Recent advances in clinical practice
Gut: first published as 10.1136/gutjnl-2019-318536 on 29 November 2019. Downloaded from http://gut.bmj.com/ on November 30, 2019 at Lund University Libraries. Protected by copyright.
1
Gastroenterology and
Hepatology, University Hospitals
Leuven, Leuven, Belgium
2
Translational Research in
Gastrointestinal Disorders, KU
Leuven, Leuven, Belgium
3
Faculty of Health and Medicine,
University of Newcastle,
Newcastle, New South Wales,
Australia
4
School of medicine and
public Health, Hunter Medical
Research Institute, New
Lambton Heights, New South
Wales, Australia
5
Anatomical Pathology,
University of Newcastle,
Newcastle, New South Wales,
Australia
Correspondence to
Professor Nicholas J Talley,
Health, University of Newcastle,
Callaghan, NSW 2305,
Australia;
​Nicholas.​Talley@n​ ewcastle.​
edu.a​ u
Received 29 May 2019
Revised 18 November 2019
Accepted 19 November 2019
© Author(s) (or their
employer(s)) 2019. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Wauters L, Talley NJ,
Walker MM, et al. Gut Epub
ahead of print: [please
include Day Month Year].
doi:10.1136/
gutjnl-2019-318536
Novel concepts in the pathophysiology and treatment
of functional dyspepsia
Lucas Wauters,1,2 Nicholas J Talley  ‍ ‍,3,4 Marjorie M Walker,5 Jan Tack,1,2
Tim Vanuytsel1,2
ABSTRACT
Emerging data increasingly point towards the duodenum
as a key region underlying the pathophysiology of
functional dyspepsia (FD), one of the most prevalent
functional GI disorders. The duodenum plays a major
role in the control and coordination of gastroduodenal
function. Impaired duodenal mucosal integrity and low-­
grade inflammation have been associated with altered
neuronal signalling and systemic immune activation,
and these alterations may ultimately lead to dyspeptic
symptoms. Likely luminal candidates inducing the
duodenal barrier defect include acid, bile, the microbiota
and food antigens although no causal association
with symptoms has been convincingly demonstrated.
Recognition of duodenal pathology in FD will hopefully
lead to the discovery of new biomarkers and therapeutic
targets, allowing biologically targeted rather than
symptom-­based therapy. In this review, we summarise
the recent advances in the diagnosis and treatment of FD
with a focus on the duodenum.
Introduction
Functional dyspepsia (FD) is a chronic GI disorder
defined by upper abdominal symptoms consid-
ered to originate from the gastroduodenal region
with no structural disease on routine investigation,
including upper GI endoscopy.1 Two subgroups
of FD were proposed by the Rome III consensus
and following publication of additional supporting
evidence, reiterated in the Rome IV version: post-
prandial distress syndrome (PDS) with postpran-
dial fullness or early satiation, and epigastric pain
syndrome (EPS) with epigastric pain or epigastric
burning.2 In addition, symptoms must be severe
enough to impact on usual activities with a minimal
frequency of 1 (EPS) or 3 (PDS) days per week and
present for 3 months with symptom onset at least
6 months before diagnosis (table 1).2 Patients with
FD have a reduced quality of life and experience
increased healthcare costs with loss of productivity,
confirmed by a recent cross-­sectional population-­
based study.3
A meta-­ analysis using a broad definition
reported that the global prevalence of uninvesti-
gated dyspepsia is 21%, with a higher prevalence
in women, smokers, users of non-­ steroidal anti-­
inflammatory drugs (NSAIDs) and in those with
Helicobacter pylori (Hp) infection.4 Recent figures
from the USA, Canada and UK showed a 10% prev-
alence of FD in the adult population using the Rome
IV criteria, with a similar distribution pattern across
different regions (61% PDS, 18% EPS and 21%
Wauters L, et al. Gut 2019;0:1–10. doi:10.1136/gutjnl-2019-318536
Key messages
►► Functional dyspepsia (FD) refers to a common
unexplained disorder characterised by
epigastric pain and/or postprandial discomfort
(fullness, early satiety).
►► The major FD subgroups are the postprandial
distress syndrome and epigastric pain syndrome
(PDS and EPS, respectively). PDS is the most
prevalent subgroup but often overlaps with
EPS in those who consult and frequently co-­
exists with gastro-­oesophageal reflux and IBS,
resulting in complex and under-­recognised
symptom patterns.
►► Duodenal mucosal hyperpermeability and
low-­grade duodenal inflammation have been
associated with altered neuronal signalling and
systemic immune activation in FD.
►► Psychiatric comorbidity such as anxiety and
depression is common and may arise from gut
dysfunction or immune activation, or in other
cases alter gastroduodenal function potentially
leading to dyspeptic symptom generation.
►► Recognition of subtle pathology in FD may lead
to the discovery of new potential biomarkers
and therapeutic targets, ultimately contributing
to diagnosis and treatment.
►► Future classifications should include markers of
underlying pathophysiology to allow targeted
rather than symptom-­based therapy and to
identify subgroups that respond to specific
interventions.
overlap).3 Whereas PDS is characterised by meal-­
related symptoms, epigastric pain and/or burning in
EPS may be unrelated to the meal although patients
often under-­ report meal-­
related pain because it
may be delayed after eating.5 Although the PDS-­
EPS overlap group is still substantial, recognising
postprandial symptoms (including epigastric pain
or burning) as part of the PDS subgroup in Rome
IV substantially reduced overlap compared with the
Rome III definition.2 6 In FD, symptoms of upper
abdominal bloating, belching, heartburn and nausea
can be present, although functional nausea and
vomiting, and functional bloating are categorised
separately.
Symptoms of heartburn and/or IBS often co-­exist
with FD. Heartburn in FD may be due to patholog-
ical acid reflux or functional heartburn.7 Although
functional heartburn (12%) and IBS (32%)
were independent factors associated with all FD
   1
 Recent advances in clinical practice

