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Bifidobacterium bifidum YIT 10347 fermented milk exerts beneficial effects on gastrointestinal discomfort and symptoms in healthy adults: A double-blind, randomized, placebo-controlled study

Open AccessPublished:March 22, 2018DOI:https://doi.org/10.3168/jds.2017-13803

      ABSTRACT

      In a preliminary open-label trial by our group, Bifidobacterium bifidum YIT 10347 (YIT10347) relieved gastric symptoms in patients with functional gastrointestinal disorders. Hence, in this study, we investigated the effects of YIT10347 on gastrointestinal symptoms in healthy adults. In this prospective double-blind, randomized, placebo-controlled trial (UMIN000024654), 100 healthy Japanese adults were randomly assigned to a YIT10347 group or placebo group and consumed 100 mL of YIT10347-fermented milk or placebo fermented milk, respectively, every day for 4 wk. Gastrointestinal symptoms were evaluated by using the modified Frequency Scale for Symptoms of Gastroesophageal Reflux Disease (m-FSSG) and Gastrointestinal Symptom Rating Scale (GSRS) as primary endpoints. Mental symptoms, quality of life, salivary stress markers, and gastric emptying were evaluated as secondary endpoints. Effectiveness and safety were analyzed in a per-protocol set (YIT10347 group, n = 39; placebo group, n = 40) and full analysis set (YIT10347 group, n = 50; placebo group, n = 50), respectively. In the m-FSSG evaluation, the YIT10347 group had a significantly higher relief rate of postprandial discomfort and greater changes in postprandial epigastric pain score from baseline than the placebo group. In the GSRS evaluation, the YIT10347 group had significantly higher relief rates of overall gastrointestinal symptoms, upper gastrointestinal symptoms, flatus, and diarrhea than the placebo group. We detected no significant differences in scores or relief rates of mental symptoms and quality of life, a salivary stress marker, or gastric emptying between the 2 groups. No severe adverse events associated with test beverage consumption were observed in either group. These findings suggest that daily consumption of YIT10347-fermented milk exerts beneficial effects on gastrointestinal discomfort and symptoms such as postprandial discomfort and epigastric pain in healthy adults.

      Key words

      INTRODUCTION

      Increasing numbers of healthy Japanese adults occasionally have abdominal symptoms, with epidemiological studies revealing that about one-quarter of the Japanese population experiences digestive symptoms such as abdominal pain, stomach heaviness, and acidic regurgitation (
      • Stanghellini V.
      Three-month prevalence rates of gastrointestinal symptoms and the influence of demographic factors: Results from the Domestic/International Gastroenterology Surveillance Study (DIGEST).
      ). Gastrointestinal (GI) symptoms can occur in the presence or absence of organic abnormalities such as gastritis caused by Helicobacter pylori infection (
      • Manabe N.
      • Haruma K.
      • Kamada T.
      • Kusunoki H.
      • Inoue K.
      • Murao T.
      • Imamura H.
      • Matsumoto H.
      • Tarumi K.
      • Shiotani A.
      • Hata J.
      Changes of upper gastrointestinal symptoms and endoscopic findings in Japan over 25 years.
      ). However, those who temporarily experience GI symptoms often prefer to receive functional foods rather than medical treatment because their symptoms are mild and temporary.
      Probiotics, which are living microorganisms that confer health benefits in the host (
      • FAO/WHO
      Joint FAO/WHO Working Group: Guidelines for the Evaluation of Probiotics in Food.
      ), might have beneficial effects on not only the gut but also the upper GI tract. Bifidobacterium bifidum YIT 10347 (YIT10347) is a typical probiotic with benefits on upper GI symptoms such as H. pylori-associated gastritis (
      • Miki K.
      • Urita Y.
      • Ishikawa F.
      • Iino T.
      • Shibahara-Sone H.
      • Akahoshi R.
      • Mizusawa S.
      • Nose A.
      • Nozaki D.
      • Hirano K.
      • Nonaka C.
      • Yokokura T.
      Effect of Bifidobacterium bifidum fermented milk on Helicobacter pylori and serum pepsinogen levels in humans.
      ) and gastric symptoms of serious functional gastrointestinal disorders (FGID;
      • Urita Y.
      • Goto M.
      • Watanabe T.
      • Matsuzaki M.
      • Gomi A.
      • Kano M.
      • Miyazaki K.
      • Kaneko H.
      Continuous consumption of fermented milk containing Bifidobacterium bifidum YIT 10347 improves gastrointestinal and psychological symptoms in patients with functional gastrointestinal disorders.
      ) in patients with FGID, gastric symptoms in healthy adults (
      • Gomi A.
      • Iino T.
      • Nonaka C.
      • Miyazaki K.
      • Ishikawa F.
      Health benefits of fermented milk containing Bifidobacterium bifidum YIT 10347 on gastric symptoms in adults.
      ), and acute gastric mucosal injury in an animal model (
      • Gomi A.
      • Harima-Mizusawa N.
      • Shibahara-Sone H.
      • Kano M.
      • Miyazaki K.
      • Ishikawa F.
      Effect of Bifidobacterium bifidum BF-1 on gastric protection and mucin production in an acute gastric injury rat model.
      ), via its strong adherence to the gastric mucosa (
      • Shibahara-Sone H.
      • Gomi A.
      • Iino T.
      • Kano M.
      • Nonaka C.
      • Watanabe O.
      • Miyazaki K.
      • Ohkusa T.
      Living cells of probiotic Bifidobacterium bifidum YIT 10347 detected on gastric mucosa in humans.
      ). However, there is little evidence regarding its effects on temporary gastric symptoms in healthy adults.
      Therefore, in this study we aimed to clarify the beneficial effects of YIT10347 on temporary gastric symptoms in healthy Japanese adults in a prospective randomized, double-blind, placebo-controlled, parallel-group trial.

