Acceleration of small bowel motility after oral administration of dai-kenchu-to (TJ-100) assessed by cine magnetic resonance imaging
Acceleration of small bowel motility after oral administration of dai-kenchu-to (TJ-100) assessed by cine magnetic resonance imaging
Akitoshi Inoue 0 1
Akira Furukawa 1
Hiroshi Yamamoto 1
Shinichi Ohta 0 1
Nguyen Dai Hung Linh 1
Tulyeubai Syerikjan 1
Sachiko Kaida 1
Tsuyoshi Yamaguchi 1
Satoshi Murata 1
Toru Obata 1
Masaji Tani 1
Kiyoshi Murata 0 1
0 Department of Radiology, Shiga University of Medical Science , Otsu, Shiga , Japan , 2 Department of Radiological Science, Tokyo Metropolitan University , Arakawa, Tokyo , Japan , 3 Department of Surgery, Shiga University of Medical Science , Otsu, Shiga , Japan
1 Editor: Ichio Aoki, National Institute of Radiological Sciences , QST , JAPAN
Dai-kenchu-to (TJ-100) is an herbal medicine used to shorten the duration of intestinal transit by accelerating intestinal movement. However, intestinal movement in itself has not been evaluated in healthy volunteers using radiography, fluoroscopy, and radioisotopes because of exposure to ionizing radiation. The purpose of this study was to evaluate the effect of TJ100 on intestinal motility using cinematic magnetic resonance imaging (cine MRI) with a steady-state free precession sequence. Ten healthy male volunteers received 5 g of either TJ-100 or lactose without disclosure of the identity of the substance. Each volunteer underwent two MRI examinations after taking the substances (TJ-100 and lactose) on separate days. They drank 1200 mL of tap water and underwent cine MRI after 10 min. A steadystate free precession sequence was used for imaging, which was performed thrice at 0, 10, 20, 30, 40, and 50 min. The bowel contraction frequency and distention score were assessed. Wilcoxon signed-rank test was used, and differences were considered significant at a P-value <0.05. The bowel contraction frequency tended to be greater in the TJ-100 group and was significantly different in the ileum at 20 (TJ-100, 8.95 ± 2.88; lactose, 4.80 ± 2.92; P < 0.05) and 50 min (TJ-100, 9.45 ± 4.49; lactose, 4.45 ± 2.65; P < 0.05) between the groups. No significant differences were observed in the bowel distention scores. Cine MRI demonstrated that TJ-100 activated intestinal motility without dependence on ileum distention.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
Dai-kenchu-to (TJ-100) is an herbal medicine used to shorten the duration of intestinal transit
by accelerating intestinal movement. TJ-100 is routinely used for postoperative ileus,
prevention of adhesive bowel obstruction after abdominal surgery, and prevention of various
gastrointestinal symptoms, including functional gastrointestinal disorders, especially abdominal
distention, weak intestinal peristalsis, and constipation [
]. Scientific and clinical research
has been performed to elucidate the mechanism and establish the clinical roles of herbal
Previous studies have shown that three major mechanisms enhanced intestinal motility,
and it has been shown that TJ-100 has an acetylcholine-releasing action in the smooth muscle
tissues of the ileum and that 5-HT3 and 5-HT4 receptors were involved in this action [
The administration of TJ-100 was found to significantly increase motilin levels, which
improved intestinal motility . TJ-100 acts on transient receptor potential V1 (TRPV1),
which is distributed in the sensory nerve and is a channel opened by a nociceptive stimulus,
and results in the release of substance P that influences bowel contraction [
TJ-100 can increase intestinal blood flow. TJ-100 is an agonist for transit receptor potential A1
(TRPA1) and TRPV1, and stimulation of these receptors induces release of adrenomedullin
(ADM) from the intestinal epithelium and calcitonin gene-related peptide (CGRP) from the
nerve terminal in vascular smooth muscles, which is referred to as a vasodilator peptide
]. Moreover, TJ-100 has an anti-inflammatory effect through the release of ADM
and suppression of cycloxygenase-2 (COX-2) .