Box 1  FD subgroups and overlap
►► Distribution of functional dyspepsia (FD) subtypes was similar
across countries (61% postprandial distress syndrome (PDS),
18% epigastric pain syndrome and 21% overlap) with a 10%
prevalence in the adult population (Rome IV).
►► PDS is characterised by meal-­related symptoms and
recognising postprandial symptoms (eg, epigastric pain or
burning) as part of the PDS subgroup reduces overlap.
►► Epigastric bloating, belching and nausea as well as weight
loss are part of the dyspepsia spectrum, but vomiting
suggests an alternative diagnosis.
►► Symptoms of heartburn and IBS are independently associated
with all FD subtypes and especially the overlap group, which
may be related to duodenal eosinophilia.
Gut: first published as 10.1136/gutjnl-2019-318536 on 29 November 2019. Downloaded from http://gut.bmj.com/ on November 30, 2019 at Lund University Libraries. Protected by copyright.
peripheral manifestations from an Australian longitudinal study
illustrated that depression without GI symptoms at baseline
predicted FD, whereas anxiety and depression developed in FD
patients without psychological comorbidity at baseline after 12
years of follow-­up.19 Similar results were obtained in an inde-
pendent population sample.20 These findings indicate an oppor-
tunity for prevention, as an average period of more than 3 years
was noted before the development of GI symptoms in patients
with mood or anxiety disorders.21
Gastric sensorimotor abnormalities
Abnormalities of gastric function including delayed emptying,
impaired accommodation and hypersensitivity to distention have
been reported in FD, but these changes correlate poorly or not at
all with symptoms.22 Moreover, the prevalence of altered gastric
sensorimotor function was similar in the Rome III-­defined PDS

Table 1  Rome IV criteria for FD

Rome IV criteria Frequency, duration and onset Remarks and other symptoms
FD Bothersome postprandial fullness, early ≥1 symptom for the past 3 months with Vomiting suggests another disorder. Symptoms should not be
satiation, epigastric pain or burning AND onset ≥6 months before diagnosis relieved by evacuation of faeces or gas. Symptoms of GORD and
no evidence of structural disease likely to IBS may coexist with FD (PDS and EPS).
explain symptoms
PDS Bothersome postprandial fullness and/or ≥3 days/week for the past 3 months with Postprandial epigastric pain or burning, epigastric bloating,
early satiation severe enough to interfere onset ≥6 months before diagnosis excessive belching, nausea and heartburn can be present.
with daily activities or to prevent finishing
a meal
EPS Bothersome epigastric pain and/or epigastric ≥1 day/week for the past 3 months with Postprandial epigastric bloating, belching and nausea can be
burning severe enough to interfere with daily onset ≥6 months before diagnosis present. Pain may be induced or relieved by ingestion of a meal or
activities occur while fasting and does not fulfil biliary pain criteria.
EPS, epigastric pain syndrome; FD, functional dyspepsia; PDS, postprandial distress syndrome.

subtypes, the strongest association was found with the overlap-

ping group.3 In the Swedish Kalixanda study, overlap of FD was
present with GORD in 4%, IBS in 2% and both in 6%.8 In a
follow-­up study, new-­onset GORD was common in FD with a
higher risk in patients with duodenal eosinophilia.9 10 Moreover,
a population-­based study from Mayo Clinic concluded that FD is
often underdiagnosed and mislabelled as GORD (box 1).11
and EPS subgroups in a large tertiary care study, suggesting a
limited contribution to symptom generation.22 Although cardinal
FD symptoms did not correlate with gastric emptying,23 24 a
recent systematic review and meta-­analysis supported associa-
tions between upper GI symptoms and gastric emptying when

Translational science concepts

Brain-gut interactions
Functional GI disorders are classified by the Rome IV criteria
as disorders of gut-­brain interaction with contributions of both
altered brain processing and luminal changes including dysbi-
osis (figure 1).12 13 Up to half of the subjects with uninvestigated
dyspepsia in the general population identify stress as a trigger for
their symptoms.14 There is evidence to support that the effect of
stress may be mediated by increased permeability and immune
activation.15 Recent preclinical studies indicate that stress can
lead to intestinal dysbiosis, which in turn affects central nervous
system function and behaviour,16 and these findings have led
to the concept of the bidirectional ‘brain-­ gut axis’ although
supporting human data are scarce. A systematic review of func-
tional neuroimaging studies in FD concluded that several brain
regions including the frontal and somatosensory cortex showed
anomalies.17 Abnormal central modulation (brain to gut) and
overactive visceral sensory signalling (gut to brain) may both
be involved in the pathophysiology of FD, and these pathways
are likely activated or modulated through psychological factors Figure 1  The gut-­brain axis in FD and mechanisms of overlap
and the hypothalamic-­pituitary-­adrenal axis stress response.17 18 with GORD and IBS. FD, functional dyspepsia; TLESR, transient lower
Evidence for a bidirectional interaction between central and oesophageal sphincter relaxation.
2 Wauters L, et al. Gut 2019;0:1–10. doi:10.1136/gutjnl-2019-318536
 Recent advances in clinical practice