      MATERIALS AND METHODS

      Test Beverage

      Milk fermented with YIT10347 was prepared by anaerobic culture of YIT10347 and Streptococcus thermophilus YIT 2021, obtained from the Culture Collection Laboratory at Yakult Central Institute (Tokyo, Japan). The placebo milk was prepared by anaerobic culture of Streptococcus thermophilus YIT 2021 and was followed by the addition of lactic acid and acetic acid to match the appearance, taste, flavor, pH, and nutritional content of the active fermented milk as much as possible. The beverages (100 mL/package), which had identical appearance, packaging, and labeling to maintain blinding of investigators and participants, were delivered to subjects at 1-wk intervals and stored in a refrigerator (≤10°C) before and during delivery and before consumption. During the trial, the active beverage, YIT10347-fermented milk, contained more than 3 × 107 cfu/mL of YIT10347 and more than 1 × 107 cfu/mL of S. thermophilus YIT 2021, whereas the placebo milk contained more than 1 × 107 cfu/mL of S. thermophilus YIT 2021 only.

      Trial Design

      This prospective, randomized, double-blind, placebo-controlled, parallel-group trial (UMIN Clinical Trials Registry number: UMIN000024654; http://www.umin.ac.jp/ctr/), designed by the authors (Figure 1), was conducted from October 2016 to March 2017. The study protocol was approved by the Ethics Committee of Nihonbashi Cardiology Clinic (Tokyo, Japan; No. YLT-008-01; October 7, 2016), and written informed consent was obtained before subject enrollment. The study was performed in accordance with the principles of the Declaration of Helsinki and Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan (http://www.mhlw.go.jp/file/06-Seisakujouhou-10600000-Daijinkanboukouseikagakuka/0000080278.pdf).
      Figure thumbnail gr1
      Figure 1Study design. Subjects consumed 100 mL of milk fermented with Bifidobacterium bifidum YIT 10347 (YIT10347 group) or placebo fermented milk daily for 4 wk.

      Participants

      The study enrolled healthy adults aged from 20 to 64 yr who had temporary gastric symptoms with a modified Frequency Scale for Symptoms of Gastroesophageal reflux disease (m-FSSG) score ≥8 (
      • Kusano M.
      • Hosaka H.
      • Kawada A.
      • Kuribayashi S.
      • Shimoyama Y.
      • Kawamura O.
      • Moki F.
      Development and evaluation of a modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease to distinguish functional dyspepsia from non-erosive reflux disease.
      ) but were not defined as having “functional dyspepsia” by the Rome IV classification (
      • Stanghellini V.
      Rome IV—Gastroduodenal disorders.
      ). The participants had one or more symptoms but no evidence of organic diseases such as peptic ulcer disease, H. pylori-associated gastritis diagnosed by the presence of anti-H. pylori antibodies in the blood, gastric cancer, or gastritis, based on their answers to a physician's questions.
      The enrolled participants met the following inclusion criteria: (1) healthy men and women aged from 20 to 64 yr old, (2) with an m-FSSG score of ≥8, and (3) who understood the details of the study and provided written informed consent. Exclusion criteria were (1) H. pylori infection; (2) regular use of gastrointestinal drugs; (3) functional dyspepsia (Rome IV classification); (4) refusal to stop ingestion of probiotics, prebiotics, foods containing lactic acid bacteria or bifidobacteria, and other healthy foods that might affect gastrointestinal symptoms; (5) food allergy; (6) severe complications or diseases requiring urgent treatment; (7) a medical history of diseases or operations affecting digestion, absorption, or defecation; (8) those deemed unsuitable for the study based on blood results of the screening test; (9) those who were pregnant or lactating or planning to become pregnant during the study; (10) those receiving treatment for or with a history of drug addiction or alcoholism; (11) those planning to participate or already participating in other clinical studies; and (12) those deemed unsuitable for the study by the investigator for other reasons.

