Original Article

診療と新薬 2019; 56: 907‑916

Eﬀects of Isomaltodextrin Intake
on the Skin Condition and QOL of Healthy Subjects:

診療と新薬 WebA Randomized, Double-blind, Parallel-group,
Placebo-controlled Study with Intake for 8 Consecutive Weeks

Yuki ISHIDA1）／Tsuyoshi SADAKIYO 1）／Hikaru WATANABE 1）／Hitoshi MITSUZUMI 1）／
Shimpei USHIO 1）／Shuji NAKADA 2）● Abstract
Eﬀects of the intake of isomaltodextrin（IMD）, a water-soluble dietary ﬁber, on the skin condition and qualityof life（QOL）of healthy adults were studied in a randomized, double-blind, parallel-group, placebo-controlled
study. Forty healthy men and women with awareness of dry skin symptoms and a tendency toward
constipation were administered IMD or placebo for 8 weeks, and 39 completed the study. The results showedthat continuous intake of IMD had an improvement in skin condition with evaluation by a dermatologist in all
subjects. Of these, in 15 of the 39 subjects who had dry skin probably caused by a disorder of intestinal
environment, a signiﬁcantly higher moisture content of the skin on the dorsal foot 8 weeks after intake of IMD
versus placebo. Furthermore, the serum phenol concentration, an indicator of the composition of the intestinal
environment, was signiﬁcantly lower 8 weeks after intake, and the frequency of defecation and number of daysof defecation, indicators of bowel movement, were signiﬁcantly higher 4 to 8 weeks after intake comparedwith placebo. The above results suggest that IMD intake may be an eﬀective way to moisturize the skin andpromote QOL by improving the composition of the intestinal environment. The reason for this may be that
continuous intake of IMD contributed to the continuous production of short-chain fatty acids in the intestine.
IMD shows promise as an effective material for forming an intestinal environment that suppresses the
production of phenols by intestinal bacteria.
Key words: isomaltodextrin, skin moisturization, skin condition, phenol, prebiotics, human study, QOL

1. INTRODUCTION
In general, constipation is a condition characterized bydifficulty in having a smooth bowel movement due todecrease in intestinal peristaltic movement, caused byunhealthy dietary or lifestyle habits 12）13）. According to the
National Basic Survey 3） conducted by the Ministry of
Health, Labour and Welfare in 2016, 11％ of Japanese
adults have an awareness of constipation symptoms, andconstipation is a serious issue for people in modern
society due to multiple factors, such as increased stress,
lack of exercise, and irregular habits, in addition to asimplified diet and nutritional intake biased by taste
preference. Furthermore, constipation is said to be a signof an imbalance in the intestinal flora, and repeatedepisodes of constipation increases the production ofintestinal putrefactive products, including ammonia,
amines, phenols, indoles, and hydrogen sulfate. These
1）R&D Division, Hayashibara Co., Ltd.
2）Medical Corporation Bokushinkai CLINTEXE Clinic

compounds, produced during the metabolism of proteinsor amino acids by intestinal bacteria, are cytotoxic andare involved in aging or onset of lifestyle disease 11）12）.
Among them, phenols produced by the metabolism oftyrosine（an amino acid）, were found to have harmful
eﬀects on the human body 10）16）. Iizuka et al. reported theresults of mouse and human studies showing that phenols
had adverse eﬀects on the formation of the epidermis 4）5）.
It is considered that phenols absorbed from the intestine
are transferred to the bloodstream and are involved in theworsening of skin conditions. Thus, constipation has agreat impact on quality of life（QOL）. In general, roughskin is caused not only by external factors, such as
ultraviolet light, dryness, or dirt on the skin, but also
constipation, as one of internal factors, is noted. Several
investigators have reported an association of constipation
with skin conditions 1）8）13）14）, and an improvement in roughskin was reported as one of the beneﬁcial eﬀects of oral
intake of fermented milk containing Bifidobacterium inhumans 8）. Moreover, Yamamoto et al.20） reported thatabout half of young women have an awareness ofconstipation symptoms, and 90％ of them also have skin

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診療と新薬・第 56 巻

conditions, such as dryness or pimples. Thus, a greatneed for an improvement in rough skin exists amongindividuals with constipation.
We recently found that consecutive ad libitum intake ofisomaltodextrin（IMD）, a soluble dietary ﬁber, inhibitedthe production of phenols in vivo in a tyrosine load test in
rats 17）. IMD, a highly branched α-glucan with acharacteristic structure composed only of glucose units,is produced from starch by enzymatic reactions with αglucosyltransferase and α-amylase derived from
Paenibacillus alginolyticus PP710 19）. Since IMD has
different binding profiles from indigestible dextrin or
polydextrose, which are known as similar soluble dietaryfibers, IMD is expected to have unique physiologicaleﬀects. We have reported that consecutive intake of IMD
improved bowel movements in humans 6）7）. In addition,
since Nishimura et al. reported that consecutive
administration of IMD increased Bifidobacterium
populations in rats 15）, IMD is expected to improve roughskin caused by disorders of the intestinal environment.
However, the eﬀect of IMD intake on skin conditions inhumans has not yet been reported. Therefore, we studied
the effects of IMD intake on skin condition and QOL in
healthy adult men and women with symptoms of dry skinand a tendency toward constipation.

