Patients with dyspepsia have impaired mucosal integrity both in the duodenum and jejunum: in vivo assessment of small bowel mucosal integrity using baseline impedance

Abstract

Background
Recent studies reported that impaired proximal duodenal mucosa, assessed by duodenal biopsy, could play an important role in the development of dyspeptic symptoms. The aims of this study were (a) to develop a method to measure “in vivo” duodenal and jejunal baseline impedance (BI) and (b) to assess small bowel mucosal integrity in patients with functional dyspepsia (FD) and healthy controls (HC).

Methods
We recruited 16 patients with FD and 15 HC. All subjects underwent ambulatory duodeno-jejunal manometry combined with impedance (HRM/Z), BI were determined by measuring impedance immediately after the passage of nocturnal migrating motor complex (MMC) phase IIIs.

Results
The number of MMC phase IIIs in FD was significantly lower than that in HC (2.6 ± 1.4 vs 4.8 ± 1.7, p < 0.001). The BI in patients was significantly lower than that in HC in D1(164.2 ± 59.8 Ω in FD and 243.1 ± 40.5 Ω in HC, p = 0.0061), D2 (191.2 ± 34.1 and 256.5 ± 91.4 Ω, p = 0.01), D3 (214.0 ± 76.9 and 278.1 ± 45.3 Ω, p = 0.009), D4 (270.8 ± 54.2 and 351.8 ± 50.2 Ω, p < 0.001), and J1 (312.2 ± 55.4 and 379.3 ± 38.3 Ω, p = 0.001).

Conclusions
This is the first study reporting the duodenal and jejunal BI in vivo. The results have shown significantly lowered BI in the proximal small intestine in patients with FD compared to HC. Furthermore it suggests that measurements of small bowel BI could be used as a biomarker for diagnosis and follow up of patients with FD.

Full text

ORIGINAL ARTICLE—ALIMENTARY TRACT
Patients with dyspepsia have impaired mucosal integrity
both in the duodenum and jejunum: in vivo assessment of small
bowel mucosal integrity using baseline impedance
Kenichiro Nakagawa
1,3
•Ken Hara
1,4
•Asma Fikree
1
•Shahab Siddiqi
2
•
Philip Woodland
1
•Atsushi Masamune
3
•Qasim Aziz
1
•Daniel Sifrim
1
•
Etsuro Yazaki
1
Received: 15 February 2019 / Accepted: 9 August 2019
ÓThe Author(s) 2019
Abstract
Background Recent studies reported that impaired proxi-
mal duodenal mucosa, assessed by duodenal biopsy, could
play an important role in the development of dyspeptic
symptoms. The aims of this study were (a) to develop a
method to measure ‘‘in vivo’’ duodenal and jejunal baseline
impedance (BI) and (b) to assess small bowel mucosal
integrity in patients with functional dyspepsia (FD) and
healthy controls (HC).
Methods We recruited 16 patients with FD and 15 HC. All
subjects underwent ambulatory duodeno-jejunal manome-
try combined with impedance (HRM/Z), BI were deter-
mined by measuring impedance immediately after the
passage of nocturnal migrating motor complex (MMC)
phase IIIs.
Results The number of MMC phase IIIs in FD was sig-
nificantly lower than that in HC (2.6 ±1.4 vs 4.8 ±1.7,
p\0.001). The BI in patients was significantly lower than
that in HC in D1(164.2 ±59.8 Xin FD and 243.1 ±40.5
Xin HC, p=0.0061), D2 (191.2 ±34.1 and
256.5 ±91.4 X,p=0.01), D3 (214.0 ±76.9 and
278.1 ±45.3 X,p=0.009), D4 (270.8 ±54.2 and
351.8 ±50.2 X,p\0.001), and J1 (312.2 ±55.4 and
379.3 ±38.3 X,p=0.001).
Conclusions This is the first study reporting the duodenal
and jejunal BI in vivo. The results have shown significantly
lowered BI in the proximal small intestine in patients with
FD compared to HC. Furthermore it suggests that mea-
surements of small bowel BI could be used as a biomarker
for diagnosis and follow up of patients with FD.
Keywords Functional dyspepsia Small bowel motility 
Small bowel mucosal integrity
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s00535-019-01614-5) contains sup-
plementary material, which is available to authorized users.
&Etsuro Yazaki
e.yazaki@qmul.ac.uk
Kenichiro Nakagawa
k.nakagawa@qmul.ac.uk
Ken Hara
kenhara0704@yahoo.co.jp
Asma Fikree
asma.fikree@bartshealth.nhs.uk
Shahab Siddiqi
shahab.siddiqi@meht.nhs.uk
Philip Woodland
p.woodland@qmul.ac.uk
Atsushi Masamune
amasamune@med.tohoku.ac.jp
Qasim Aziz
q.aziz@qmul.ac.uk
Daniel Sifrim
d.sifrim@qmul.ac.uk
1
Wingate Institute of Neurogastroenterology, Barts and The
London School of Medicine and Dentistry, Queen Mary
University of London, 26 Ashfield Street, Whitechapel,
London E1 AJ, UK
2
Division of General Surgery, Broomfield Hospital, Court Rd,
Broomfield, Chelmsford CM1 7ET, UK
3
Division of Gastroenterology, Tohoku University Graduate
School of Medicine, 1-1 Seiryo-machi, Aobaku,
Sendai 980-8574, Japan
123
J Gastroenterol
https://doi.org/10.1007/s00535-019-01614-5