      Sample Size and Study Conduct

      According to a previous trial (
      • Gomi A.
      • Iino T.
      • Nonaka C.
      • Miyazaki K.
      • Ishikawa F.
      Health benefits of fermented milk containing Bifidobacterium bifidum YIT 10347 on gastric symptoms in adults.
      ), the relief rates of dyspepsia symptoms in healthy volunteers were presumed to be 32 and 60% in the placebo and YIT10347 groups, respectively. We determined that a similar percentage of volunteers should be treated with YIT10347 in this study. Assuming an effective YIT10347 ratio of 60%, placebo effective ratio of 32%, α-error of 0.05, β-error of 0.20, and power of 0.80, approximately 100 participants would be required, 50 in the placebo group and 50 in the YIT10347 group. Therefore, 100 healthy adults were recruited in this study.

      Randomization

      During the pre-ingestion period, 100 participants were sequentially randomized 1:1 to the 2 groups by the data analysis department of KSO Corp. (Tokyo, Japan). Participant allocation was concealed by the controller for clinical trials (Tsurumi Univ., Kanagawa, Japan). After all data had been collected by the data analysis department of KSO Corp., the data code key was requested from the controller, enabling data analysis.

      Study Design

      During the pre-ingestion and consumption periods, upper GI symptoms were evaluated using the m-FSSG questionnaire, which comprises 14 questions as follows: 1, heartburn; 2, bloated stomach; 3, heavy stomach after meals; 4, subconscious chest rubbing; 5, postprandial discomfort; 6, heartburn after meals; 7, unusual sensation in throat; 8, full feeling while eating meals; 9, food stuck when swallowing; 10, acid coming up into throat; 11, burping; 12, heartburn while bending over; 13, postprandial epigastric pain; and 14, epigastric pain before meals. The scores for the 14 questions were assigned as follows: never = 0; occasionally = 1; sometimes = 2; often = 3; and always = 4, with lower and higher scores indicating milder and more severe symptoms, respectively. Based on the questions, the reflux syndrome score (RS; questions 1, 4, 6, 7, 9, 10, and 12), acid-related dyspepsia score (ARD; questions 2, 3, 5, 8, 11, 13, and 14), and total score (questions 1–14; given by the sum of both scores) were calculated (
      • Kusano M.
      • Shimoyama Y.
      • Sugimoto S.
      • Kawamura O.
      • Maeda M.
      • Minashi K.
      • Kuribayashi S.
      • Higuchi T.
      • Zai H.
      • Ino K.
      • Horikoshi T.
      • Sugiyama T.
      • Toki M.
      • Ohwada T.
      • Mori M.
      Development and evaluation of FSSG: Frequency scale for the symptoms of GERD.
      ,
      • Kusano M.
      • Hosaka H.
      • Kawada A.
      • Kuribayashi S.
      • Shimoyama Y.
      • Kawamura O.
      • Moki F.
      Development and evaluation of a modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease to distinguish functional dyspepsia from non-erosive reflux disease.
      ;
      • Kusano M.
      [Questionnaires for GERD, QUEST and F scale].
      ). In addition, the relief rate was evaluated via a modification of the protocol in the previous report (
      • Kusunoki H.
      • Kusaka M.
      • Kido S.
      • Yamauchi R.
      • Fujimura Y.
      • Watanabe Y.
      • Kobori M.
      • Miwa H.
      • Tomita T.
      • Kin Y.
      • Hori K.
      • Tano N.
      • Sugimoto K.
      • Nakamura Y.
      • Fujimoto K.
      • Oza N.
      • Matsunobu A.
      • Ono N.
      • Fuyuno S.
      • Kinoshita Y.
      • Adachi K.
      • Yuki M.
      • Fujisawa T.
      • Haruma K.
      Comparison of the effects of omeprazole and famotidine in treatment of upper abdominal symptoms in patients with reflux esophagitis.
      ). Relief rate was defined as the number of participants whose symptom ratings were “alleviated,” “no change,” or “deteriorated” by comparing the “before ingestion” and “after ingestion” scores.