The clinical effects of some of these medicines have been accepted. In a previous study, the
acceleration of gastrointestinal and colonic transit by TJ-100 was demonstrated in humans [
In addition, the acceleration of colonic motility was proven by colonoscopy in healthy
]. Studies have shown that TJ-100 activated jejunal contraction in rabbit jejunum [
spontaneous small intestinal activity in mice [
], and small intestinal motility in mice [
However, intestinal movement in itself has not been evaluated in humans because the use
of radiography, fluoroscopy, and radioisotopes in healthy volunteers presents an ethical
problem owing to ionizing radiation exposure. Therefore, an alternative imaging method for
measuring intestinal movement is required for assessing pharmacological effects. Recently, cine
magnetic resonance imaging (MRI) was shown to allow direct visualization of intestinal
]. Previous studies have shown the clinical significance of cine MRI in the assessment
of organic diseases, such as Crohn's disease [16±18] and intra-abdominal adhesion [19±22]. In
addition, cine MRI has been used to evaluate functional diseases, such as chronic intestinal
], pharmacological action associated with intestinal motility [
and intestinal motility after bariatric surgery . In this way, cine MRI allows the evaluation
of intestinal movement without ionizing radiation.
The effect of TJ-100 on small intestinal movements is unclear. Thus, the present study
aimed to evaluate the effect of TJ-100 on small intestinal movements using cine MRI in healthy
Materials and methods
This prospective double-blind study was approved by our institutional review board (approval
number: 26±156), and written informed consent was obtained from all volunteers prior to
their participation. In total, 10 healthy men (mean age, 39.1 [range, 25±53] years; mean body
mass index, 23.2 [range, 20.3±26.7] kg/m2) were enrolled. The exclusion criteria were presence
of ongoing gastrointestinal disease, history of abdominal surgery, and contraindications to
Oral contrast agent administration
The volunteers fasted for 6 h without fluid intake for 2 h and were then administered TJ-100
(dai-kenchu-to, Tsumura, Tokyo, Japan) or lactose (lactose ªHoei,º Pfizer, Tokyo, Japan) at a
dose of 5 g wrapped in a wafer, with eyes closed in order to block visual and gustatory
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Fig 1. Examination protocol.
information. A controller not involved in the evaluation of cine MRI prepared TJ-100 and
lactose for the double-blind test. After 20 min, the volunteers drank 1200 mL of tap water to
distend the small bowel and underwent MRI examinations (Fig 1). Each volunteer underwent
two MRI examinations on separate days, and in the second examination, the other substance
was administered (TJ-100 or lactose) after preparation as mentioned above. The interval
between the two examinations was 1 week.
MRI examination protocol
MRI examinations were performed using a 1.5-T MRI system (Signa HDx 1.5T; GE
Healthcare, Milwaukee, WI, USA) with an 8-channel body array coil (GE Healthcare). The volunteers
were placed in the prone position with breath held after inspiration during examination.
Before real cine MRI, coronal images (FIESTA sequence: TR, 3.4 ms; TE, 1.1 ms; flip angle,
75Ê; slice thickness, 10 mm; matrix, 256 × 256; field of view, 450 mm) of the entire abdomen
were obtained, and the best slice reflecting the maximum length of the small bowel was
determined. A successive coronal scan consisting of 70 images in 35 s was obtained thrice in the
respective selected plane. A steady-state free precession sequence (FIESTA sequence: TR, 3.4
ms; TE, 1.1 ms; flip angle, 75Ê; slice thickness, 10 mm; matrix, 256 × 256; field of view, 450
mm) was used for imaging. Imaging was performed in three series at 0, 10, 20, 30, 40, and 50
min after drinking tap water. Fig 1 shows the examination protocol.
Image evaluations were performed by consensus between two radiologists with 9 and 32 years
of experience reading gastrointestinal images, who were blinded to information about the
administered substances (TJ-100 or lactose). A single loop in the left upper abdomen that stayed
in a slice section during each scanning period and represented the patterns of contraction of
other loops in the left upper abdomen was selected as a representative loop for the jejunum. In
the same way, another loop in the right lower abdomen was selected as a representative loop for
the ileum. Cine MRI images were analyzed for the frequency of bowel contraction (contraction
frequency) of the representative loops in the jejunum and ileum in respective phases. The
frequencies of contraction in the representative bowel loops were counted visually on cine MRI
(Fig 2). Distended bowel loops were filled with fluid and demonstrated high intensity on MRI
with our sequence, while collapsed bowel loops demonstrated low intensity that represented the
intensity of the bowel wall, and the cycle of bowel contraction (dilation, collapse, and
re-dilation) was reflected on cine MRI. Bowel contraction was judged as ªfull contraction = 1º when
the entire cycle of contraction was confirmed, and it was judged as ªhalf contraction = 0.5º
when the dilated intestine collapsed or the collapsed intestine dilated.