Abbreviations
DSS Dyspeptic symptom score
EPS Epigastric pain syndrome
FD Functional dyspepsia
HC Healthy controls
HRM/Z High-resolution manometry and impedance
IBS Irritable bowel syndrome
LHBT Lactulose hydrogen breath test
MMC Migrating motor complex
NSAIDs Non-steroidal anti-inflammatory drugs
PDS Postprandial distress syndrome
SIBO Small bowel bacterial overgrowth
GI Gastro-intestinal
Introduction
Functional dyspepsia (FD) is a disorder defined by Rome
IV criteria as the presence of chronic bothersome early
satiety, postprandial fullness, epigastric pain or burning
without any organic, systemic or metabolic disease that is
likely to explain the symptoms [1]. FD is a common gas-
troduodenal disorder, affecting up to 15–20% of the gen-
eral population [2] and is associated with significant
negative impact on the quality of life [3].
Traditionally, pathophysiological factors underlying FD
focused on gastric functional and/or structural abnormali-
ties, including gastric acid hyper-secretion, impaired gas-
tric accommodation, delayed gastric emptying and hyper-
sensitivity to gastric distention and helicobacter pylori
infection [4–8].
More recently, it has been proposed that another
pathophysiological factor in FD can be an alteration in the
duodenal mucosa [9–13]. Talley et al. reported an
increased number of duodenal eosinophils and mast cells in
patients with FD compared to controls [9] and suggested a
role of low-grade inflammation in FD. More recent studies
have reported that proximal duodenal mucosal biopsies
from patients with FD showed lower transepithelial elec-
trical resistance and increased mucosal permeability com-
pared to those from healthy controls [10]. The authors
suggested that impaired duodenal mucosal barrier function
could facilitate the passage of luminal antigens through the
epithelium, which may induce low-grade inflammation and
would contribute to bothersome dyspeptic symptoms.
Whether these mucosal abnormalities are restricted to the
duodenum or they further affect the proximal small intes-
tine is unknown.
So far, duodenal mucosal integrity has been assessed
through analysis of biopsies ‘‘in vitro’’. In recent years,
attempts have been made to assess mucosal integrity in the
esophagus ‘‘in vivo’’. Intraluminal esophageal impedance
is a technique to detect gastro-esophageal reflux. Impe-
dance measurements in the absence of reflux or swallowing
(baseline impedance) reflects the integrity of the esopha-
geal mucosa [14]. Low baseline impedance in the esoph-
agus is widely accepted as a surrogate marker of abnormal
mucosal integrity [15–17].
We hypothesized that measurements of intestinal
mucosal baseline impedance could be used to assess small
bowel mucosal integrity ‘‘in vivo’’.
The aims of this study were (1) to develop a method to
measure ‘‘in vivo’’ duodenal and jejunal baseline impe-
dance and (2) to assess small bowel mucosal integrity in
patients with FD and healthy controls.
Methods
Subjects
We recruited a total of 16 patients (14 females and 2 males;
mean age 42.1 ±12.1 years) meeting Rome IV criteria for
FD [1] and 15 healthy controls (7 females and 8 males;
mean age 36.6 ±11.5 years) at the Upper Gastrointestinal
Physiology Unit of the Royal London Hospital, UK.
Patients were recruited on the basis of dyspeptic
symptoms (bothersome postprandial fullness and epigastric
pain) by Rome IV diagnostic questionnaire for adults. The
severity of dyspeptic symptoms was scored using dyspeptic
symptom score (DSS) [18]. In all FD patients, organic,
systemic, or metabolic disease, likely to explain the
symptoms were excluded by clinical and biochemical
examination, ultrasound of the upper abdomen and eso-
phago-gastro-duodenoscopy. Subjects with a history of
abdominal surgery (other than appendicectomy), coeliac
disease, or inflammatory bowel disease were excluded.
Subjects had no intake of non-steroidal anti-inflammatory
drugs (NSAIDs), corticosteroids or other immunosuppres-
sive drugs in the preceding 6 months.
All healthy asymptomatic controls had both negative
Helicobacter pylori infection by
13
C urea breath test (Di-
abact UBT, Kibion, Uppsala, Sweden) and negative lac-
tulose hydrogen breath test (LHBT).
The study protocol was approved by the ethics com-
mittee of the London – Central Research Ethics Committee
(ref: 17/LO/0701) and written informed consent was
obtained from all the subjects.
Ambulatory duodena-jejunal high-resolution
manometry and impedance (HRM/Z)
Duodeno-jejunal HRM/Z was recorded simultaneously
using a dedicated ambulatory system (MMS, Version 9.2r,
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123