2. MATERIALS AND METHODS
2.1. Subjects
A total of 40 healthy Japanese volunteers（4 men and 36
women）aged between 20 and 59 years with awareness ofdry skin symptoms and a tendency toward constipation（stool frequency of 4 per week）were enrolled.
Recruitment of the study candidates, an explanatory
meeting, and investigation of their backgroundcharacteristics（pre-examination）were conducted by
TES Holdings Co., Ltd.（Tokyo, Japan）. From 81 study
candidates, 40 subjects had not received medications thatwould interfere with the results and no chronic physicaldisease including skin disease, and were judged suitablefor enrollment by the investigator. Other exclusion
criteria were as follows: 1）food or seasonal allergy; 2）
smoker; 3）use of health foods or supplements that wouldinterfere with the results; 4）pregnancy, lactation, or
planning to become pregnant; 5）participation in anotherclinical study. The number of subjects in this study wasdetermined on the basis of a similar study 8）, in which thedifference in skin moisture content between the test
article and placebo was about 20％（about a 25％ standard
deviation）. Applying the above results to this study, we
converted these values to 4 for the difference between
the study diets and 4.5 for the standard deviation,
because the skin moisture content was determined with aCorneometer CM825（Courage + Khazaka electronicGmbH, Cologne, Germany）. As a result, the number ofsubjects needed for the study was 17. Considering a

第 12 号（2019 年 12 月）

dropout rate of about 15％ , we set the number needed as
20 subjects per group.
2.2. Study diet
The study diet consisted of the test food and a placebo
food. Five grams of the test food（IMD［Fibryxa ,Hayashibara Co., Ltd., Okayama, Japan］）and theplacebo food（maltodextrin［Pinedex #1, Matsutani
Chemical Industry Co., Ltd., Hyogo, Japan］）on the drysolid basis was inserted into an aluminum sachet. Boththe test and placebo foods were a white powder withoutodor or taste, and were conﬁrmed to be indistinguishable
in appearance or taste by subjects before they were used.
The dietary ﬁber content per sachet was calculated to
be 4.29 g, based on the dietary fiber content of IMD（determined with an enzyme-HPLC method）of the lot
used in this study.
2.3. Study design
This study was a randomized, double-blind, parallelgroup, placebo-controlled study. An individual who was
not directly involved in the study randomly assigned the
40 subjects to 2 groups of 20 subjects each（groups A andB）using random numbers, so that the groups had thesame sex ratio and age range, based on the skin moisture
content at pre-examination. Next, a study diet was
assigned to each group. The Assignment Person sealed
the assignment table for subjects and study diets and kept
it conﬁdential until the ﬁxation of all data. We conﬁrmedthat there were no signiﬁcant diﬀerences in sex ratio or
age range between groups before starting the study.
The subjects received either the test or placebo foodonce daily（1 sachet）for 8 consecutive weeks, the intake
timing was not limited. They visited the clinic for
examination before intake（week 0）, and at 4 and 8
weeks after intake（3 times in total）. Each subject kept adiary to note the intake of the study diet and bowel
movement data during the study period. The subjects
were instructed not to work outdoors for a long time, andto carry on as usual during the study period. In
particular, a shortage of sleep, overeating /overdrinking,or over-exercise was avoided to maintain quality andquantity in their daily lives. Furthermore, to unify theconditions of the subjects as much as possible, a prespecified meal was given for supper on the day before
each visit day（3 times）. At each visit, the subjects had
fasted from after supper（a pre-specified meal）on thenight before until the next morning, for more than 12hours, except for a small amount of water.
2.4. Endpoints and methods of measurement andassessment
The primary endpoints were dermatologist s findings（skin texture and skin quality）and skin measurements（skin moisture content and transepidermal water loss as
indicators of skin condition）. The secondary endpoints

診療と新薬・第 56 巻

were serum concentrations of putrefactive products（ phenol and p -cresol）as indicators of the composition of
the intestinal environment; and a questionnaire survey on
bowel movements and skin condition as indicators of
QOL.
2.5. Visual assessment by a dermatologist
A dermatologist assessed the texture and quality of theskin as objective indicators for dryness of skin condition.
These assessments were performed in the sameenvironment as that of the skin measurements.
The texture of the skin was assessed at the center of aline connecting the bottom of the earlobe and the edge ofthe lips on the left side of the face, and the 3 items
including sulci cuts , cristae cutis, and overall assessment
were scored on a 5-point scale（−2＝poor, −1＝slightly
poor, 0 ＝ average, 1 ＝ slightly good, 2 ＝ good）using a
DermLite（DL100, J. Hewitt, CA, USA）and a Digital
Microscope（KH-1300, Hirox Co. Ltd., Tokyo, Japan）.
The lower the score, the poorer the skin texture.
The entire face was assessed for skin quality, and 5
items, including dryness , erythema , scaly skin , irritation ,and itching were scored on a 5-point scale by visual
examination and interview（0 ＝ none［no symptoms］,1＝ minor［very slight symptoms］, 2 ＝ mild（slight
symptoms）, 3 ＝ moderate［apparent symptoms］, 4 ＝sever［severe symptoms］）. The higher the score, thepoorer the skin quality.
2.6. Skin measurements
As indicators of water retention and barrier function of
the skin, the skin moisture content and transepidermal
water loss were measured at the following 3 sites: thecheek（at the top of the cheekbone）, the upper arm（atthe medial side of the upper arm）
, and the foot（at thedorsal foot）. After the measurement sites were washed,
the subjects were acclimatized in a constant temperatureand humidity room（set at 21℃ ± 1℃ and 50％ ± 5％
relative humidity）for more than 20 minutes prior tomeasurements.
The skin moisture content was measured 5 times at
each site with a Corneometer® CM825. The highest andlowest values were eliminated, and the mean of theremaining 3 measurements was used. The transepidermal
water loss was continuously measured every second formore than 60 seconds with a Tewameter ® TM300（Courage + Khazaka Electronic GmbH, Cologne,
Germany）. The mean of the measurements（of which
standard deviation was minimum）for 30 seconds before
the end of measurement was used.
2.7. Determination of serum concentrations ofputrefactive products
Blood was collected from each subject to determine thecirculating serum concentrations of phenols（phenol andp -cresol）, putrefactive products, as indicators of the