The degree of jejunal and ileal distention (distention score) was then assessed visually and
scored using a 3-grade ranking. The distention score was judged as ª0º when less than 30% of
the loops of the jejunum or ileum were dilated, with fluid demonstrating high intensity on
MRI. Similarly, the distention score was judged as ª1º when between 30% and 70% of the
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Fig 2. Evaluation of contraction frequency. The arrow indicates a representative ileum. The intestine is dilated (A),
collapsed by contraction (B), and re-dilated (C). This cycle is counted as one contraction. Bowel contraction was
judged as half contraction when the dilated intestine collapsed or the collapsed intestine dilated.
loops of the jejunum or ileum were dilated and as ª2º when more than 70% of the loops were
dilated, with fluid demonstrating high intensity on MRI (Fig 3).
The results for the contraction frequency and distention score from three scans were added
together in the respective phase.
The mean contraction frequency and distention score in the respective phase was calculated
by averaging the data of all volunteers. The Wilcoxon signed-rank test was used to compare
the mean contraction frequency and distention score in the respective phase between the
TJ100 and lactose groups. The correlation between the added bowel contraction frequency and
bowel distention score was evaluated using Spearman's rank correlation coefficient. Statistical
tests were performed using SPSS statistics 22 (IBM Corp., Armonk, NY, USA). A P-value <
0.05 was considered to indicate a statistically significant difference.
Eight volunteers successfully completed all scans. Two volunteers in the lactose study were not
able to undergo cine MRI at 30 min because of the urge to urinate. Therefore, statistical
analysis at 30 min was performed without two volunteers.
Fig 3. Evaluation of the bowel distention score. The small intestine separated by the white line in the left upper
abdomen is the jejunum and by the white line in the right lower abdomen is the ileum. More than 70% of the jejunum
and ileum is well filled with fluid, and the bowel distention score for both parts is ª2º (A). Less than 30% of the
jejunum is filled with a small amount of fluid, and the bowel distention score is ª0º (B). Between 30% and 70% of the
ileum is filled with a moderate amount of fluid, and the bowel distention score is ª1º (B).
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Bowel contraction frequency
The total jejunal contraction frequencies were almost equal at 0 and 10 min and were higher at
20 and 30 min in the lactose group than in the TJ-100 group. In contrast, at 40 and 50 min, the
total jejunal contraction frequencies were higher in the TJ-100 group than in the lactose group.
There was no significant difference in jejunal contraction in any phase between the TJ-100 and
lactose groups (Table 1 and Fig 4). The ileum contracted more frequently in all phases in the
TJ-100 group than in the lactose group. There were significant differences in the contraction
frequencies (P < 0.05) in the ileum at 20 and 50 min between the two groups (Table 1, Fig 4,
and S1 and S2 Videos).
Bowel distention score
The highest bowel distention score was observed at 0 min, and it gradually decreased with
time in both the jejunum and ileum (Table 2 and Fig 5). There was no significant difference in
the bowel distention scores in any phase between the TJ-100 and lactose groups. Fig 6 presents
scatter plots with linear regression between the contraction frequency and distention score.
Positive correlations were observed between the contraction frequency and bowel distention
Fig 4. Contraction frequency. Bowel contraction tended to be more frequent in the jejunum in the TJ-100 group,
without significance (A). Significant differences ( P < 0.05) are observed at 20 and 50 min in the ileum (B).
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score in the jejunum and ileum. Spearman's rank correlation coefficient showed statistical
correlations for the jejunum in the lactose group (R = 0.595, p < 0.001) and TJ-100 group
(R = 0.439, p < 0.001), and for the ileum in the TJ-100 group (R = 0.44, p < 0.001).