B.V.) and stored for subsequent display, and analysis. The
HRM/Z catheter (UniSensor, Switzerland) comprises 20
pressure sensors spaced 2 cm apart and 9 pairs of impe-
dance electrodes (Fig. 1).
All subjects were asked to stop proton pump inhibitors
for at least 1 week prior to the study. Subjects were fasted
for at least 6 h before the intubation of the HRM/Z
catheter. The catheter was inserted transnasally into the
stomach, and its progression was monitored using fluoro-
scopic screening within the limited radiation dosage
(0.2–0.4 mSv for each study) [19]. When the tip of the
catheter was passed through the pylorus, a balloon attached
to the tip of the catheter was inflated with 5 ml of air for
further propulsion. The catheter was advanced until the tip
was positioned beyond the ligament of Treitz and at least
three pressure sensors remained in the gastric antrum. The
balloon was then deflated. Figure 2shows the position of
the catheter. Pressure and impedance sensors were dis-
tributed from the antrum to the proximal jejunum.
After the intubation, HRM/Z recordings were started.
Subjects were then given a standard meal (630 kcal, Fat
28 g, Carbs 77 g, Protein 19 g), and rested in a sitting
position for 1 h. Recordings were continued in ambulatory
settings. Subjects were allowed to have only water on day
1, and they were allowed to eat their typical breakfasts on
the day 2. They returned to the hospital in the morning of
the day 2, and the catheter was removed. A diary was
provided to record their activities including timing of meals
and sleeping.
Detection of small intestinal bacterial overgrowth
(SIBO) and H. pylori infection
LHBT was performed to assess SIBO. Subjects were asked
to fast for 8–12 h and avoid fermentable foods such as
complex carbohydrate 24 h prior to LHBT. Also, all sub-
jects, if applicable, stopped antibiotics for at least 4 weeks
and pro-motility drugs and laxatives at least one week prior
to LHBT. After oral administration of 10 g of lactulose in
200 ml of water, breath samples were collected every
20 min for 120 min. A rise in hydrogen level of C20 ppm
by 60 min was considered positive for SIBO [20].
Helicobacter pylori infection was assessed by
13
C urea
breath test. All subjects, if applicable, stopped acid sup-
pressive medication for at least 2 weeks. After 8–12 h
fasting period, breath samples were collected before and
10 min after the administration of
13
C urea capsule with
200 ml water. H. pylori infection was considered to be
negative if
13
CO
2
value was below a 2.5%level in the
breath sample after 10 min [21,22].
Analysis of HRM/impedance recording
The manometric parameters were analyzed both semi-au-
tomatically (quantitative) and visually (qualitative). The
pressure and impedance sensors in duodenum and jejunum
could be fluoroscopically identified in D1, D2, D3, D4 and
J1. The nocturnal and meal periods were identified based
on diary entries. Automated analysis was initially per-
formed for the identification of duodeno-jejunal contractile
events [23]. A pressure event that exceeded a threshold of
10 mmHg, for which there was no simultaneous event
occurring in the other channels, was assessed by the
algorithm as being the consequence of an enteric
contraction.
Phase III of the migrating motor complex (MMC) was
defined as the presence of a period of phasic contractions
that: (1) occurred for at least 2 min; (2) recurred at a fre-
quency of 10–12 per min in duodenum and jejunum; (3)
propagated ab-orally, as indicated by at least two recording
sites and (4) was subsequently followed by a period of
motor quiescence (phase I) [24–26].
The following parameters in proximal duodenum (D2)
were calculated: (1) Duration of phase III; (2) Peak con-
traction amplitude of phase III; (3) MMC cycle period. The
peak contraction amplitude of phase III was taken as the
peak average amplitude of MMC in each subject. The
MMC cycle period was taken as a period between the onset
of phase III to the next onset of phase III.
Baseline impedance measurement
In the small intestine, unlike in the esophagus, the mucosa
is almost constantly covered by fluids, making it more
Fig. 1 High-resolution manometry combined with impedance
catheter. The high-resolution manometry combined with impedance
catheter (UniSensor, Switzerland) comprises 20 pressure sensors
spaced 2 cm apart and 9 pairs of impedance electrodes. Ppressure
sensor, Eelectrode, TPUTr thermoplastic polyurethane transparent,
TPUO thermoplastic polyurethane orange
J Gastroenterol
123