optimal test methods were used.25 The distinction with gastropa-
resis should be made as nausea may be present but vomiting is
unusual in FD,2 and nausea and vomiting are significant symp-
toms in idiopathic and diabetic gastroparesis.26 Gastric hyper-
sensitivity and impaired accommodation may overlap, and no
association with symptoms was found for (dys-­)accommodation
except for severe PDS symptoms.22 27 Indeed, dyspeptic symp-
toms were significantly associated with psychosocial factors such
as depression and somatisation and to a lesser extent with gastric
sensorimotor function.28 As impaired gastric accommodation
was reported in 43% of 1267 patients with functional gastro-
duodenal symptoms seen at a single tertiary centre and half of
these patients also had abnormal gastric emptying, the study and
treatment of gastric motor dysfunction likely remain relevant in
at least a subset of patients.29
Emerging data increasingly point towards the duodenum as
the key integrator in dyspepsia symptom generation, and it has
been proposed that gastric motor dysfunction may be attributed
to disordered duodeno-­ gastric feedback.30 31 Several studies
have now reported duodenal mucosal low-­grade inflammation
and increased small intestinal homing T cells as markers of
intestinal inflammation, which correlated with delayed gastric
emptying and dyspeptic symptom severity.32 33 Evidence for
the role of duodenal inflammation in neuronal signalling in FD
comes from a study in Leuven showing correlations between
duodenal eosinophils or mast cells and calcium transient ampli-
tudes to high K+ or electrical stimulation.34 The exact mecha-
nism through which duodenal inflammation induces neuronal
hyperexcitability is still incompletely understood, but in analogy
to IBS, a role for histamine and proteases—among others—is
Gut: first published as 10.1136/gutjnl-2019-318536 on 29 November 2019. Downloaded from http://gut.bmj.com/ on November 30, 2019 at Lund University Libraries. Protected by copyright.
hypothesised. Therefore, gastric disturbances could be secondary
and not primary in FD.35 Also, altered duodeno-­gastric reflexes
and impaired gastric accommodation may underlie co-­existing
reflux symptoms through increased transient lower oesophageal
sphincter relaxations leading to new-­onset GORD, as heartburn
was found to develop more often in patients with duodenal
pathology including duodenal eosinophilia.10 36 Moreover, it has
also been suggested that overlapping IBS symptoms in FD could
be explained by more extensive intestinal inflammation with
alteration of neuronal signalling and visceral hypersensitivity37
(figure 1).
Duodenal barrier defect and immune activation
The duodenum has emerged as a key player in both GI and
metabolic diseases as it regulates the passage of food as chyme
from the stomach to the small intestine, where nutrients
are absorbed.38 Autocrine and paracrine mechanisms in the
duodenum are also involved in the mucosal defence to acid
and the luminal digestion of nutrients with secretion of bile
and pancreatic juice.39 Activation of duodeno-­ gastric feed-
back mechanisms by chemical or mechanical triggers influ-
ences gastric emptying, with an important role of intestinal or
pancreatic hormones including incretins and gastric orexigenic
hormones, which also signal to the brain.40 Besides nutrient
sensing, transmucosal passage of luminal content is likely in
the proximal small intestine due to regional variation in the
mucosal barrier along the GI tract and the crypt-­villus axis,
ranging from >20 angstrom at the crypt base to 5 angstrom
at the villus tip in the proximal small intestine, which is also

