors in FD is also
strongly suggested by the fact that FD patients respond to placebos
at higher rates (35% to 40%) than do patients with other diseases,
and that FD patients respond to hypnotherapy.27 Recently, several
reports containing experimental evidence of modification of
gastrointestinal function by psychological factors have received
attention.28,29
Journal of Gastroenterology and Hepatology 26 (2011) Suppl. 3; 53–60
© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
Pathogenesis of functional dyspepsia
Excessive secretion of gastric acid
Gastric acid is also attracting attention as a causative factor in FD.
Proton pump inhibitors (PPIs), which inhibit secretion of gastric
acid, have been reported to be extremely effective in uninvesti-
gated dyspepsia (i.e. dyspepsia that has not been investigated
endoscopically),30 and it was hoped that they would also prove to
be effective in FD. Recently, it has been shown that perfusion of
acid solution (pH 1) into the stomach31 or duodenum32 induces a
variety of dyspeptic symptoms, which strongly suggests that such
symptoms are related to acid. Figure 3 shows the results of a
double-blind study in which acid and water were perfused into the
stomachs of healthy adult volunteers, and their symptoms were
investigated.31 The results show that intragastric perfusion of acid
induced dyspeptic symptoms even in healthy adults, and that those
adults manifested a variety of dyspeptic symptoms.
Nevertheless, based on the clinical trial data obtained so far, the
therapeutic efficacy of PPIs in FD patients has not been especially
impressive. Although PPIs showed efficacy in FD patients in
studies conducted in Europe and the United States,33,34 they did not
in a study conducted in Asia.35 PPIs are widely known to be useful
as the initial treatment of patients with uninvestigated dyspepsia,9
but many of those patients probably have gastroesophageal reflux
disease (GERD), so the efficacy of PPIs in FD should be consid-
ered separately.
Helicobacter pylori
H. pylori infection is thought to be a cause of FD symptoms.
Although the relationship between H. pylori infection and FD has
been studied vigorously, consistent results on the response of FD
symptoms to H. pylori eradication therapy have not been obtained.
Discussion of improvement in symptoms must be based on ran-
domized, double-blind clinical studies, but despite the fact that
many rigorous, high-quality clinical studies have been conducted,
the question as to whether treating H. pylori infection improves FD
symptoms remains highly controversial.36,37 In our randomized,
double-blind study conducted to investigate this question in Japa-
nese FD patients, no significant difference in symptoms between
the treatment group and the placebo group was observed.38
However, a study conducted in Chinese patients found that eradi-
cation of H. pylori improved FD symptoms.39 A meta-analysis
showed that H. pylori eradication therapy significantly improved
the symptoms of FD patients, but the effect was not large; in order
to eliminate the symptoms in one patient, it was necessary to
administer the therapy to 15 patients.40 Given this result, it is
difficult to believe that H. pylori infection is an important factor in
the pathophysiology of FD. Clinical practice guidelines from Asia
on H. pylori infection do maintain that H. pylori infection accom-
panying FD should be eradicated; however, since they also recog-
nize that the effect of such eradication on FD will be limited, the
statement was probably made taking into consideration the benefit
to society that results from preventing ulcers and cancer by eradi-
cating H. pylori.41
Genetics
It has been hypothesized that genetic factors predispose
some persons to FD. The finding that manifestation of dyspeptic
55
Pathogenesis of functional dyspepsia H Miwa et al.

bloating*

satiety abdominal
distension*
* p<0.05
paired t test
n=27 (cm × min)

5
heartburn nausea*

15

25

gastric pain belching*

Figure 3 Induction of dyspeptic symptoms in healthy subjects by intragastric perfusion of acid. The involvement of acid in the manifestation of upper
abdominal symptoms was investigated by perfusing acid into the stomachs of healthy adult volunteers, and noting the type and severity of the
symptoms experienced by the subjects. Although the types of symptoms and their severity varied widely by subject, intragastric perfusion of
acid induced symptoms that were significantly more severe than those induced by perfusion of water. Since significant differences between acid
and water were observed for bloating, abdominal distension, nausea, and belching, which have been considered dysmotility-type symptoms, the
results demonstrated experimentally that acid causes not only pain, but also dysmotility-type symptoms. Adapted from Miwa et al.31 with modifica-
tions. , Distilled water; , Acid (0.1M HCl).