difficult to assess the baseline mucosal impedance. We
hypothesized that immediately after the passage of a phase
III of the MMC, the intestinal segment is devoid of fluids
and allows measurement of intestinal mucosal baseline
impedance. The baseline impedance was obtained during
nocturnal periods where artefacts were minimal.
The mean baseline impedance was measured by taking
an average impedance value of 10-minute time windows
after the passage of MMC phase III, where a plateau in
impedance was visually identified (Fig. 3a, b).
Statistical analysis
All data were expressed as mean ±standard deviation
(SD). Single comparisons were made with an unpaired
student’s ttest (parametric data) or Mann–Whitney Utest
(nonparametric data) wherever appropriate. Correlations
were tested using the Spearman and Pearson tests wherever
appropriate. Fisher’s exact test was used to test propor-
tional differences. Significance was declared at p\0.05.
Statistical analysis was performed with Microsoft Excel
2016 or JMP Pro 14 (SAS Institute, Cary, NC, USA).
Results
All 16 patients with FD (14 females and 2 males; mean age
42.8 ±11.8 years) and 15 healthy controls (HC) (7
females and 8 males; mean age 36.7 ±11.5 years) com-
pleted the study. Seven patients with FD were diagnosed by
Rome IV criteria as postprandial distress syndrome (PDS)
and 3 were epigastric pain syndrome (EPS), 6 were over-
lapping PDS and EPS characteristics. Clinical character-
istics of the patients were described in Table 1. There was
no significant difference in age between patients and HC.
The proportion of female in patients with FD was
significantly higher than that in HC. Body mass index
(BMI) in both groups was within the normal range. The
number of H. pylori positive was 1/16 patient. Eight out of
16 patients underwent LHBT during the study periods. 1
out of 8 was positive for SIBO. Seven patients concomitant
irritable bowel syndrome (IBS) symptoms. None of par-
ticipants were on NSAIDs, corticosteroids or other
immunosuppressive medications.
Manometric parameters
The total duration of the nocturnal periods in patients with
dyspepsia and control was 8.19 ±1.6 and 8.63 ±1.1 h
(N.S.), respectively. Table 2summarizes the parameters
characterizing nocturnal duodeno-jejunal MMC phase III
contractions. All subjects had at least one complete MMC
cycle recorded during nocturnal period. In total, 108 noc-
turnal MMC phase IIIs (mean 3.92 per subject, SD 1.96)
were identified. The number of MMC phase IIIs in patients
was significantly lower than that in HC (2.6 ±1.4 vs
4.8 ±1.7, p\0.001). The average interval of MMC cycle
in FD was significantly longer than that in HC
(153.4 ±85.8 vs 81.1 ±21.4 min, p=0.004). There
were no statistical differences in the duration of MMC
phase III and the peak amplitude between the two groups
(5.6 ±2.6 vs 5.1 ±1.7 min, N.S; 82.3 ±16.8 vs
82.0 ±24.7 mmHg, N.S, respectively).
Duodeno-jejunal baseline impedance
Duodeno-jejunal baseline impedance values in each seg-
ment (D1, D2, D3, D4, J1) in patients and HC were shown
in Table 3and graphically in Fig. 4. The baseline impe-
dance increased from D1 to J1 in both FD and HC group.
The baseline impedance in patients was significantly lower
than that in HC in D1 (164.2 ±59.8 Xin FD and
243.1 ±40.5 Xin HC, p=0.0061), D2 (191.2 ±34.1
and 256.5 ±91.4 X,p=0.01), D3 (214.0 ±76.9 and
278.1 ±45.3 X,p=0.009), D4 (270.8 ±54.2 and
351.8 ±50.2 X,p\0.001), and J1 (312.2 ±55.4 and
379.3 ±38.3 X,p=0.001). Also, there was no statistical
difference in baseline impedance between female and male
in D1 (254.1 ±43.6 and 228.4 ±38.9 X, N.S.), in D2
(275.6 ±128.8 and 239.8 ±42.6 X, N.S.), in D3
(277.7 ±47.1 and 278.4 ±46.8 X, N.S.), in D4
(356.8 ±48.5 and 347.4 ±54.6 X, N.S.), and J1
(369.1 ±47.7 and 388.3 ±28.1 X, N.S.)
The correlation between baseline impedance
and the number of MMC phase III contractions
There were weak positive correlations between baseline
impedance and the number of MMC phase III contractions
Fig. 2 The position of catheter, pressure and impedance sensors.
Pressure and impedance sensors were distributed from the antrum to
the proximal jejunum
J Gastroenterol
123