Figure 2  The duodenal microenvironment in health and FD with pathophysiological mechanisms. In health (left), duodenal luminal content is
separated from the mucosal immune system by an intact duodenal barrier. In case of duodenal barrier dysfunction such as observed in FD (right),
luminal triggers from altered duodenal content and/or dysbiosis may lead to both local and systemic immune activation with disturbed signalling
of duodeno-­gastric feedback mechanisms by neuronal changes in afferent nerves. These changes in the duodenal microenvironment may generate
dyspeptic symptoms. Arrows (red) indicate impaired duodenal mucosal integrity and eosinophil-­mast cell signalling. FD, functional dyspepsia.
Wauters L, et al. Gut 2019;0:1–10. doi:10.1136/gutjnl-2019-318536 3
 Recent advances in clinical practice
the most permeable region with the largest intercellular pores
of the GI tract.41 Although the small bowel microenvironment
with a loose glycocalyx (which covers the brush border on the
apical surface of the epithelial cells) allows for a closer inter-
action between the lumen and the host cells in comparison
with the colon, the defence against potential noxious luminal
factors is reflected in the barrier function and distribution
of immune cells42 (figure 2). Ussing chamber experiments
have shown an increased duodenal mucosal permeability
in FD with a lower transepithelial electrical resistance and
higher paracellular passage of fluorescent-­ labelled dextran
molecules.32 The expression of particular cell-­ to-­
cell adhe-
sion proteins, including tight junctions (ZO-1 and occludin),
adherins junctions (β-catenin and E-­ cadherin) and desmo-
somes (desmoglein-2), was also significantly decreased and
correlated with duodenal hyperpermeability and the severity
of low-­grade mucosal inflammation, including duodenal mast
cells and eosinophils.32 This study of FD patients from Leuven
(Belgium) confirmed the initial reports on duodenal eosin-
ophilia in adults from Sweden43 and activation of duodenal
eosinophils in children in an uncontrolled pilot study from the
USA.44 Studies using duodenal mucosal impedance measure-
ment also showed lower values in FD patients although the
comparison with controls did not reach statistical significance
after adjusting for potential confounders (eg, NSAIDs).45
Mucosal impedance values were also positively correlated
with ZO-1 (tight junction protein) and inversely correlated
with tissue interleukin (IL)-­1b expression, implicating the role
of low-­grade inflammation in duodenal barrier dysfunction.45
However, challenges remain in the interpretation and repro-
ducibility of the experimental methods. One of the limitations
of the ex vivo studies is that only the integrity of the epithelial
layer is measured, lacking both the superficial mucus layer and
innervation by the enteric nervous system, which also affect
mucosal barrier function.
The local and systemic inflammatory changes in FD were
recently summarised in two systematic reviews46 47 (table 2).
Mast cells have been implicated in the pathophysiology of
IBS and stress-­ induced small intestinal hyperpermeability,
measured with the urinary lactulose-­mannitol ratio in healthy
students undergoing psychological stress during an oral exam-
ination.15 The finding of duodenal mast cells in the Leuven
cohort may be explained by overlapping FD and IBS, as mast
cells in the duodenum were characteristic of IBS in another
study.48 The finding of duodenal eosinophilia49–51 was accom-
panied by cytotoxic T cell52 or mast cell32 34 50 53 infiltration in
a subset of studies. Eosinophil-­mast cell signalling may also be
involved in stress-­induced hyperpermeability as administration
of corticotropin-­release hormone, which can activate specific
receptors on both eosinophils and mast cells,54 increased
small intestinal permeability, and this effect was blocked by
pretreatment with the mast cell stabiliser disodium cromogly-
cate (DSCG).15 Increased duodenal mucosal eosinophil counts
have been associated with postprandial symptoms in Austra-
lian adults55 and children.56 The relation between duodenal
eosinophilia and meal-­ related symptoms may be explained
by altered duodeno-­ gastric reflexes and gastric dysaccom-
modation in response to the meal, although studies directly
correlating duodenal abnormalities and gastric sensorimotor
dysfunction are scarce.48 55 Recently, duodenal hyperperme-
ability (measured in Ussing chambers) was correlated with
gastric emptying to solids in an FD patient cohort from Leuven
(Belgium), supporting the hypothesis of altered duodeno-­
gastric feedback in symptom generation.57 Functional and
4 Wauters L, et al. Gut 2019;0:1–10. doi:10.1136/gutjnl-2019-318536
Gut: first published as 10.1136/gutjnl-2019-318536 on 29 November 2019. Downloaded from http://gut.bmj.com/ on November 30, 2019 at Lund University Libraries. Protected by copyright.
structural submucosal neuronal changes have indeed been
reported in the duodenum of FD patients, correlating with
accumulation of eosinophils and mast cells in close proximity
to neurons.34 Activation and degranulation of eosinophils in
the presence of normal numbers may also result in neuronal
changes with dyspeptic symptom generation.44 58 59 Although
systemic markers of inflammation were elevated and linked
with both duodenal hyperpermeability and gastric emptying as
well as dyspeptic symptoms,33 57 local hypersensitivity in the
duodenum could also be implicated in FD.60 61
The most attractive hypothesis for symptom generation is
loss of mucosal integrity as a primary event, which could lead
to immune activation through antigen presentation with a
predominant T-­helper type 2 (Th2) or a Th17 response leading
to recruitment and degranulation of eosinophils, triggering
visceral hypersensitivity and altered motor control1 (figure 2).
Eosinophils are critical effector cells of a Th2 response charac-
terised by Th2 allergic inflammation.62 The consistent finding
of duodenal eosinophilia may help explain the observed link
with atopy in a UK-­based primary care registry of functional
GI disorders including FD63 and also autoimmune disease.64
The association with allergy may indicate a hypersensitivity
reaction in some patients with early satiety.65 Also, associa-
tions of dyspeptic symptoms in the general population with
herbivore but not carnivore pets and antibiotics suggest the
involvement of microbiota-­ related components in the gut
although this was not tested and further studies should control
for allergy and other atopic conditions.66 Thus, a luminal
trigger (food, microbiota or secreted endogenous mediators)
in the duodenum may cause the observed mucosal changes in
FD patients.
Duodenal acid, duodenal bile and dysbiosis
Although the causes of the barrier defect and immune activation
in FD are still unknown, likely candidates include duodenal acid,
bile, stress and food or microbial components. Duodenal acid
perfusion resulted in delayed gastric emptying, impaired accom-
modation and hypersensitivity to distension in healthy subjects,
suggesting a potential role for duodenal acid exposure and alter-
ations in gastric sensorimotor function although these perfusion
experiments do not reflect physiological changes occurring in
the distal duodenum.67–69 Although gastric acid secretion in FD
is normal, an increased duodenal acid exposure, possibly due to
delayed duodenal acid clearance, has been reported with acid
perfusion experiments in FD patients.60 70 Moreover, duodenal
acid perfusion in healthy subjects resulted in both gastric relax-
ation and duodenal mucosal hyperpermeability and mast cell
activation, which were however not reversed by pretreatment
with DSCG.71 The role of food in triggering FD symptoms and its
role in duodenal low-­grade inflammatory changes have remained
unexplored to date. Duodenal hypersensitivity to lipids has been
reported in FD,30 with modulation of upper GI symptoms via
cholecystokinin signalling in response to fat.61 The role of gluten
in FD has not been investigated although symptoms may overlap
with non-­celiac gluten sensitivity, in which duodenal eosinophils
may also cause gastric sensorimotor dysfunction (box 2).72
The release of bile salts in the duodenum has been impli-
cated in the onset or worsening of dyspeptic symptoms after
a meal.73 Bile salts and bacteria have a bidirectional relation-
ship since specific bile salts have antimicrobial effects against
selected bacteria and bacteria are responsible for bile salt trans-
formation, mainly in the colon with reabsorption and reconju-
gation of primary and secondary bile salts before excretion in
 Recent advances in clinical practice