(a) (b)
**
100% 100%

80% 80%
41.6 51.0 58.2
Figure 4 G-protein beta-3 subunit position
60% 60%
825 genotypes and GI symptoms. Manifesta-
tion of dyspeptic symptoms is associated with
40% 40% SNP genotypes at position 825 of the G-protein
beta-3 subunit gene (GNB3). In the initial data,
20%
* which were obtained from Germans, a higher
20% 41.9
26.5 32.4
32 4 frequency of abdominal symptoms was asso-
0% ciated with the CC genotype (A). In Japanese,
0% abdominal symptoms were present at higher
blood blood donor FD control FD EPS
donor
d with
ith symptt (n=67)
( 67) ( 761)
(n=761) ((n=68)
68) ((n=43)
43) frequency in persons with the TT genotype (B).
(n=161) (n=98) Adapted from Holtmann et al.42 and Oshima
**P = 0.007 *P = 0.03 vs CC/CT et al.44 with modifications. , CC; , CT; , TT.

symptoms is associated with a single-nucleotide polymorphism
(SNP) genotype at position 825 of the G-protein beta-3 subunit
gene (GNB3)42 touched off much research in the field of FD.
Subsequently, many studies related to genetic polymorphisms
associated with predisposition to FD appeared; however, for
various reasons including the fact that in most of those studies
the odds ratio of the genetic mutations having an effect was
only about 2 to 3,42–45 there is a need for further research on the
clinical significance of genetic polymorphisms as causative
factors for FD. It is interesting that the results of the studies
varied by race and geographical region. The initial data on
the above-mentioned GNB3 SNP, which were obtained in
Germans, showed a higher frequency of abdominal symptoms in
persons with the CC homozygous genotype,42 but in Japanese,
abdominal symptoms were present at higher frequency in
persons with the TT homozygous genotype44,45 (Fig. 4). Further-
more, a study from the United States found that the CT heterozy-
gous genotype was in involved in manifestation of abdominal
symptoms.43 Thus, it is possible that genetic relationships vary
by race and geographic region. It is also interesting that genetic
differences may help explain regional differences in the inci-
dence of FD.5