in J1 (R=0.22, p=0.014). However, no correlations
were shown in D1, D2, D3 and D4.
The correlation between baseline impedance
and severity of symptoms
Severity of dyspeptic symptoms were assessed using DSS.
There were no statistical correlations between baseline
impedance in the each segment and severity of symptoms
(D1, R=0.07, N.S; D2, R=0.01, N.S; D3, R=0.01,
N.S; D4, R=0.04, N.S; J1, R=0.03, N.S.)
Discussion
Dyspeptic symptoms significantly impact on daily life. The
causes of these symptoms, such as postprandial fullness,
early satiety, epigastric discomfort/pain and burning, are
not fully explained [1,27]. However, recent studies
Fig. 3 a Manometry and impedance traces at the timing of MMC
pIII. MMC pIII migrating motor complex phase III, BI baseline
impedance. bExample of measurement of baseline impedance. The
mean baseline impedance was measured by taking an average
impedance value of 10-min time windows after the passage of MMC
phase III, where a plateau in impedance was visually identified. MMC
migrating motor complex, P3 pressure channel 3, Z1 impedance
channel 1, BI baseline impedance
Table 1 Clinical characteristics
FD n=16 HC n=15 pvalue
Age 42.8 (11.8) 36.7 (11.5) N.S
Male/female 2/14 8/7 0.023
BMI 24.8 (3.2) 23.9 (2.9) N.S
Dyspeptic symptom score 13.5 (4.4) 0 (0) \0.001
H.pylori positive/negative 1/15 0/15 –
LHBT positive/negative 1/7 0/15 –
Data is shown as mean ±SD
FD functional dyspepsia, HC healthy controls, BMI body mass index,
H. pylori Helicobacter pylori, LHBT lactulose hydrogen breath test
J Gastroenterol
123