第 12 号（2019 年 12 月）

29 （909）

composition of the intestinal environment. Prior to bloodcollection, subjects did not eat or drink for more than 12hours after supper（pre-speciﬁed meal）on the day before
each visit day. Blood samples were centrifuged at 3000
rpm at 15℃ to 24℃ for 10 minutes, and serum wascollected and stored at − 80℃ until analysis.
The serum concentrations of phenols（phenol andp -cresol）were analyzed by high-performance liquid
chromatography（HPLC）according to the method ofKano et al. 8）, with some modiﬁcations. A total of 25μL ofserum, 500μL of ion-exchanged water（IEW）, 250μL ofconcentrated hydrochloric acid, and 10μL of the internal
standard（10μg/mL in IEW）were mixed and heated to
95℃ for 60 minutes to hydrolyze the phenol conjugates.
After cooling, the whole solution was loaded onto an
Oasis HLB 1 cc（30 mg）reversed-phase cartridge（Waters, MA, USA）, washed 2 times with IEW（1000μL）, and eluded with methanol（500μL）and IEW（500μL）to prepare a sample for HPLC analysis. The
Oasis HLB 1 cc was previously conditioned andequilibrated with methanol（500μL）and IEW（1000μL）
prior to use.
The HPLC system（Prominence, SHIMADZU, Tokyo,
Japan）was equipped with API 3200TM LC-MS/MS（SCIEX, MA, USA）and Kinetex® Biphenyl（SHIMADZU,Tokyo, Japan; 2.1 mm（i.d.）× 100 mm（length）and 5
μm particle size）as an HPLC-APCI-MS apparatus. The
sample（10μL）was automatically injected onto the
HPLC column and eluted with a linear gradient ofacetonitrile-IEW at 40℃ at a ﬂow rate of 0.2 mL/minute.
The concentrations of phenols（phenol and p -cresol）
were calculated according to calibration curves, whichwere obtained by determining the ratio of the peak areaof phenol（FUJIFILM Wako Pure Chemical Corporation,
Osaka, Japan）or p -cresol（FUJIFILM Wako Pure
Chemical Corporation, Osaka, Japan）to that of theinternal standard（4-chlorophenol, Tokyo Chemical
Industry Co., Ltd., Tokyo, Japan）.
2.8. Questionnaire survey on bowel movements andskin condition
Since this study was conducted in subjects withsymptoms of dry skin and a tendency toward constipation,
we carried out a questionnaire survey on bowel
movements and skin condition to examine whether IMD
intake contributes to the improvement of QOL.
The questionnaire on bowel movements was in the formof a diary: the number of bowel movements, number ofdays of defecation, and fecal amount（converted to a
medium-sized egg unit: 4.0 cm in the minor axis and 5.5
cm in the major axis）were tallied every week during thestudy period.
The questionnaire on skin condition contained 3questions about subject s perception, based on the Visual
Analogue Scale（VAS）, which was used for questions
about the face and whole body. The subject was asked to30 （910）

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第 12 号（2019 年 12 月）

Table 1 The characteristics of subjects
Selected subjects
Total
Men（n）
Women（n）
Total subjects（n）

All subjects

Test food Placebo food
group
group

Total

Subgroup analysis subjects

Test food Placebo food
group
group

Total

Test food Placebo food
group
group

4
36
40

2
18
20

2
18
20

4
35
39

2
17
19

2
18
20

1
14
15

0
6
6

1
8
9

Age
（years old）

40.3
±10.1

39.7
±9.0

40.9
±11.2

40.8
±9.7

40.7
±8.0

40.9
±11.2

44.0
±9.6

40.7
±8.6

46.2
±10.0

Skin moisture content（cheek）

40.5
±10.1

39.9
±10.7

41.1
±9.8

40.5
±10.3

39.9
±11.0

41.1
±9.8

40.3
±9.0

40.8
±11.2

39.9
±7.9

Mean ± SD

mark his/her current condition on the 100-mm line withanchor statements on the left end（never better or not
noticeable at all / insensitive / not concerned ）and on theright end（never worse or very noticeable / sensitive /concerned ）, and the examiner scored the VAS bymeasuring the distance from the left end. Higher scores
reﬂected lower QOL.
Questions about the face
Overall satisfaction ; skin conditions; moisture（wetness）
of the skin ; rough skin around the eyes or mouth ;wrinkles around the eyes ; softness of the skin ;transparency of the skin ; firmness or elasticity of theskin ; plump feeling of the skin; rough texture of the skin;redness of the skin ; notable pores in the skin; clogged
pores in the skin ; sagging skin; pigmented spots; andmake-up sitting on the skin（only for women）
Questions about the whole body
Dryness of the skin ; redness of the skin; itching of theskin ; and condition of the skinSpeciﬁc perception
Free/open description by the subject
2.9. Safety
Adverse events based on signs and symptoms wererecorded by the investigator or subinvestigators during
the study period.
2.10. Ethics
The study was approved by the ethics committee ofHayashibara Co., Ltd.（December 19, 2017, registration
No. 211）and by the ethical review committee of Oriental
Ueno Health Checkup Center（Tokyo, Japan; January 23,
2018, Protocol No. HR-2018-HN03）, and thereafter
conducted in accordance with the ethical principles thathave their origin in the Declaration of Helsinki, andethical guidelines for medical and health research
involving human subjects（The Ministry of Health,Labour and Welfare Ministerial Notiﬁcation, Ministry of
Education, Culture, Sports, Science and Technology）