      Overall GI symptoms were also assessed using the Japanese version of the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire, which includes 15 scoring criteria: abdominal pain, heartburn, acid regurgitation, sucking sensations in the epigastrium, nausea and vomiting, borborygmus, abdominal distension, eructation, increased flatus, decreased passage of stools, increased passage of stools, loose stools, hard stools, urgent need for defecation, and feeling of incomplete evacuation, scored on a 7-point Likert scale. This gives a total value range between 15 and 105, where the highest score (7) for any item represents the most pronounced symptom and the lowest score (1) represents no symptoms. The criteria were grouped into the following 5 domains: RS (questions 2 and 3), abdominal pain (AP; questions 1, 4, and 5), indigestion syndrome (IS; questions 6, 7, 8, and 9), constipation syndrome (CS; questions 10, 13, and 15), and diarrhea syndrome (DS; questions 11, 12, and 14). Furthermore, these 5 domains were subdivided into upper GI symptoms (RS, AP, and IS) and lower GI symptoms (CS and DS) (
      • Svedlund J.
      • Sjodin I.
      • Dotevall G.
      GSRS—A clinical rating scale for gastrointestinal symptoms in patients with irritable bowel syndrome and peptic ulcer disease.
      ;
      • Hongo M.
      • Fukuhara T.
      • Green J.
      QOL in digestive region.
      ). These 5 domains, upper and lower GI symptoms, and total score were calculated as (sum of each question score)/(number of questions).
      Subjective psychological symptoms were evaluated using the Japanese translation of the Profile of Mood States 2nd Edition-Adult Short (POMS 2; Kaneko Shobo Inc., Tokyo, Japan;
      • McNair D.M.
      • Lorr M.
      • Droppleman L.F.
      Profile of Mood States.
      ;
      • Yokoyama K.
      • Araki S.
      • Kawakami N.
      • Tkakeshita T.
      [Production of the Japanese edition of Profile of Mood States (POMS): Assessment of reliability and validity.].
      ;
      • Heuchert J.P.
      • McNair D.M.
      Profile of Mood States.
      . The questionnaire includes 35 items and uses a 5-point Likert scale to evaluate 7 domains; namely, anger–hostility, confusion–bewilderment, depression–dejection, fatigue–inertia, tension–anxiety, vigor–activity, and friendliness. Higher scores indicate more severe symptoms of anger–hostility, confusion–bewilderment, depression–dejection, fatigue–inertia, tension–anxiety, but better conditions of vigor–activity, and friendliness; each item was scored from 0 to 100 and compared with values from normal individuals.
      Subjective quality of life was evaluated using the 36-Item Short Form Health Survey version 2 (SF-36v2;
      • Fukuhara S.
      • Suzukamo Y.
      Manual of SF-36v2; Japanese version.
      ). The questionnaire includes 36 items and uses a 5-point Likert scale to evaluate 3 domains; namely, physical component summary, mental component score, and role–social component score, and 8 subdomains; namely, physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health; each item was scored from 0 to 100 and compared with values from normal individuals.
      Subjects were asked to report their symptoms about the past 1 wk from “before ingestion” (visit 2) and “after ingestion” (visit 3).

      Salivary Cortisol and Gastric Emptying

      Saliva samples were taken while participants were fasting in the morning at a predetermined time. Cortisol levels were determined using a commercial salivary cortisol enzyme assay kit (Salimetrics, State College, PA).
      Subjective gastric emptying was evaluated using the 13C-acetate breath test according to a previously reported method (
      • Sanaka M.
      • Urita Y.
      • Yamamoto T.
      • Shirai T.
      • Kimura S.
      • Aoyagi H.
      • Kuyama Y.
      Right recumbent position on gastric emptying of water evidenced by (13)C breath testing.
      ). Participants consumed a liquid test meal (protein 8.76 g, fat 4.46 g, carbohydrate 31.24 g, 200 kcal/200 mL; Racol, Otsuka Pharmaceuticals Co. Ltd., Tokyo, Japan). Breath samples were collected at baseline and every 10 min after consumption of the liquid test meal until 120 min. Samples were analyzed for 13CO2 using an infrared spectrophotometer (UBiT-IR200; Otsuka Electronics Co. Ltd., Osaka, Japan). Gastric emptying time was expressed as the time of maximal 13CO2 excretion (Tmax).