reported that low-grade inflammation in the proximal
duodenum and impaired proximal duodenal mucosal
integrity, assessed by duodenal biopsy, could play an
important role in the development of dyspeptic symptoms
[9,10]. Cirillo et al. reported neuronal functional abnor-
malities and altered ganglionic architecture in the duodenal
submucous plexus in biopsies from patients with FD [28].
They suggested that low grade inflammation induced by
impairment of intestinal barrier function may affect
specific neuronal pathways underlying dyspeptic symptoms
such as early satiety and postprandial fullness. Miwa et al.
also proposed the possibility that the duodenum of patients
with FD is more sensitive to noxious stimuli because of
low-grade inflammation and increased mucosal perme-
ability, and gastric motility abnormalities and gastric
hypersensitive might be induced by stimulation of the
duodenum [12]. In this study, we have assessed ‘‘in vivo’’
the integrity of duodenal and jejunal mucosa using, for the
first time, measurements of baseline impedance during
ambulatory duodeno-jejunal HRM-impedance monitoring.
To measure duodeno-jejunal baseline impedance, we
had to simultaneously measure small intestinal motility and
impedance, and identify phase III of the migrating motor
complex. By doing so, we have also found that patients
with FD have decreased number of phase III contractions
of the MMC.
Small bowel manometry has been regarded as one of the
clinical investigation tools to evaluate functional gastro-
intestinal (GI) disorders. Vantrappen et al.have reported
that the MMC phase III regulated by enteric nerve system
is important in helping to maintain fasting aboral transit
and low bacterial counts in the small intestine [26]. MMC
phase III is therefore thought to be a housekeeping phe-
nomenon clearing the gastrointestinal contents in digestive
processes. In the present study, manometric finding showed
the number of nocturnal MMC phase IIIs in patients with
FD was significantly lower than that in HC. This result was
in agreement with previous reports by Jebbink et al. [29]
and Wilmer et al. [30]. They demonstrated, using ambu-
latory manometry technique, that MMC cycles in patients
with FD occurred less frequently than in control group and
suggested that this reduced incidence of MMC cycle could
lead to delayed interdigestive transit then might cause
dyspeptic symptoms. Also, Jacobs et al. suggested that
impaired MMC phase III can cause SIBO [31]. LHBT was
performed only in 8 out of 16 patients with FD. It may be
therefore difficult to discuss the possible correlation
between SIBO and MMC phase III. We showed that there
was a weak but positive correlation between the nocturnal
number of MMC phase III and baseline impedance in the
proximal jejunum. This might suggest that reduced phase
III leads to prolonged exposure of the jejunum to luminal
contents and hence mucosal damage could occur. Further
Table 2 The manometric
parameters (D2) FD n=16 HC n=15 pvalue
The number of MMC pIII 41 67 –
The number of MMC pIII/patient 2.6 (1.4) 4.8 (1.7) \0.001
The duration of MMC pIII (min) 3.8 (1.4) 4.4 (1.3) N.S
The average of peak amplitude (mmHg) 82.3 (16.8) 82.0 (24.7) N.S
The average duration of MMC cycle (min) 148.4 (82.1) 85.8 (18.4) 0.008
Data is shown as mean ±SD
FD functional dyspepsia, HC healthy controls, MMC pIII migrating motor complex phase III
Table 3 Baseline impedance after MMC pIII
Segment FD n=16 HC n=15 pvalue
D1 164.2 (59.8) 243.1 (40.5) 0.006
D2 191.2 (34.1) 256.5 (91.4) 0.01
D3 214.0 (76.9) 278.1 (45.3) 0.009
D4 270.8 (54.2) 351.8 (50.2) \0.001
J1 312.2 (55.4) 379.3 (38.3) 0.001
Data is shown as mean ±SD
MMC pIII migrating motor complex phase III, FD functional dys-
pepsia, HC healthy controls
Fig. 4 Differences in duodeno-jejunal baseline impedance in FD and
HC. FD functional dyspepsia, HC healthy controls
J Gastroenterol
123