TJ-100 is one of the medicines known to enhance bowel contraction and peristalsis, and it is
often administered to patients whose bowel motility function is impaired, such as those who
have undergone abdominal surgery [
]. In a previous study, the acceleration of gastrointestinal
and colonic transit by TJ-100 was demonstrated in humans [
]. TJ-100 has been shown to
include 44 ingredients by liquid chromatography±tandem mass spectrometry analysis [
Sanshool extracted from the zanthoxylum fruit, shogaols extracted from ginger, and
ginsenosides extracted from ginseng are major ingredients in TJ-100 (Fig 7). Hydroxy-alpha-sanshool
(HAS) has the highest plasma concentration among the ingredients in TJ-100, and it reaches
the maximum concentration within 30 min after administration, with a median half-life of
1.6±1.7 h [
]. MRI in our study was performed 30±80 min after the administration of TJ-100,
because the plasma concentration of HAS was higher than the effective level during that
In cine MRI, the steady-state free precession sequence has been widely applied, and it was
used in this study. The sequence provides contiguous dynamic MRI images every 0.5 s, which
Fig 5. Distention scores. The score decreases gradually in both the jejunum (A) and ileum (B).
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Fig 6. Interrelationship between the bowel contraction frequency and distention score. The points above the line
show the relationship between the bowel contraction frequency (vertical axis) and distention score (horizontal axis) in
the jejunum and ileum in all phases of respective volunteers. Spearman's rank correlation coefficient shows positive
correlations in the jejunum and ileum treated with lactose (A, B) and the ileum treated with TJ-100 (D).
enables cine MRI to demonstrate bowel contraction. Because the bowel should preferably be
distended to a certain degree during imaging, various types of intraluminal fluids are
administered transorally before MRI examinations. In previous reports, good bowel distention was
obtained using Niflex (non-absorbable fluid by Ajinomoto, Tokyo, Japan), VoLumen
containing 2.0% or 1.4% sorbitol [
], and 2.5% mannitol in tap water with or without 0.2% locust
bean gum. Although tap water alone provides less bowel distention because of absorption
during the examination, we used tap water in this study because we wanted to exclude any other
factors that might influence bowel contraction. For the same reason, lactose was used as it is
included in TJ-100 and has no pharmacological effects on bowel contraction.
Overall, both the jejunum and ileum tended to more frequently contract in volunteers
treated with TJ-100 than in those treated with lactose, and the difference was more clear in the
ileum. In the jejunum, relatively larger differences were observed at 40 and 50 min after
completion of oral intake of the test fluid, although the differences did not reach significance. The
reason why more frequent contractions were observed in volunteers treated with lactose at 20
min is unclear. The differences were more apparent in the ileum, and higher contraction
frequencies continued at 50 min after completion of oral intake of the test fluid in volunteers
treated with TJ 100, while contraction frequencies decreased after 20 min in those treated with
lactose. Significantly more frequent contractions of the ileum were observed in volunteers
treated with TJ-100 than in those treated with lactose at 20 and 50 min. The results may
demonstrate higher and continuous stimulation of TJ-100 on bowel contraction in the ileum.
The collapsed bowel contracted less frequently than the distended ileum, and there was a
linear relationship between the frequency of bowel contraction and the degree of bowel
distention; i.e., greater bowel distention was associated with more frequent bowel contraction. This
finding was consistent with the results of a previous study [
] and with the fact that bowel
contraction is regulated by the volume and content in the bowel (i.e., fasting period,
postprandial period, type of food, and amount of calories) and various factors, including intrinsic and
extrinsic nerves and a variety of hormone and hormone-like substances [
In the ileum, the interrelationship between bowel contraction frequency and distention
score showed a positive correlation statistically in both volunteers treated with lactose and
TJ7 / 11
Fig 7. Major ingredients in TJ-100. A: ginsenoside, B: sanshool, C: shogaol.
100. In the ileum, TJ-100 was associated with contraction frequencies independent from bowel
distention because of comparisons under the same condition. On the other hand, in the
jejunum, statistical analysis showed a positive correlation in volunteers treated with lactose, but no
significant correlation in volunteers treated with TJ-100. Therefore, it was difficult to assess
the pharmacologic effect of TJ-100 in the jejunum because the distention score was different
between volunteers treated with lactose and those treated with TJ-100.
Postoperative bowel obstruction is a common complication of abdominal surgery, and
sometimes recurrence can occur, which might require operation if strangulation is noted.