under the supervision of Medical Corporation Bokushinkai
CLINTEXE Clinic（Tokyo, Japan）. The study was preregistered in the Clinical Trial Registration System
operated by the University Hospital Medical Information
Network.
All subjects received complete information on thecontent, purpose, and significance of the study, andsigned a consent form about participation in the study andabout possible publication of the study results, in which
all information was recorded in such a manner that
subjects could not be identiﬁed.
2. 11. Statistical analysis
All data were expressed as mean ± standard deviation（SD）or standard error（SE）of the mean. For efficacy
assessment, the comparison before and after intake ofeach study diet was performed with a paired t-test or
Wilcoxon rank sum test, and the comparison between
intake groups was performed with an unpaired t-test or
Wilcoxon rank sum test, with a P value ＜ 0.05（twosided）being considered statistically signiﬁcant. SAS® 9.4（SAS Institute Inc., NC, USA）or IBM SPSS Statistics19（International Business Machines Corporation, NY,
USA）was used for statistical analysis.
In addition, to assess the results in more detail, asubgroup analysis was performed by serum phenol
concentration, as an indicator of the composition of theintestinal environment, according to the protocol.

3. RESULTS
3.1. Subjects
The study started with 40 subjects; 1 subject in the test
food group withdrew before the examination at 4 weeks
after intake, because the subject could not be present for
the examination due to schedule reasons. The intake rateof the study diet was 99.9％ ± 0.6％ for the 39 subjects
who completed the study, and 100％ until the day before
the one subject withdrew. The 40 subjects who received

診療と新薬・第 56 巻

第 12 号（2019 年 12 月）

31 （911）

Table 2 Visual assessment by a dermatologist
Item

Skin
textureSubgroup
analysis
subjects

Allsubjects

Skin
quality

Subgroup
analysis
subjects

week 04 weeks

8 weeks

Test− 0.5 ± 0.1− 0.2 ± 0.1

Placebo− 0.7 ± 0.2− 0.7 ± 0.1

Sulci cutis

Test
Placebo− 0.8 ± 0.1− 1.0 ± 0.1− 0.8 ± 0.1− 0.9 ± 0.1− 0.6 ± 0.1− 0.8 ± 0.1 †Overallassessment

Test
Placebo− 0.8 ± 0.1− 0.9 ± 0.1− 0.6 ± 0.1− 0.9 ± 0.1− 0.4 ± 0.2 *− 0.4 ± 0.2 *Crista cutis

Test
Placebo− 0.8 ± 0.2− 0.6 ± 0.2− 0.3 ± 0.3− 0.6 ± 0.2− 0.3 ± 0.3
0.0 ± 0.2 †Sulci cutis

Test
Placebo− 0.8 ± 0.2− 0.9 ± 0.1− 0.8 ± 0.2− 0.9 ± 0.1− 0.7 ± 0.2− 0.7 ± 0.2

Overallassessment

Test
Placebo− 1.0 ± 0.0− 0.8 ± 0.1− 0.7 ± 0.2− 0.9 ± 0.1− 0.7 ± 0.2− 0.2 ± 0.2 †Dryness

Test
Placebo

1.7 ± 0.2
1.9 ± 0.2

1.3 ± 0.2 *‡1.9 ± 0.2

1.2 ± 0.2 *1.5 ± 0.2

Erythema

Test
Placebo

0.3 ± 0.1
0.5 ± 0.2

0.1 ± 0.1
0.3 ± 0.2

0.1 ± 0.1 *0.2 ± 0.1

Scaly skin

Test
Placebo

1.3 ± 0.2
1.5 ± 0.2

0.9 ± 0.2 *‡1.7 ± 0.2

0.8 ± 0.2 *1.2 ± 0.2

Irritation

Test
Placebo

0.2 ± 0.1
0.1 ± 0.1

0.0 ± 0.0
0.0 ± 0.0

0.0 ± 0.0
0.0 ± 0.0

Itching

Test
Placebo

0.0 ± 0.0
0.1 ± 0.1

0.0 ± 0.0
0.1 ± 0.1

0.0 ± 0.0
0.0 ± 0.0

Dryness

Test
Placebo

1.8 ± 0.4
1.7 ± 0.2

1.5 ± 0.2
1.7 ± 0.2

1.0 ± 0.3
1.1 ± 0.3 †Erythema

Test
Placebo

0.5 ± 0.2
0.3 ± 0.2

0.2 ± 0.2
0.2 ± 0.2

0.0 ± 0.0 †0.2 ± 0.2

Scaly skin

Test
Placebo

1.5 ± 0.2
1.3 ± 0.3

1.0 ± 0.4 †1.3 ± 0.3

0.5 ± 0.3 *0.9 ± 0.2

Irritation

Test
Placebo

0.0 ± 0.0
0.0 ± 0.0

0.0 ± 0.0
0.0 ± 0.0

0.0 ± 0.0
0.0 ± 0.0

Itching

Test
Placebo

0.0 ± 0.0
0.1 ± 0.1

0.0 ± 0.0
0.0 ± 0.0

0.0 ± 0.0
0.0 ± 0.0

Crista cutisAllsubjects

Group‡− 0.1 ± 0.2− 0.1 ± 0.1 *Mean ± SE
Comparison within a group（* p ＜ 0.05, † p ＜ 0.10)
Comparison between groups（‡ p ＜ 0.05)