      Blood Examination and Vital Signs

      Blood was collected at clinical visit 1 for the general biochemical examination and evaluation of H. pylori infection via anti-H. pylori antibodies. Vital signs were evaluated at all clinical visits.

      Outcomes

      Most analyses were conducted in the per-protocol set (PPS), which excluded several ineligible participants according to the protocol from the full intake set (FIS) population. Some analyses were conducted in the FIS, which excluded the participants who dropped out from the full analysis set (FAS) population. Adverse events were evaluated in the FAS.

      Primary Endpoint

      The primary endpoint was defined as relief of GI symptoms evaluated by m-FSSG and GSRS questionnaires at wk 4 of the consumption period between the YIT10347 and placebo groups in the PPS population.

      Secondary Endpoints

      The secondary endpoints were (1) changes in the scores of psychological symptoms and quality of life at wk 4 during the consumption period from the baseline in the YIT10347 and placebo groups; and (2) gastric emptying time measured by the 13C breath test in the 2 groups.

      Adverse Events

      Adverse events were defined as any undesirable medical symptoms or conditions that emerged in participants during the consumption period, regardless of an apparent causal relationship. If serious adverse events occurred in association with test beverage consumption, the attending physician was to immediately stop participants' consumption of the test beverage.

      Compliance

      Compliance with test beverage consumption was self-recorded daily by participants in a diary. An acceptable compliance was defined as a consumption rate exceeding 80%.

      Statistical Analysis

      All data were analyzed by a statistician in the contract research organization (KSO Co., Tokyo, Japan) using IBM Statistics 24 (IBM Japan Ltd., Tokyo, Japan). Baseline characteristics of participants were compared between the YIT10347 and placebo groups by an unpaired t-test for continuous variables. Gastrointestinal symptoms were compared between the 2 groups by the Wilcoxon signed-rank and chi-squared tests. Data are expressed as means ± standard deviations. Two-sided P-values < 0.05 were considered statistically significant.

      RESULTS

      Participants

      The flowchart in Figure 2 shows the enrollment, allocation, dropout, and inclusion of participants in the analysis. Based on the inclusion criteria, 100 participants were enrolled from 203 initial participants and randomized to either the YIT10347 group (n = 50) or the placebo group (n = 50). They consumed YIT10347-fermented milk or placebo milk once a day for 4 wk. In the YIT10347 group, one subject dropped out and was excluded from the FIS population due to an injury caused by a fall while walking. The fall was considered by the attending physician to have no association with daily consumption of the test beverage. Therefore, the FIS analysis included 99 participants, and the YIT10347 and placebo groups had 49 and 50 participants, respectively.
      Figure thumbnail gr2
      Figure 2Flow of participants throughout the study. FAS = full analysis set; FIS = full intake set; PPS = per-protocol set. Safety was evaluated using the FAS; efficiency was evaluated using PPS and FIS. Subjects consumed 100 mL of milk fermented with Bifidobacterium bifidum YIT 10347 (YIT10347 group) or placebo fermented milk daily for 4 wk. FSSG score = Frequency Scale for Symptoms of Gastroesophageal Reflux Disease.
      In addition, because 20 of the participants who completed the trial did not meet the primary inclusion criteria—that is, their m-FSSG scores were <8 at wk 0, despite ≥8 to satisfy the inclusion criteria at prescreening—they were excluded from the PPS population. Therefore, the PPS analysis included 79 participants, and the YIT10347 group and placebo groups had 39 and 40 participants, respectively.
      Table 1 (PPS) and Supplemental Table S1 (https://doi.org/10.3168/jds.2017-13803; FIS and FAS) show the baseline demographics and clinical characteristics of both groups in the PPS, FIS, and FAS populations. We detected no significant differences in the characteristics of the 2 treatment groups among the populations, showing that participant randomization was well balanced.
      Table 1Background characteristics of participants (per-protocol set)
      Data are expressed as the mean ± SD or the number of subjects. Subjects consumed 100 mL of milk fermented with Bifidobacterium bifidum YIT 10347 (YIT10347 group) or placebo fermented milk daily for 4 wk.
      CharacteristicYIT10347 (n = 39)Placebo (n = 40)
      Age, yr41.1 ± 10.141.6 ± 9.9
      Sex, no. male/female19/2019/21
      Body mass index21.7 ± 2.022.6 ± 2.4
      m-FSSG total score
      Modified Frequency Scale for Symptoms of Gastroesophageal Reflux Disease.
      15.4 ± 4.715.0 ± 4.6
      1 Data are expressed as the mean ± SD or the number of subjects. Subjects consumed 100 mL of milk fermented with Bifidobacterium bifidum YIT 10347 (YIT10347 group) or placebo fermented milk daily for 4 wk.
      2 Modified Frequency Scale for Symptoms of Gastroesophageal Reflux Disease.
      Compliance with test beverage consumption exceeded 95% for all participants.