Box 2 New observations in the duodenum
►► Duodenal changes including mucosal hyperpermeability and
low-­grade inflammation have been associated with altered
neuronal signalling and systemic immune activation.
►► Immune activation has been observed, and patients
with functional dyspepsia may have an allergic or atopic
background with a Th2-­predominant immune profile.
►► The cause of the barrier dysfunction is unknown and
likely candidates include duodenal acid, bile salts, food
components, stress and the mucosal microbiome.
►► Gastric dysfunction may be driven by impaired duodeno-­
gastric feedback mechanisms through local signalling or
changes in systemic immune activation.
the duodenum.74 Although bacterial deconjungation may also
occur in the small bowel, deconjugated bile salts were only
reported at or below the detection limit in nasoduodenal aspi-
rates from FD patients with decreased fasted concentrations of
primary bile salts.75 Moreover, a decreased ratio of primary to
secondary bile salts was found during fed state in FD patients
compared with controls, correlating with duodenal mucosal
permeability although secondary bile salt concentrations were
similar between groups.76 These data suggest that the relative
abundance of primary versus secondary bile salts, rather than
their absolute concentrations, affects intestinal barrier function
Gut: first published as 10.1136/gutjnl-2019-318536 on 29 November 2019. Downloaded from http://gut.bmj.com/ on November 30, 2019 at Lund University Libraries. Protected by copyright.
but conclusive evidence is lacking and more in-­depth studies are
needed to elucidate the pathophysiological mechanism.
Immune activation in the pathogenesis of FD is very evident in
the postinfectious setting,77 with persisting changes in duodenal
mucosal immune cells after the initial event and systemic immune
activation in acute compared with unspecified-­onset FD, indicating
the inability of the immune system to recover from the triggering
infectious insult.77 78 Similar to studies in IBS, antibodies to cyto-
lethal distending toxin B, produced by Gram-­negative bacteria
causing acute gastroenteritis, were more common in FD and
IBS/FD overlap compared with healthy controls in an Australian
population-­based study, suggesting possible under-­recognition of
postinfectious FD.79 The disruption in structural and/or func-
tional microbial configuration, defined as ‘dysbiosis’, has been
studied in both functional and inflammatory GI disorders.80 81
Culture-­ independent metagenomics and high-­ throughput 16S
ribosomal RNA gene sequencing have revolutionised our under-
standing of the human gut microbiome or collective genome of
microorganisms inhabiting the GI tract.82 However, the focus
has almost been exclusively on faecal microbiota, which may not
reflect the mucosa-­associated microbiota (MAM).83 In addition,
the duodenal microbiome has hardly been studied although the
commensal gut microbiota of the small intestine play an essen-
tial role in nutrient acquisition, colonisation resistance to patho-
gens, immune development and epithelial barrier function.42
The combination of gastric acid, bile, digestive enzymes and
rapid transit time in the duodenum may contribute to a hostile

Table 2  Mucosal and systemic immune activation in FD

Findings FD subtype Reference
Mucosal immune cells Duodenal eosinophil infiltration NUD (FD) Talley et al 200743
PDS Walker et al 201065
Walker et al 201455
Paediatric Friesen et al 200244
Wauters et al 201744
PI-­FD Futagami et al 201049
Unspecified Walker et al 200948
Vanheel et al 201432
Cirillo et al 201534
Wang et al 201550
Du et al 201658
Tanaka et al 201651
Duodenal eosinophil degranulation Paediatric Friesen et al 200244
Unspecified Du et al 201658
Vanheel et al 201859
Duodenal mast cell infiltration FD-­IBS overlap Walker et al 200948
Unspecified Vanheel et al 201432
Cirillo et al 201534
Wang et al 201550
Yuan et al 201553
Duodenal mast cell degranulation Unspecified Vanheel et al 201859
Duodenal (CCR2+) macrophage infiltration PI-­FD Futagami et al 201049
Kindt et al 200977
Duodenal CD8+T-­cell infiltration Unspecified Gargala et al 200752
Decrease in CD4+ cells PI-­FD Kindt et al 200977
No change in CD3+ lymphocyte
Mucosal cytokines No studies
Circulating immune cells CD45RA+ (naive)/ CD45RO+ (activated) lymphocytes PI-­FD Kindt et al 200978
α4β7-­T cells (gut-­homing) Unspecified Liebregts et al 201133
Circulating cytokines IL-10 PI-­FD Kindt et al 200978
IL-1β and TNF-­a Unspecified Liebregts et al 201133
FD, functional dyspepsia;IL, interleukin ; NUD, non-­ulcer dyspepsia; PDS, postprandial distress syndrome; PI-­FD, post-­infectious functional dyspepsia; TNF, tumour necrosis factor.