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H Miwa et al.
Environment
It has been observed for a comparatively long time that severe
stress, particularly during childhood or adolescence, contributes to
development of the functional gastrointestinal disorder IBS. The
frequency of sexual abuse was significantly higher in college stu-
dents with IBS than in controls,46 and the risk of IBS was increased
in persons who were exposed to wartime conditions during early
life.47 In the neonatal maternal separation model of IBS, rats that
are separated from their mothers for 2 to 3 h per day for 2 to
3 weeks during the neonatal period experience nearly intolerable
stress, and after maturing, exhibit defecation abnormalities and
hypersensitivity.48,49 These results suggest that in human traumatic
stress during early life may be associated with development of IBS
later in life. In addition, when Persian Gulf War veterans who had
experienced high stress during the war were subjected to cutane-
ous and visceral (rectal distension) pain stimuli, both somatic and
visceral sensitivity were increased,50 suggesting that severe stress
during adulthood can also affect visceral sensitivity. These data are
not easy to interpret. Recently, there have been similar reports
concerning FD. Gastric hypersensitivity was greater in FD patients
with a history of physical or sexual abuse in childhood than in
control FD patients, and a history of abuse after reaching adult-
hood was associated with changes in gastric accommodation.51
Although the mechanism by which traumatic stress in early life
affects the development of functional gastrointestinal disorders is
still unclear, such stress probably should be recognized as a patho-
genic factor.
Dietary factors and lifestyle
It is highly likely that diet affects manifestation of FD symptoms,
but the number of studies addressing such effects remains rela-
tively small. Dietary factors include factors directly related to food
ingestion, such as patterns of nutrient intake and potential intoler-
ance to specific foods or macronutrients, and cognitive factors.52
Since FD symptoms are often triggered by ingestion of food, the
relationships between FD symptoms and foods should probably
receive greater attention. So far, there have been reports that inges-
tion of fat may worsen dyspeptic symptoms,53,54 and that abdomi-
nal fullness is correlated with ingestion of fat and amount of food
ingested.53 Another study showed that glutamic acid promoted
gastric motility after ingestion of high-protein, high-calorie food.55
In addition, Gonlachanvit recently proposed the interesting idea
that since rice and spicy food (chili pepper) decrease dyspeptic
symptoms, the consumption of large amounts of such foods in
some Asian countries may explain the low prevalence of dyspeptic
symptoms there.56 On the other hand, there are epidemiological
studies that did not find a clear relationship between diet and
dyspeptic symptoms,57,58 so additional research is necessary.
There has not been much research on the relationship between
lifestyle and FD. A report of the Functional Dyspepsia Research
Group of The Japanese Society of Gastroenterology notes that
many persons with dyspeptic symptoms have an irregular lifestyle,
and opines that it is highly likely that diet and lifestyle are related
to dyspeptic symptom improvement and exacerbation (unpub-
lished data). Lifestyle factors including poor socio-economical
status, smoking, excessive caffeine consumption, poor living envi-
ronment, and chronic illness are thought to cause or exacerbate
Journal of Gastroenterology and Hepatology 26 (2011) Suppl. 3; 53–60
© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
Pathogenesis of functional dyspepsia
dyspeptic symptoms,59–62 but it is difficult to identify the risk
factors for FD among the risk factors for dyspepsia in general.61
Post-infectious FD
A number of studies have focused on the risk of post-infectious
FD. The risk of developing IBS was found to increase after Sal-
monella infection.63,64 Likewise, a cohort study found that the risk
of developing FD increased in patients with acute Salmonella
enterogastritis; this is so-called post-infectious FD. Tack et al.
studied 400 dyspeptic patients by recall and found that 17% of the
cases were post-infectious and that the post-infectious FD patients
had certain characteristics, such as higher prevalence of early
satiety.65 Subsequently, Mearin et al. reported that one year after
an outbreak of acute Salmonella gastroenteritis, the prevalence of
FD and IBS was higher in the persons who had experienced
Salmonella gastroenteritis than in controls; FD occurred in one of
seven post-infectious persons, which was an incidence 5.2 times
higher than that in the controls. Persons who had experienced
severe abdominal pain and vomiting during gastroenteritis were
more likely to develop FD.66 Recently, a study from Japan found
that infiltration of the duodenal mucosa by macrophages was sig-
nificantly increased in post-infectious FD patients,67 and attracted
attention as step toward elucidation of the pathological mechanism
of post-infectious FD.
Interaction of pathogenic factors
As discussed above, the pathophysiology of FD is thought to
involve multiple factors. We think that those factors interact and
cause changes in physiological function that lead to the symptoms
of FD. The question is, how are the factors related? Those rela-
tionships are extremely complex, but motility disorders and vis-
ceral hypersensitivity are generally thought to be the functional
abnormalities that are directly linked to symptoms. Although there