      Primary Endpoint

      Table 2 shows the changes in the m-FSSG score and relief rate of m-FSSG scores in the PPS population. We detected no significant differences in RS, ARD, and total score change of the m-FSSG between the YIT10347 and placebo groups. However, compared with the placebo group, the YIT10347 group had a significantly higher relief rate of postprandial discomfort and a greater change in the postprandial epigastric pain score from baseline (both P < 0.05). In addition, the YIT10347 group tended to have higher scores for subconscious chest rubbing and burping and higher relief rate of burping than the placebo group (P = 0.077, 0.084, and 0.052, respectively). We found similar results in the FIS population (Supplemental Table S2; https://doi.org/10.3168/jds.2017-13803), with the YIT10347 group showing significantly higher relief rates of postprandial discomfort and burping than the placebo group (both P < 0.05).
      Table 2Total, reflux syndrome, and acid-related dyspepsia score changes and relief rates on the modified Frequency Scale for Symptoms of Gastroesophageal Reflux Disease (m-FSSG) (per-protocol set)
      Data are expressed as the mean ± SD or number of subjects. Subjects consumed 100 mL of milk fermented with Bifidobacterium bifidum YIT 10347 (YIT10347 group) or placebo fermented milk daily for 4 wk. Subjects were asked to report their symptoms about the past week from “before ingestion” (wk 0) and “after ingestion” (wk 4).
      Symptom (items)GroupScore change
      Total score = sum of the scores for the 14 individual questions, each of which was scored as follows: never = 0; occasionally = 1; sometimes = 2; often = 3; and always = 4.
      P-value WilcoxonRelief rate
      Relief rate = numbers of participants whose symptoms were alleviated, did not change, or deteriorated according to the “before ingestion” and “after ingestion” scores.
      P-value χ
      Total score = sum of the scores for the 14 individual questions, each of which was scored as follows: never = 0; occasionally = 1; sometimes = 2; often = 3; and always = 4.
      Wk 0Wk 4Δ (Wk 4 – 0)AlleviateNo changeDeteriorate
      TotalYIT1034715.36 ± 4.749.64 ± 5.36−5.72 ± 5.360.22233150.529
      Placebo15.00 ± 4.6410.58 ± 5.32−4.43 ± 5.803019
      Reflux syndrome (1, 4, 6, 7, 9, 10, 12)YIT103476.51 ± 2.714.08 ± 3.26−2.44 ± 3.080.43831260.472
      Placebo6.28 ± 3.054.33 ± 2.78−1.95 ± 2.942857
       1. HeartburnYIT103471.31 ± 0.730.82 ± 0.60−0.49 ± 0.640.360182010.508
      Placebo1.23 ± 0.660.88 ± 0.61−0.35 ± 0.7015223
       4. Subconsciously rubYIT103470.79 ± 0.520.41 ± 0.59−0.38 ± 0.630.077
      P < 0.1
      162120.222
      Placebo0.70 ± 0.690.60 ± 0.78−0.10 ± 0.6710255
       6. Heartburn after mealsYIT103471.31 ± 0.690.77 ± 0.74−0.54 ± 0.790.312201630.654
      Placebo1.25 ± 0.670.90 ± 0.67−0.35 ± 0.7717185
       7. Unusual sensation in throatYIT103470.69 ± 0.770.56 ± 0.75−0.13 ± 0.860.460121980.419
      Placebo0.70 ± 0.970.43 ± 0.75−0.28 ± 0.7213234
       9. Food stuck when swallowingYIT103470.85 ± 0.960.49 ± 0.68−0.36 ± 0.900.857142050.929
      Placebo1.05 ± 0.960.70 ± 0.85−0.35 ± 0.8016195
       10. Acid coming up into throatYIT103471.03 ± 0.810.77 ± 0.78−0.26 ± 0.750.872161850.835
      Placebo0.95 ± 0.880.60 ± 0.59−0.35 ± 0.7715214
       12. Heartburn while bending overYIT103470.54 ± 0.720.26 ± 0.59−0.28 ± 0.720.665112530.946