Wauters L, et al. Gut 2019;0:1–10. doi:10.1136/gutjnl-2019-318536 5

 Recent advances in clinical practice
Figure 3  Old and new treatments based on potential pathways and therapeutic targets in functional dyspepsia. Effective treatments are indicated
with green boxes and arrows, with solid lines for evidence from randomised controlled trials and dashed lines for evidence from non-­randomised
controlled trials. Red boxes indicate potentially harmful side-­effects of treatments. PPI, proton pump inhibitor.
environment with lower density but greater diversity in the
duodenal bacterial flora compared with the rectum.84 Although
more challenging to study because of the lower bacterial abun-
dance and difficult sampling, host-­ microbiome interactions
could be more important in the small intestine with predom-
inant Gram-­positive aerobes in the duodenum compared with
obligate anaerobes in the colon.80 Data on the duodenal MAM
in FD are currently limited to one pilot study involving nine
FD patients, with an increase in Streptococcus and total bacte-
rial load in the duodenal MAM compared with controls, which
correlated with meal-­related symptom severity and quality of
life.85 However, sample size was small with no information on
medication, which is an important confounder, nor IBS overlap,
which has also been associated with faecal and duodenal dysbi-
osis.80 84 86 87 Interestingly, the abundance of Veillonella in the
duodenal MAM was negatively correlated with gastric emptying
time,88 but replication and further studies are needed in order to
unravel the potential role of the gut microbiota in FD.
Advances in clinical practice
Investigation and management
A systematic review and meta-­ analysis reported that endo-
scopic investigation for dyspeptic symptoms was normal in over
70% of referrals, thus leading to a diagnosis of FD.89 Although
peptic ulcers and gastric cancer have become uncommon and
rarer causes of dyspepsia, upper endoscopy with duodenal and
gastric biopsies is still the preferred diagnostic method for the
exclusion of coeliac disease and Hp infection, which may also
cause dyspeptic symptoms.1 Following Rome IV criteria, the
diagnosis of FD can only be made in the absence of structural
disease including upper endoscopy,2 but this does not exclude
the presence of microscopic changes such as duodenal eosino-
philia. Based on a control group selected from 1001 community
subjects in Sweden,43 a cut-­off of 22 eosinophils per 5 high-­power
fields was proposed for adults,65 although results can also be
expressed per mm2 as shown in adult patients,55 and a duodenal
eosinophil count of >112 per mm2 was associated with a 33-­fold
increased risk of FD in a paediatric Australian cohort.56 Due to
the limited availability of experimental investigations for testing
duodenal barrier (eg, Ussing chambers32 or mucosal impedance
6 Wauters L, et al. Gut 2019;0:1–10. doi:10.1136/gutjnl-2019-318536
Gut: first published as 10.1136/gutjnl-2019-318536 on 29 November 2019. Downloaded from http://gut.bmj.com/ on November 30, 2019 at Lund University Libraries. Protected by copyright.
studies45) and neuronal function (eg, calcium imaging34), new
biomarkers from duodenal biopsies may include mucosal tight
junction proteins32 or IL-­1B expression.45 Nevertheless, none of
these advanced tests can be recommended for routine clinical
practice since their outcome does not affect the management.
The routine use of gastric function testing is questionable as
discussed below.
The complexity of the syndrome indicates a multifactorial
origin, and the lack of effective therapies has been recognised
by international societies such as the American College of
Gastroenterology (ACG) and Canadian Association of Gastro-
enterology (CAG), which have recently issued guidelines.90 As
discussed below, the commonly used therapies affect brain-­gut
or gastric pathways, which do however not always correlate with
symptoms and only limited treatments target the underlying
duodenal pathophysiology (figure 3). In addition, an increased
awareness of side effects has limited the routine use of some
drugs, including neuromodulators and prokinetics. Evidence for
dysbiosis and overgrowth with oral species with proton pump
inhibitors (PPI)91 92 has provided evidence for changes in the gut
environment although the link with GI symptoms is still unclear.
Moreover, although still early days, randomised controlled trials
of probiotics and selective antibiotics have shown improvement
in both symptoms and the microbiome of FD patients.93–95
Targeting brain-gut and gastric abnormalities
The efficacy of neuromodulators versus placebo (risk ratio (RR)
0.78; 95% CI 0.68 to 0.91; number needed to treat (NNT)=6)
was limited to antipsychotics and tricyclic antidepressants
(TCAs) in a recent systematic review and meta-­analysis of 13
studies including 1241 patients.96 In the Functional Dyspepsia
Treatment Trial, amitriptyline but not escitalopram was effec-
tive for the treatment of ulcer-­like (painful) FD, with a three-
fold increased odds of reporting adequate relief of symptoms
compared with placebo.97 In addition, FD patients with delayed
gastric emptying did not respond to amitriptyline and this was
not related to a treatment-­induced delay in gastric emptying,
indicating an effect on visceral sensitivity and abdominal pain
rather than gastric motility.97 98 However, little is known on
the longer-­term efficacy of neuromodulators as the longest