at least one serving of the study diet were included in thesafety analysis data set（Full Analysis Set［FAS］）, andthe 39 subjects who completed the study were included in
the eﬃcacy analysis data set（Per Protocol Set［PPS］）.
For a more detailed efficacy assessment of IMD, a
subgroup analysis was performed for 15 subjects whose
serum phenol concentrations were higher than the meanvalue（0.83 ng/mL in serum）, in addition to the analysisof all 39 subjects. The characteristics of the subjects
analyzed are shown in table 1.

3.2. Visual assessment by a dermatologist
Table 2 shows the scores for skin texture and skinquality, with each item evaluated by a dermatologist.
In the comparison of skin texture between groups, there
was a signiﬁcant improvement in the crista cutis score in
the test food group compared with that in the placebo
food group at 4 weeks after intake. Meanwhile, comparedwith before intake, there were signiﬁcant improvementsin the overall assessment score in both groups and asignificant improvement in the crista cutis score in the32 （912）

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第 12 号（2019 年 12 月）

Table 3 Skin measurements

All subjects

Skin moisture
content
Subgroup
analysis
subjects

All subjects

Transepidermal
water loss
（g/hm2）Subgroup
analysis
subjects

Site

Group

week 04 weeks

8 weeks

Cheek

Test
Placebo39.9 ± 2.5
41.1 ± 2.2

52.4 ± 3.0 *49.3 ± 2.3 *

Upper
arm

Test
Placebo25.8 ± 1.9
24.9 ± 1.3

Foot

Test
Placebo

Cheek

Percent change （％）
4 weeks

8 weeks

52.6 ± 3.1 *51.4 ± 2.2 *135.9 *
122.9 *

140.3 *
129.8 *

27.0 ± 1.2
26.6 ± 1.7

25.1 ± 1.2§
28.7 ± 1.5 *110.4 †
108.6

103.0
117.3 *

22.1 ± 1.1
22.2 ± 1.6

23.8 ± 1.4
22.7 ± 1.4

24.0 ± 1.4
21.1 ± 1.3

108.6 †
108.3

110.0 †
100.9

Test
Placebo40.8 ± 4.6
39.9 ± 2.6

55.7 ± 4.8 *48.0 ± 2.0 *52.5 ± 5.5 †51.5 ± 2.9 *146.0 †
122.7 *

137.9
131.9 *

Upper
arm

Test
Placebo29.1 ± 2.6
25.6 ± 2.1

28.9 ± 1.7
25.1 ± 1.7

27.3 ± 2.1
27.8 ± 1.7

102.4
100.5

98.1
110.5 †Foot

Test
Placebo22.3 ± 1.7
21.2 ± 2.3

25.0 ± 1.8
21.7 ± 2.2

24.8 ± 2.0
19.2 ± 1.6

113.2
105.1

112.8
96.8

Cheek

Test
Placebo18.6 ± 0.9
17.8 ± 1.0

19.2 ± 1.4
19.4 ± 1.5

18.4 ± 1.1
16.9 ± 1.1

103.9
109.8

100.5
95.6

Upper
arm

Test
Placebo

8.9 ± 0.5
9.2 ± 0.6

8.5 ± 0.6
7.5 ± 0.7 *8.6 ± 0.5
7.3 ± 0.6 *

97.3
83.8 *

98.2
86.6

Foot

Test
Placebo

10.4 ± 0.8
10.4 ± 0.6

11.1 ± 0.6
10.3 ± 0.5

9.0 ± 0.7 †9.7 ± 0.7

114.1
103.1

90.6
95.8

Cheek

Test
Placebo17.1 ± 1.7
15.6 ± 1.1

18.9 ± 1.5
17.7 ± 1.8

18.5 ± 2.4
16.0 ± 1.8

113.3
113.6

110.5
101.2

Upper
arm

Test
Placebo

8.1 ± 0.6
8.2 ± 0.7

8.2 ± 1.1
7.4 ± 0.5

8.1 ± 0.9
6.9 ± 1.0

102.2
95.7

102.2
93.0

Foot

Test
Placebo

9.3 ± 1.1
10.2 ± 0.8

10.4 ± 1.3
9.3 ± 0.9

8.7 ± 1.7
10.4 ± 1.3

119.1
92.7

91.7
106.5

‡

Mean ± SE
Comparison within a group（* p ＜ 0.05, † p ＜ 0.10）
Comparison between groups（‡ p ＜ 0.05, § p ＜ 0.10）
The percent change shows the rate of change on skin moisture content or transepidermal water loss from week 0（before intake）.