      Placebo0.40 ± 0.590.23 ± 0.53−0.18 ± 0.5510273
      Acid-related dyspepsia (2, 3, 5, 8, 11, 13, 14)YIT103478.85 ± 2.905.56 ± 2.65−3.28 ± 3.020.19331530.114
      Placebo8.73 ± 2.656.25 ± 3.11−2.48 ± 3.372929
       2. Bloated stomachYIT103471.95 ± 0.791.49 ± 0.76−0.46 ± 0.790.498181920.848
      Placebo1.85 ± 0.861.23 ± 0.89−0.63 ± 0.8421172
       3. Heavy stomach after mealsYIT103471.77 ± 0.711.28 ± 0.83−0.49 ± 0.640.881182010.357
      Placebo1.78 ± 0.731.25 ± 0.78−0.53 ± 0.8819174
       5. Postprandial discomfortYIT103471.18 ± 0.720.62 ± 0.67−0.56 ± 0.850.103231150.017
      P < 0.05.
      Placebo1.10 ± 0.710.78 ± 0.77−0.33 ± 0.7313243
       8. Full feeling while eating mealsYIT103471.13 ± 0.920.69 ± 0.66−0.44 ± 0.970.460171840.312
      Placebo1.03 ± 0.860.75 ± 0.74−0.28 ± 0.6813252
       11. BurpingYIT103471.67 ± 1.241.05 ± 1.02−0.62 ± 0.710.084
      P < 0.1
      192000.052
      P < 0.1
      Placebo1.73 ± 1.261.35 ± 1.17−0.38 ± 0.8711263
       13. Postprandial epigastric painYIT103470.51 ± 0.680.13 ± 0.34−0.38 ± 0.670.047
      P < 0.05.
      152220.113
      Placebo0.43 ± 0.710.35 ± 0.62−0.08 ± 0.699247
       14. Epigastric pain before mealsYIT103470.64 ± 0.780.31 ± 0.57−0.33 ± 0.660.777132420.911
      Placebo0.83 ± 0.930.55 ± 0.90−0.28 ± 0.6413243
      1 Data are expressed as the mean ± SD or number of subjects. Subjects consumed 100 mL of milk fermented with Bifidobacterium bifidum YIT 10347 (YIT10347 group) or placebo fermented milk daily for 4 wk. Subjects were asked to report their symptoms about the past week from “before ingestion” (wk 0) and “after ingestion” (wk 4).
      2 Total score = sum of the scores for the 14 individual questions, each of which was scored as follows: never = 0; occasionally = 1; sometimes = 2; often = 3; and always = 4.
      3 Relief rate = numbers of participants whose symptoms were alleviated, did not change, or deteriorated according to the “before ingestion” and “after ingestion” scores.
      P < 0.1
      * P < 0.05.
      Table 3 shows the changes in the GSRS scores and relief rates of GSRS scores in the PPS population. The relief rates of overall GI symptoms, upper GI symptoms, flatus, and diarrhea were significantly higher in the YIT10347 group than in the placebo group (all P < 0.05). In addition, compared with the placebo group, the YIT10347 group had tendencies for greater changes in upper GI symptoms, abdominal pain, and heartburn scores from baseline (P = 0.089, 0.097, and 0.063, respectively), showing tendencies for relief in these parameters; the YIT10347 groups also had higher relief rates of heartburn and borborygmus (P = 0.085 and 0.074, respectively). We found similar results in the FIS population (Supplemental Table S3; https://doi.org/10.3168/jds.2017-13803), showing that the YIT10347 group had significantly higher relief rates in overall GI symptoms and improved flatus than the placebo group (both P < 0.05).
      Table 3Overall, upper, and lower gastrointestinal (GI) score change and relief rate of Gastrointestinal Symptom Rating Scale (per-protocol set)
      Data are expressed as the mean ± SD or number of subjects. Subjects consumed 100 mL of milk fermented with Bifidobacterium bifidum YIT 10347 (YIT10347 group) or placebo fermented milk daily for 4 wk. Subjects were asked to report their symptoms about the past week from “before ingestion” (wk 0) and “after ingestion” (wk 4).