study will be needed to assess the relationship between
jejunal impedance and intestinal motility.
The usage of ambulatory manometry together with
impedance recordings provide the information of not only
motor activity but possibly mucosal status as expressed by
the baseline impedance value. To our knowledge this study
has shown, for the first time, significantly lower baseline
impedance from the duodenum to the proximal jejunum in
patients with FD when compared to HC. The relationship
between low basal impedance and symptoms is not com-
pletely clear. In the esophagus, patients with lower baseline
impedance have higher esophageal sensitivity to acid
exposure [32]. It is possible that similar relationship occurs
in the intestine. We did not show a correlation between
severity of symptoms and baseline impedance values. We
should acknowledge however that perception of dyspeptic
symptoms is likely to be a consequence of a complex
pathophysiological cascade from intestine to central ner-
vous system, and symptom questionnaires usually used to
assess patients with FD are unlikely to be sensitive enough
to detect the isolated role of impaired mucosal integrity.
Like esophageal mucosal integrity in non-erosive reflux
disease, a low baseline impedance in the proximal small
intestine (in the absence of endoscopic findings) could be
used as a biomarker to identify patients with proximal
functional GI disorders and theoretically to evaluate the
outcome of treatment. However, further studies are needed
to clarify whether the baseline impedance can indeed
recover after treatments with acid suppression therapy
[33,34], prokinetic drugs [35] and/or acotiamide [36,37].
In this study, a gradual increase in baseline impedance
from D1 to J1 was observed in both patients with FD and
HC. These impedance changes could be explained in two
ways. Firstly, structural/anatomical differences of intestinal
villus and tight junctions from the proximal duodenum to
jejunum may affect the baseline impedance values. Sec-
ondly, duodenal mucosa could have more direct burden due
to several digestive enzymes such as pepsin, hydrochloric
acid as gastric juice and trypsin, amylase and lipase as
pancreatic juice, which may affect the proximal duodenum
most, and those chemical impacts could gradually be fad-
ing towards the jejunum.
In our patients, we found impaired mucosal integrity not
only in the duodenum (as previously reported using biop-
sies), but also in the jejunum. FD and IBS are the two most
prevalent functional gastrointestinal disorders and they
might have overlapping pathophysiological mechanisms
such as increased mast cell and intraepithelial lymphocyte
concentrations, and increased paracellular intestinal per-
meability [38,39]. It is possible, therefore that our finding
of jejunal mucosal impairment in patients with FD could be
due to concomitant IBS. However, our FD patients without
IBS symptoms (n=9), still had low jejunal baseline
impedance compared to controls (see supplementary
Table 1and supplementary Figure 1).
The following limitations of our study are acknowl-
edged. We did not perform microscopic assessment of
mucosal changes to investigate mucosal barrier function.
Our study therefore does not provide a correlation between
duodenal baseline impedance and in vitro measurements of
duodenal mucosa in using chambers. However, previous
studies have already described that impaired duodenal
mucosal integrity and permeability using biopsy sample
[10] in patients with FD, and increased mucosal admittance
through endoscopic technique [40] in FD compared to HC.
This study did not show a significant statistical correlation
between baseline impedance and severity of dyspeptic
symptoms. A study using increased numbers of FD patients
with wider symptom severity would further assess this
possible correlation.
In conclusion, this is the first study reporting the duo-
denal and jejunal baseline impedance in vivo. The results
have shown significantly lowered baseline impedance in
the proximal small intestine in patients with FD compared
to HC. These findings confirm previous ‘‘in vitro’’ assess-
ments. This suggests that impaired small bowel mucosal
integrity may play an important role in pathophysiology of
FD. Furthermore it suggests that, as techniques are refined,
measurements of small bowel baseline impedance could
theoretically be used as a biomarker for diagnosis and
follow up of patients with FD.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://crea
tivecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
made.
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