treatment duration was 12 weeks.96 The tetracyclic antidepres-
sant mirtazapine significantly improved PDS symptoms, quality
of life, nutrient tolerance and body weight in a randomised trial
of 34 FD patients with significant weight loss (>10% of orig-
inal body weight) and no depression or anxiety, which could
be linked to the antagonism of histamine-1, adrenergic α2 and
both serotonin-­2C and serotonin-3 receptors.99 Finally, treat-
ment with buspirone, a serotonin-­1A receptor agonist, which
relaxes the proximal stomach in healthy individuals, signifi-
cantly reduced both overall and PDS-­type symptoms in FD and
improved gastric accommodation.100 Although the solid gastric
emptying rate was unchanged, a delay in liquid gastric emptying
was noted but the relevance for dyspeptic symptoms is probably
limited.100
Prokinetics enhance gastric emptying, and although delayed
gastric emptying and impaired gastric accommodation may be
more common in PDS patients, this was not confirmed in a
large study that showed a similar prevalence of gastric motor
abnormalities in Rome III-­defined FD subgroups.22 Moreover,
a systematic analysis of 34 studies showed no evidence of a
correlation between the acceleration of gastric emptying and
symptom improvement in the treatment of diabetic and idio-
pathic gastroparesis.101 Delayed gastric emptying may be present
in about 23% of FD patients, and prokinetics also affect gastric
accommodation and sensitivity, which were disturbed in 37% of
FD patients.22 These effects may explain the significant benefit
of prokinetics in reducing ongoing dyspeptic symptoms (RR
0.81; 95% CI 0.74 to 0.89; NNT=7) in a recent meta-­analysis
of 29 studies involving 10 044 FD patients.102 However, signif-
icant heterogeneity and publication bias were noted and the
overall effect was less convincing after removing cisapride from
the meta-­analysis (NNT=12), which was withdrawn from the
market due to cardiac adverse events.102 Other prokinetics such
as domperidone and acotiamide are not widely available, and
extrapyramidal side effects (for dopamine receptor antagonists)
and QTc prolongation with domperidone limit their chronic use,
leading the ACG/CAG guidelines to recommend TCA in PPI-­
refractory FD patients before prokinetics.90
Acid-suppressive and anti-inflammatory therapies
Acid-­suppressive therapy with PPIs is recommended as first-­
line treatment for FD by the ACG/CAG guidelines90 and the
National Institute for Health and Care Excellence (NICE)103
after eradication of Hp or in Hp-­negative patients. Empirical
PPI therapy before a test-­and-­treat approach for Hp has also
been proposed in cases of low (<20%) Hp prevalence.104 In a
recent Cochrane meta-­analysis including 6172 patients, a reduc-
tion of global dyspeptic symptoms (RR 0.88; 95% CI 0.82 to
0.94; NNT=11) with similar quality of life on PPI compared
with placebo was reported.105 This was confirmed by the
meta-­analysis of the ACG/CAG90 (NNT=10) with no differ-
ences for different doses or types of PPI.90 105 According to
the Rome IV consensus, PPIs are considered ineffective for the
PDS subgroup,2 which was based on the results from an older
meta-­analysis including showing efficacy of PPIs in the epigas-
tric pain but not the dysmotility-­like FD subgroups according
to Rome I and II criteria.106 However, a tendency for a higher
efficacy of PPI in PDS (RR 0.89; 95% CI 0.77 to 1.03) versus
EPS (RR 0.99; 95% CI 0.76 to 1.28) was shown in the recent
Cochrane meta-­analysis although the number of included ‘pure
EPS’ patients was low.105 While the exact mechanism of action
in PDS is unknown, PPIs are beneficial for overlapping GORD
symptoms and may also reduce duodenal acid exposure.30 In
Wauters L, et al. Gut 2019;0:1–10. doi:10.1136/gutjnl-2019-318536
Recent advances in clinical practice
Gut: first published as 10.1136/gutjnl-2019-318536 on 29 November 2019. Downloaded from http://gut.bmj.com/ on November 30, 2019 at Lund University Libraries. Protected by copyright.
addition, anti-­inflammatory effects such as the downregulation
of eotaxin gene transcription seen in eosinophilic oesophagitis
may also reduce duodenal eosinophilia as recently shown in a
cross-­sectional study,107 although this requires confirmation in a
prospective setting, using the Rome IV-­defined subgroups.
Acid suppression with histamine-2 receptor antagonists
(H2RA) is also possible with a lower NNT of 7 compared with
placebo-­ controlled studies of PPI according to a Cochrane
review from 2006 with inclusion of older studies.108 In contrast,
the recent Cochrane meta-­analysis also included studies directly
comparing PPI and H2RA with no difference between both
treatments (RR 0.88; 95% CI 0.74 to 1.04).105 However, due to
the lack of high-­quality comparative trials and superior antise-
cretory effect of PPIs, the ACG/CAG guidelines suggest PPI over
H2RA as first-­line therapy,90 although both are proposed in the
NICE guidelines.103 Anti-­inflammatory effects of H1RA due to
blockade of histamine have been studied in the generation of
visceral hypersensitivity in IBS109 and may also prove benefi-
cial in FD patients with duodenal mast cell infiltration. More-
over, combined histamine-1 and histamine-2 receptor blockade
with the mast cell stabiliser cromoglycate in non-­responders led
to an overall response rate of 90% in dyspeptic children with
duodenal eosinophilia who previously had failed on H2RA.110
The beneficial effect of combined histamine-1 and histamine-2
receptor blockade was also reported in a recent retrospective
case series from Australia with a trend for higher duodenal eosin-
ophil counts at baseline in responders versus non-­responders.111
Treatment with the leucotriene-1 receptor antagonist montelu-
kast resulted in a 62% clinical response rate compared with 32%
on placebo (p<0.02). In another paediatric cohort,112 the short-­
term clinical response of montelukast was not associated with
changes in eosinophil density or activation.113
Targeting duodenal dysbiosis
Although the ACG/CAG and NICE guidelines advice against
dose escalation in case of insufficient improvement with a one
time per day dose of PPI during 4–8 weeks, inappropriate and
prolonged use of PPIs even in the absence of clinical benefit is
frequently reported. Moreover, PPIs have been associated with
an increased risk of enteric infections (including Clostridium
difficile)114 and overabundance of oral or potentially patho-
genic flora in the gastric115 and faecal microbiome.91 Data
on the duodenal microbiota are still lacking. The increase in
oral or potentially pathogenic flora on PPI was represented
by Streptococcus in the gastric MAM, and this may have