placebo food group at 8 weeks after intake. In thecomparison of skin quality between groups, there weresigniﬁcant improvements in the dry skin score and scaly
skin score in the test food group compared with those in
the placebo food group 4 weeks after intake. Meanwhile,
compared with before intake, there were significant
improvements in the erythema score as well as in the dryskin score and scaly skin score in the test food group at 4
or 8 weeks after intake.
The subgroup analysis showed no signiﬁcant diﬀerencesin skin texture or skin quality between groups. However,compared with before intake, there was a significant
improvement in skin quality in the test food group at 8
weeks after intake.
3.3. Skin measurements
Table 3 shows the data on skin moisture content andtransepidermal water loss and the percent change inthese parameters from week 0（before intake）at 3 sites.
In the comparison of skin moisture content between
groups, there was no significant difference at any site.
However, compared with before intake, there weresigniﬁcant increases at 4 and 8 weeks after intake in thecheek in both groups, and at 8 weeks in the upper arm in
the placebo food group. On the foot, there were nochanges in either group. However, there was a signiﬁcant
percent increase or a trend toward an increase at all 3
sites where skin measurements were performed in thetest food group 4 or 8 weeks after intake. In thecomparison of transepidermal water loss between groups,
there was no signiﬁcant diﬀerence at any site. However,compared with before intake, there were significant
decreases in the upper arm in the placebo food group at 4
and 8 weeks after intake, and there was a decreasing

診療と新薬・第 56 巻

第 12 号（2019 年 12 月）

33 （913）

Table 4 Serum phenols
Item

Group

4 weeks

PhenolTest− 0.1 ± 0.2（ng/mL Plasma） Placebo
0.0 ± 0.1
Allsubjects p -Cresol
Test
0.7 ± 0.3 †（ng/mL Plasma） Placebo
0.0 ± 0.2

Changes inserum concentrations of
PhenolTest− 0.7 ± 0.4
putrefactive products
Subgroup（ng/mL Plasma） Placebo − 0.1 ± 0.1
analysisTest
0.5 ± 0.3
subjects p -Cresol（ng/mL Plasma） Placebo
0.0 ± 0.3

8 weeks− 0.7 ± 0.1 *− 0.6 ± 0.1 *0.0 ± 0.4
− 0.4 ± 0.3− 1.3 ± 0.1 *‡− 0.8 ± 0.1 *− 0.4 ± 0.5− 1.2 ± 0.4 *Mean ± SE
Comparison within a group（* p ＜ 0.05, † p ＜ 0.10）
Comparison between groups（‡ p ＜ 0.05）

trend on the foot in the test food group at 8 weeks after
intake. In the cheek, there were no changes in eithergroup.
The subgroup analysis showed that the skin moisturec o n t e n t o n t h e f o o t i n t h e t e s t f o od gr o u p w a s
signiﬁcantly higher than that in the placebo food group at
8 weeks after intake. However, compared with before
intake, there was a significant increase or increasing
trend at 4 and 8 weeks after intake in the cheek in bothgroups. In the upper arm, there were no changes ineither group. In addition, there was a signiﬁcant percent
increase or increasing trend at 4 and 8 weeks after intake
in the cheek and the upper arm in the placebo food group,and there was an increasing trend at 4 weeks after intake
in the cheek in the test food group. With regard totransepidermal water loss, there were no significant
changes including percent changes.
3.4. Changes in serum phenol and p -cresol
concentrations
Table 4 shows the changes in serum phenol and p -cresol
concentrations from before intake, using blood samples
collected from the subjects.
In the comparison of serum phenol concentration
changes, there were no significant differences between
groups. However, compared with before intake, there
were significant decreases in both groups at 8 weeks
after intake. Also, in the comparison of serum p -cresol
concentration changes, there were no signiﬁcant changes
in either group and no significant differences between
groups.
The subgroup analysis showed that there weresignificant decreases in serum phenol concentrations inboth groups at 8 weeks after intake compared with those
before intake, and at that time, there was a signiﬁcantly
lower value in the test food group than in the placebo
food group. With regard to serum p -cresol concentration,
there were significant decreases in the placebo foodgroup compared with that before intake, but there wereno signiﬁcant diﬀerences between groups.
3.5. Questionnaire survey on bowel movements andskin condition
The number of bowel movements, number of days ofdefecation, and fecal amount were tallied every week. In
comparisons of the number of bowel movements, numberof days of defecation, or fecal amount, there were no
significant differences between groups. However,compared with before intake, there was a significant
increase or a trend toward an increase in the number ofbowel movements, number of days of defecation, andfecal amount from week 1 to week 8 after intake in bothgroups（data not shown）.
Table 5 shows the data of the subgroup analysis. There
was a signiﬁcantly higher number of bowel movements at
6 weeks after intake and a signiﬁcantly higher number ofdays of defecation at 4, 6, and 8 weeks after intake in thetest food group than in the placebo food group.
Furthermore, compared with before intake, there was asigniﬁcant increase or a trend toward an increase in thenumber of bowel movements, number of days ofdefecation, and fecal amount from week 3 to week 8 after
intake in the test food group; however, there were no
signiﬁcant changes in the placebo food group.
A VAS score for each question about the subject s
perception of skin condition and changes in skin condition
was tallied. Compared with before intake, there was asigniﬁcant improvement or a trend toward improvementin perception on many questions at 4 or 8 weeks after
intake in both groups. Of these questions, the scores andchanges in score for redness of the skin of the face andwhole body were signiﬁcantly improved at 4 or 8 weeks
after intake in the test food group, but no significant
changes were observed in the placebo food group.
Furthermore, in a comparison between groups, there wasa significant improvement in the score for pigmented