TJ100 has an anti-inflammatory effect through the release of ADM and suppression of COX-2,
and it shortens the duration of intestinal transit, which prevents adhesion of the bowel, as seen
in rats [
]. Previous articles have proved that TJ-100 can shorten the duration of intestinal
]; however, intestinal movement in itself has not been evaluated in humans. The
acceleration of bowel movement especially in the ileum observed in this study may possibly be
one of the reasons for a reduction in the intestinal transit time with TJ-100, and accelerated
bowel movement may contribute to a reduction in bowel adhesion as well. Our results may
8 / 11
support the reasonable administration of TJ-100 in the postoperative phase for the prevention
of adhesive bowel obstruction and symptoms caused by decreased propagative intestinal
peristalsis. However, there has been no reported difference in the pharmacological mechanisms of
TJ-100, including distribution in receptors of hormones related to motility between the
jejunum and ileum, in our search, and therefore, the reasons for the difference in the
pharmacological effects between the jejunum and ileum observed in this study are unclear and further
investigations are required.
The present study has some limitations. First, the number of volunteers in the study was
relatively small. Furthermore, imaging at 30 min was not performed in two volunteers. Second,
bowel contraction was measured at certain selected loops. One in the left upper abdomen
representing the jejunum and the other in the lower right abdomen representing the ileum. As
reported by Menys et al. [
], who used MRI to quantify small bowel motility in normal
volunteers, small bowel contraction may widely vary at each segment, with relatively poor
repeatability over time. Thus, the measured loops in the present study may not have been good
representatives of the jejunum and ileum, although we attempted to select loops representing
the patterns of jejunal and ileal contraction blindly. This limitation may be overcome in future
studies using different methods of assessment for bowel motility, such as the motility mapping
method introduced by Hahnemann et al. [
]. Third, the cine MRI scan time for this study
was 35 s because of the time restriction for breath holding at inspiration. Three scans were
performed for the same slice in every phase; however, the scan time in each phase was still 105 s in
total and could not cover all bowel motilities, such as that observed in physiological in vitro
studies using an isolated small intestine. Finally, in this study, only jejunal and ileal
contractions were compared between volunteers treated with TJ-100 and lactose. Neither the motility
function of the stomach and colon nor the transit time was evaluated. Therefore, the results in
this study may not be directly related to the effect of TJ-100 on clinical symptoms.
In conclusion, our results showed that cine MRI clearly assessed contraction and distention
of the small intestine, which allowed motility functional assessment of the bowel. The finding
that bowel contraction tended to be more frequent at 20 and 50 min in volunteers treated with
TJ-100 suggests a positive pharmaceutical effect of TJ-100 on small bowel contraction.
S1 Video. Cine magnetic resonance imaging (MRI) performed in a volunteer treated with
lactose at 50 min. Akinetic jejunum and ileum are observed on cine MRI.
S2 Video. Cine magnetic resonance imaging (MRI) performed in a volunteer treated with
TJ-100 at 50 min. This cine MRI was performed in the volunteer mentioned in S1 Video at 50
min. The ileal motility is greater with TJ-100 than with lactose (S1 Video).
We would like to acknowledge the support of Yuto Hamada, Hideto Fukushima, Akira Itoh,
Katsunori Miyata, and Masahiro Yoshimura who performed MR examinations. The authors
would like to thank Enago (www.enago.jp) for the English language review.
Conceptualization: Akira Furukawa, Hiroshi Yamamoto.
9 / 11
Data curation: Akitoshi Inoue, Shinichi Ohta, Sachiko Kaida, Tsuyoshi Yamaguchi, Satoshi
Murata, Toru Obata.
Formal analysis: Akitoshi Inoue, Akira Furukawa, Shinichi Ohta, Nguyen Dai Hung Linh,
Methodology: Akitoshi Inoue, Akira Furukawa, Hiroshi Yamamoto, Shinichi Ohta.
Project administration: Akira Furukawa, Hiroshi Yamamoto.
Supervision: Akira Furukawa, Hiroshi Yamamoto, Masaji Tani, Kiyoshi Murata.
Validation: Akira Furukawa, Masaji Tani, Kiyoshi Murata.
Writing ± original draft: Akitoshi Inoue.
Writing ± review & editing: Akira Furukawa.
10 / 11
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