probably are many researchers who would cite psychosocial
factors as pathogenic factors equivalent in importance to motility
disorders and visceral hypersensitivity, we think that rather than
causing symptoms themselves, psychological factors cause symp-
toms by powerfully modifying physiological functions.
Gastric acid provides a good example of the interaction of
different pathogenic factors in FD. In healthy persons, dyspeptic
symptoms usually do not occur, even though substantial amounts
of gastric acid are secreted; however, if 100 mL of hydrochloric
acid (pH 1) is instilled in the stomachs of healthy persons, such
symptoms do occur, albeit with differences among individuals.31
Because the onset of the symptoms is delayed somewhat from
instillation of the acid, it is inferred that the symptoms are caused
by duodenal acidification as the acid enters the duodenum. Lee
et al. showed that when acid was instilled directly into the duode-
num though a tube, gastric accommodation occurred unrelated to
ingestion of food and the threshold for perception of gastric dis-
tention was decreased.32 Thus, in the above-mentioned study,
abnormal gastric motility and hypersensitivity were probably
caused by influx into the duodenum of acid that had been instilled
in the stomach. This simulated abnormality in physiological func-
tion directly caused dyspeptic symptoms. But why does gastric
acid induce symptoms in FD patients but not in healthy persons?
To answer this question, we instilled gastric acid in FD patients
57
Pathogenesis of functional dyspepsia
Inflammation
H. pylori
infection Immunity
Increased
acid
Psychosocial
factors
Motility disorders Hypersensitivity
GI symptom manifestation
and healthy volunteers according to the same procedure, and
looked for differences in manifestation of symptoms. Despite the
instilled volume of gastric acid being the same, the FD patients
experienced a greater number of types of symptoms (P < 0.01) and
greater severity of symptoms (P < 0.01) (unpublished data, data
not shown). These results suggest that the FD patients were hyper-
sensitive to acid. The same effect would probably be observed
when acid is secreted to such an excess that it cannot be neutral-
ized in the duodenum. Thus, it seems that dyspeptic symptoms are
caused by effects of acid on motility and perception, with hyper-
sensitivity also playing a role. It is possible that psychological
stress, mediated by the autonomic nervous system, modifies acid
secretion, and in H. pylori infection, there is probably a period
when acid secretion is increased. Acid secretion is also affected by
diet and lifestyle, which need hardly be mentioned, and by genet-
ics. Thus, when considering acid as a pathogenic factor, one must
understand the role of acid itself, and also its interaction with a
variety of other factors.
The same is true for psychophysiological factors. The patho-
genic mechanism of such factors may be to alter the physiological
function of the stomach. Experimentally induced anxiety caused
inhibition of meal-induced gastric relaxation,28 and auditory stress
decreased the esophageal perception threshold.29 Everyone has
probably experienced early satiation and loss of appetite from
stress and anxiety in daily life. In FD patients too, anxiety and
other psychological factors probably alter the physiological func-
tioning of the stomach and duodenum, and thereby cause dyspep-
tic symptoms. It is common knowledge that psychophysiological
factors are strongly affected by genetics, and such factors also
probably affect acid secretion. Interestingly, environmental factors
such as mental or physical trauma during early life or extremely
severe mental or physical trauma have also been hypothesized to
be strongly involved in FD by their possibly causing psychological
deviation and altering responsiveness to stress.
58
© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
H Miwa et al.
Dietary factors
Lifestyle
Genetics
Environment
Figure 5 Relationships among suggested
pathogenetic factors of FD. Many factors inter-
acting in a complex web of relationships con-
tribute to the manifestation of FD symptoms.
Ultimately, the factors directly connected to
symptoms are probably gastric motility and
hypersensitivity.
Relationships among possible factors involved in FD pathogen-
esis are diagrammed in Figure 5. The factors interact in a complex
web, but we think that ultimately the symptoms of FD are directly
connected by gastric motility disorders and hypersensitivity. Nev-
ertheless, it is well understood from experience that symptoms are
often induced by psychological or physical stress. How stress is
related to the other factors is a question that should be further
explored in future research.
Conclusion
The pathophysiology of FD involves many factors and is complex.
The important point is that the pathogenic factors interactively
contribute to manifestation of FD symptoms. Gastric motility and
hypersensitivity have attracted attention as factors connected to
symptoms, but the factor that directly causes symptoms is prob-
ably psychological and physical stress. If research focuses solely
on the physiology of the digestive tract, the role of stress cannot be
addressed. Therefore, in addition to study of physiological abnor-
malities of the digestive tract, research on the relationship between
the digestive tract and the central nervous system must be pursued.
Elucidation of the pathophysiology of FD should lead to the
understanding of why we experience FD symptoms. We will be
very pleased if this understanding results in new treatments for FD.
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