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第 12 号（2019 年 12 月）

Table 5 Bowel movements
Item

Group

week 01 week2 weeks

3 weeks

Test

3.7
± 0.7

5.2
± 1.3

5.8
± 1.6

± 2.0

± 1.1

± 0.7

± 1.1

3.2

4.0

3.9

4.4

3.9

3.8

3.8

3.8

3.7

± 0.2

± 0.6

± 0.7

± 1.0

± 0.8

± 0.5

± 0.4

± 0.5

± 0.6

Defecation frequency
PlaceboNumber of days ofanalysis
subjects（number of days/week）

5.8 *

5 weeks
4.7

6 weeks
6.3 *7 weeks
5.3± 1.0

8 weeks
5.8 *
± 1.3

‡

（number/week）

Subgroup

7.0 †4 weeks

Test

3.2

3.5

4.2

4.7

± 0.4

± 0.4

± 0.6

± 0.8

± 0.5

2.9

3.7

3.4

3.8

± 0.1

± 0.6

± 0.5

± 0.5

4.2 †

4.8 *

5.2 *

± 0.6

± 0.5

3.2

Placebo

3.6

± 0.4

± 0.4

Test
Fecal amount（number of egg unit/week）
Placebo

4.8 *
± 0.5

3.3

3.3

3.3

± 0.3

± 0.3

± 0.4

‡

defecation

4.5
± 0.7
‡

7.0

6.8

8.9

10.1

8.8

7.9

± 1.9

± 1.3

± 1.4

± 1.6

± 1.2

± 1.2

10.1 *
± 1.6

‡

8.7
± 1.6

9.1 *
± 1.7

5.3

7.6

7.1

8.4

7.8

7.5

7.3

7.2

6.3

± 0.7

± 1.6

± 1.5

± 2.2

± 1.7

± 1.4

± 1.1

± 1.2

± 1.1

Mean ± SE
Comparison within a group（* p ＜ 0.05, † p ＜ 0.10）
Comparison between groups（‡ p ＜ 0.05）

spots on the face at 8 weeks after intake in the test foodgroup compared with the placebo food group（data notshown）.
The stratified analysis also showed a significant
improvement or a trend toward improvement in the VAS
score and changes in score on many questions at 4 or 8
weeks after intake in both groups, compared with before
intake. However, in comparisons between groups, there
was a significant improvement or a trend toward
improvement in the change in score for clogged pores on
the face at 4 weeks after intake and in the score forpigmented spots on the face at 4 or 8 weeks after intake
in the test food group compared with the placebo foodgroup（data not shown）.
3.6. Safety
Regardless of the type of study diet consumed, transientloose stool or abdominal distension developed, butdisappeared in a short time in both the test and placebo
food groups. There were no serious adverse events oradverse reactions based on the symptoms reported in thequestionnaire for all subjects who received the study dietduring the study period, including the subject who
withdrew, in this study. No abnormal changes inlaboratory tests were noted before and 8 weeks after
intake.

4. DISCUSSION
The results showed that there was a significant
improvement dry skin condition with evaluation by adermatologist after intake of IMD versus placebo in all
healthy subjects with awareness of dry skin symptoms
and a tendency toward constipation. While, there wereno signiﬁcant diﬀerence between IMD and placebo in skinmeasurements with instruments because of both groups
showed an improvement dry skin condition. Since thepurpose of this study was to examine the improvement ofskin condition through improvement of the intestinal
environment, we selected those subjects who were likely
to have a disordered intestinal environment and who hadawareness of dry skin and a tendency toward
constipation. However, it was likely that we included
subjects who had an awareness of constipation tendency
but whose intestinal environment was not very
disordered. Dry skin is caused by several factors otherthan a disordered intestinal environment. Yamamoto etal. 20） reported that about 70％ of young women with anawareness of healthy bowel movements, althoughsignificantly fewer than those with an awareness ofconstipation, had skin troubles, and they indicated thatpsychological stress was the major cause. Accordingly,
we cannot rule out the possibility of including subjects
whose dry skin was caused by factors other than adisordered intestinal environment.
Therefore, we conducted a subgroup analysis in 15 of
the 39 subjects who had dry skin probably caused by adisorder of intestinal environment, whose serum phenol
concentrations before intake were higher than the meanvalue in all subjects. As the results, although there wasno statistically significant difference between IMD andplacebo in visual assessment by a dermatologist, there
was a significantly higher moisture content in the footskin 8 weeks after intake of IMD versus placebo.
Compared with before intake, there was also a signiﬁcant
increase in cheek skin moisture content in the test foodgroup, showing an improvement in dry skin.
The skin consists of the epidermis, the dermis and the
subcutaneous tissue. The horny layer of the epidermis,
the outermost layer of the skin, provides a physical診療と新薬・第 56 巻