contributed to persisting dyspeptic symptoms in a subgroup of
Box 3  Targeted treatments in FD
►► Treatments for brain-­gut and gastric dysfunction, including
neuromodulators and prokinetics, have a limited efficacy and
are hampered by side effects.
►► Proton pump inhibitors may have both acid-­suppressive
and anti-­inflammatory effects in functional dyspepsia (FD)
patients with duodenal eosinophilia and impaired barrier
function.
►► Targeting duodenal inflammation and the eosinophil-­mast
cell axis with mast cell stabilisers and antihistamines requires
studies in adult populations.
►► Duodenal dysbiosis in FD may be treated with selective
antibiotics, such as rifaximin, but requires confirmation in
Western populations.
7
 Recent advances in clinical practice
patients.116 Therefore, this study and others have questioned
the use of PPI therapy in FD patients, as does their limited
efficacy.90 These limited data suggest that stopping PPIs in
patients without a clear benefit may be a first option to target
dysbiosis in FD. Eradication therapy with antibiotics improves
symptoms in Helicobacter pylori-­ related dyspepsia (HpD),
and the effect was greater with metronidazole and in patients
with microscopic duodenitis,117 118 suggesting an effect on the
duodenal microbiome, which is distinct from Hp eradication
per se.119
Probiotics may improve HpD by inhibition of Hp, but
their efficacy was also demonstrated in Hp-­ uninfected FD
patients.93 94 Following a 12-­week period of daily yoghurt inges-
tion containing 109 colony-­forming units of Lactobacillus gasseri
OLL2716 (LG21) or placebo (fermented milk product without
L. gasseri) in Hp-­negative FD patients, a trend for a positive
overall effect on gastric symptoms (p=0.07) and significantly
higher elimination rates for the major FD symptoms including
PDS-­like but not EPS-­like symptoms was noted.93 In a follow-­up
study, changes in the gastric fluid microbiota were reported in
FD patients at baseline with a restoration after intake of LG21.94
In addition, bile acids were more frequently detected in gastric
fluid samples from FD patients compared with controls and
although bile acids did not decrease with intake of LG21, the
presence of an intestinal-­like bacterial profile was restored after
probiotics.94 This study and others have suggested the presence
of small intestinal bacterial overgrowth (SIBO) in a subset of FD
patients,94 120 which could be a marker and target although no
standardised diagnosis is available.
Treatment with rifaximin, a non-­absorbable and selective anti-
biotic with established efficacy for the treatment of abdominal
pain and bloating in non-­constipated IBS,121 may reverse SIBO
as measured with hydrogen breath testing,122 but this putative
mechanism is highly controversial. In a recent randomised trial,
rifaximin was superior to placebo for the adequate relief of
both global dyspeptic symptoms (78% vs 52%) at 8 weeks and
postprandial fullness, bloating and belching at 4 weeks in FD
patients who were Hp negative.95 The effect on symptoms was
more pronounced in women with a similar incidence of adverse
effects in the rifaximin and control group. Although the exact
mechanism of action is not known, the antibiotic effect and
increased solubility of rifaximin with bile salts could explain its
therapeutic effect in FD patients with changes in the duodenal
microenvironment (box 3).123
Conclusion
The paradigm of FD as the most common functional upper GI
disorder with ‘no evidence of structural disease’ has recently
been challenged.32 33 43 56 78 Despite the common occurrence
of FD in up to 15% of the general population, the underlying
pathophysiology remains unclear.1 2 30 Emerging data point
towards the duodenum as the key integrator in symptom
generation. Meal-­related symptoms in the PDS and overlap
group are linked with increased duodenal mucosal permea-
bility and low-­grade inflammation with submucosal neuronal
changes,32 34 43 55 providing a basis for postprandial dyspeptic
symptoms and a potential diagnostic or predictive tool.
However, it is still unclear whether these changes are indeed
causal or secondary to an unknown cause. The association
with GORD due to gastric disturbances secondary to duodenal
inflammation and the possibility of overlapping IBS depending
on the extent of intestinal inflammation also require further
study.10 Current treatment options are of limited efficacy and
8 Wauters L, et al. Gut 2019;0:1–10. doi:10.1136/gutjnl-2019-318536
Gut: first published as 10.1136/gutjnl-2019-318536 on 29 November 2019. Downloaded from http://gut.bmj.com/ on November 30, 2019 at Lund University Libraries. Protected by copyright.
target symptoms and gastric sensorimotor function rather than
the underlying duodenal pathology.35 37
Future classifications of FD subtypes should take into account
the different pathophysiological mechanisms in order to allow
targeted and not just symptom-­based therapy. Recognition of
immune activation will hopefully lead to the discovery of new
biomarkers and therapeutic targets, ultimately contributing to
the diagnosis and treatment of this chronic and challenging GI
condition. The effect of acid suppression on the microbiome
is highly relevant as PPIs are frequently scrutinised because of
overprescribing and potential long-­term adverse events. PPI-­
induced dysbiosis may also help explain the limited efficacy of
long-­term PPIs as the current first-­line treatment in FD90 and
the possibility of persisting dyspeptic symptoms in a subgroup
of patients on PPIs.117 Other treatments targeting the micro-
biome in FD look promising but require confirmation.
Contributors  LW drafted the manuscript. JT revised the manuscript. MMW revised
the manuscript. NJT drafted and revised the manuscript. TV drafted and revised the
manuscript.
Funding  LW and TV are supported by the Flanders Research Foundation (FWO
Vlaanderen) through a doctoral fellowship and a senior clinical research mandate,
respectively. JT is supported by a Methusalem grant of KU Leuven. NJT is supported
by an NHMRC Level 3 Investigator Grant and is lead investigator of an NHMRC
Centre of Research Excellence.
Competing interests  NT: Consultancy: Allergan, IM Health Sciences, Takeda,
Theravance, Danone, Sanofi. JT: Consultancy: AlfaWassermann, Allergan, Danone,
Shire, Takeda, Theravance, Tsumura and Zeria Pharmaceuticals; Speaker fees: Abbott,
Allergan, Shire, Takeda and Zeria Pharmaceuticals. TV: Speaker fees: Abbott. Research
Grant: Danone.
Patient consent for publication  Not required.
Provenance and peer review  Commissioned; externally peer reviewed.
ORCID iD
Nicholas J Talley http://​orcid.​org/​0000-​0003-​2537-​3092
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