barrier and has a biological defense mechanism. It also
plays an important role in retention of water within theskin, and the intercellular lipid lamellae located between
the horny cells contributes to water retention and skinmoisturization. The barrier function of the horny layer isa f f e c t e d b y v a r i o u s e x t e r n a l f a c t o r s（ i n c l u d i n gtemperature, humidity, and ultraviolet light）, and is also
reported to maintain skin homeostasis internally throughthe intake of various foods 2）9）18）. Phenols are putrefactive
products produced by specific intestinal bacteria fromsome amino acids in protein in foods, and can beindicators of the composition of the intestinal
environment. It was reported that phenols absorbed fromthe intestine were transferred to the bloodstream andinvolved in worsening of skin conditions 4）5）. We haverecently found in rats that phenol and p -cresol
concentrations in the body were increased by tyrosineload, and co-administration of IMD remarkably reduced
these concentrations 17）. In addition, we have conﬁrmed inhairless rats that the diﬀerentiation of epidermal cell wasdelayed and the corneocyte size was decreased bytyrosine load, and co-administration of IMD maintained
the differentiation of epidermal cell and the corneocyte
size remained normal（unpublished data）. Kano et al.
reported that intake of fermented milk containing
Bifidobacterium reduced the blood concentration ofphenol, maintained skin moisture, and likely improved
keratinocyte differentiation in healthy adult women.
According to their conclusions, suppression of the
production of phenols in the intestine by intake offermented milk containing Biﬁdobacterium inhibited themigration of phenols into the blood and skin, which led toan improvement in the condition of the epidermis and themaintenance of skin structure, resulting in an
enhancement of moisture retention 8）. Therefore, in
subjects who has dry skin probably caused by a disorderof intestinal environment intake of IMD may also havesuppressed the production of phenols in the intestine andinhibited their migration into the blood and skin. As aresult, it is speculated that the improvement of
keratinocyte diﬀerentiation and maintenance of the skinstructure enhanced the moisture retention in the skin.
Furthermore, since the test food group showedremarkable improvement in bowel movements in thisstudy, facilitated excretion of phenols by IMD may be oneof the reasons for the improvement in dry skin and theoccurrence of a moisturizing eﬀect.
Skin measurements were performed on the cheek, theupper arm, and the foot, and showed a remarkablemoisturizing effect of IMD intake on the foot in thesubgroup analysis. No superiority of IMD to the placebo
was found except for the foot skin, although there was atendency toward improvement in the skin moisture
content of the cheek. One of the reasons for this seems tobe the eﬀects of weather. This study was conducted fromthe winter to spring（between February and April 2018）,

第 12 号（2019 年 12 月）

35 （915）

when the skin is said to be dry. However, the weather
record in Tokyo by the Japan Meteorological Agency（Tokyo, Japan）, where the study facility was located,shows that the temperature and humidity in 2018
remained higher than usual in terms of the annual
average; in particular, the average humidity in March
was higher by about 10％ . Therefore, the unexpectedly
not-dry-weather seemed to be a reason for the diﬃculty
in detecting an eﬀect of IMD intake. Nevertheless, IMD
intake had an improving eﬀect on the dry skin of the footin the subgroup analysis. Of the 3 sites measured, thefoot had the lowest skin moisture, an indicator of thewater retention function of the skin. Moreover, comparedwith the other 2 sites, the foot is the site with the lowest
sebum secretion, and is easily aﬀected by dryness due torough skin. The foot may have been the site where themoisturizing eﬀect by oral intake of the study diet can beseen easily compared with other sites, because the foot isunlikely to be affected by external moisturizing factors
such as cosmetics. From these results, the moisturizing
eﬀect of IMD, looks promising not only on the foot thatwas found to be eﬀective in this study, but also for wholebody skin.
Furthermore, the placebo food group also showedsignificant improvement in bowel movements comparedwith before intake. This seems to be a placebo effect;
however, the improvement of bowel movements insubjects with an awareness of a tendency toward
constipation may have led not only to the decrease inintestinal putrefactive products due to an increase indefecation frequency, but also to the reduction in
psychological stress, and thus, this placebo effect may
have greatly affected the study results. However, allsubjects in the test food group showed an improvement inskin condition with evaluation by a dermatologist（objective assessment）, including improved perception.
This suggests that IMD is involved not only in bowel
movements but also in inhibition of the production ofsubstances that have adverse effects on the skin byaltering the intestinal flora, as we found in the rat
studies. The mechanism is speculated as follows:
continuous intake of IMD provides a carbon source,
reduces pH in the intestine by contributing to short-chain
fatty acid production in the intestine, and thereby
restores the balance of intestinal flora. In particular,
having a characteristic structure, IMD is effective forforming an intestinal environment in which the
production of phenols by intestinal bacteria is inhibited.
Consequently, continuous intake of IMD can be aneﬀective measure to enhance daily QOL by improving thedisordered intestinal environment, including constipation,
which often occurs in modern life, leading to mitigation/
improvement of dry skin or discomfort.

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5. CONCLUSIONS
The results of this study indicate that continuous intake
of IMD improves skin condition, including skin moisture,in subjects with dry skin symptoms likely caused by adisordered intestinal environment. It is speculated thatthe effects are the result of changes induced in theintestinal flora by continuous intake of IMD. Having acharacteristic structure, IMD seems to contribute to theformation of an intestinal environment in which
production of phenols is inhibited.
CONFLICT OF INTEREST
In this study, the sponsor, Hayashibara Co., Ltd. provided the appropriate
funding and entrusted TES Holdings Co., Ltd. to execute and manage thestudy. Among the authors, Y. I., T. S., H. W., M. H. and S. U. belong toHayashibara Co., Ltd. The investigator, S. N. belongs to Medical
Corporation Bokushinkai CLINTEXE Clinic.

ACKNOWLEDGEMENT
We would like to thank the staff of TES Holdings Co., Ltd., for theirsupport with the work of this clinical study.

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