      Symptom (items)GroupScore change
      Overall score = (sum of each question score)/(number of questions, 15). Upper and lower GI symptom, reflux syndrome (RS), abdominal pain (AP), indigestion syndrome (IS), diarrhea syndrome (DS), and constipation syndrome (CS) scores = (sum of each question score)/(number of questions). Each score is on a 7-point Likert scale.
      P-value WilcoxonRelief rate
      Relief rate = numbers of participants whose symptoms were alleviated, did not change, or deteriorated according to the “before ingestion” and “after ingestion” scores.
      P-value Chi- squared
      Wk 0Wk 4Δ (Wk 4 – 0)AlleviateNo changeDeteriorate
      OverallYIT103472.44 ± 0.761.77 ± 0.50−0.67 ± 0.650.36135310.016
      P < 0.05.
      Placebo2.39 ± 0.671.93 ± 0.53−0.46 ± 0.7928210
      Upper GI (1–9)YIT103472.57 ± 0.641.84 ± 0.49−0.72 ± 0.530.089
      P < 0.1
      36030.026
      P < 0.05.
      Placebo2.47 ± 0.692.02 ± 0.66−0.45 ± 0.802848
       RS (2, 3)YIT103472.45 ± 0.901.62 ± 0.54−0.83 ± 0.820.11227840.427
      Placebo2.18 ± 0.921.73 ± 0.82−0.45 ± 1.162398
       AP (1, 4, 5)YIT103472.25 ± 0.701.56 ± 0.48−0.68 ± 0.670.10433330.129
      Placebo2.13 ± 0.761.82 ± 0.98−0.31 ± 0.982668
       IS (6, 7, 8, 9)YIT103472.87 ± 0.792.17 ± 0.82−0.70 ± 0.730.20331440.332
      Placebo2.88 ± 1.002.32 ± 0.80−0.56 ± 0.872839
      1. Abdominal painYIT103472.62 ± 0.961.79 ± 0.73−0.82 ± 1.070.097
      P < 0.1
      241230.440
      Placebo2.25 ± 0.981.88 ± 1.04−0.38 ± 1.2319165
      2. HeartburnYIT103472.59 ± 1.021.69 ± 0.61−0.90 ± 1.020.063
      P < 0.1
      241320.085
      P < 0.1
      Placebo2.30 ± 1.041.93 ± 0.94−0.38 ± 1.2717158
      3. Acid regurgitationYIT103472.31 ± 1.131.54 ± 0.64−0.77 ± 1.010.443221430.582
      Placebo2.05 ± 1.081.53 ± 0.93−0.53 ± 1.2420146
      4. Sucking sensations in epigastriumYIT103472.44 ± 1.101.64 ± 0.74−0.79 ± 1.080.280241140.592
      Placebo2.43 ± 1.131.98 ± 1.17−0.45 ± 1.0821127
      5. Nausea and vomitingYIT103471.69 ± 1.101.26 ± 0.59−0.44 ± 1.100.461122430.591
      Placebo1.70 ± 1.071.60 ± 1.37−0.10 ± 1.3511236
      6. BorborygmusYIT103472.92 ± 1.042.05 ± 0.79−0.87 ± 0.950.567231600.074
      P < 0.1
      Placebo2.93 ± 1.232.30 ± 1.02−0.63 ± 1.2121145
      7. Abdominal distensionYIT103472.74 ± 1.142.13 ± 1.20−0.62 ± 1.270.984221250.812
      Placebo2.85 ± 1.292.15 ± 0.95−0.70 ± 1.1120155
      8. EructationYIT103472.38 ± 1.091.85 ± 1.18−0.54 ± 1.020.225211440.507
      Placebo2.48 ± 1.282.13 ± 1.04−0.35 ± 1.0317167
      9. Increased flatusYIT103473.41 ± 1.452.64 ± 1.14−0.77 ± 1.180.14125770.020
      P < 0.05.
      Placebo3.28 ± 1.432.70 ± 1.09−0.58 ± 1.4116195
      Lower GI (10–15)YIT103472.26 ± 1.191.67 ± 0.67−0.59 ± 1.071.00027480.320
      Placebo2.26 ± 0.941.79 ± 0.58−0.47 ± 0.9928111
       DS (11, 12, 14)YIT103472.23 ± 1.541.63 ± 0.80−0.60 ± 1.200.656191190.349
      Placebo2.30 ± 1.271.89 ± 0.95−0.41 ± 1.2622612
       CS (10, 13, 15)YIT103472.28 ± 1.161.71 ± 0.92−0.57 ± 1.220.68825860.411
      Placebo2.22 ± 0.941.69 ± 0.57−0.53 ± 1.022848
      10. Decreased passage of stoolsYIT103471.90 ± 1.191.54 ± 0.97−0.36 ± 1.140.987132330.470
      Placebo1.93 ± 1.141.63 ± 0.77−0.30 ± 1.1115196
      11. Increased passage of stoolsYIT103471.97 ± 1.651.44 ± 0.85−0.54 ± 1.330.104132330.040
      P < 0.05.
      Placebo1.95 ± 1.401.83 ± 1.34−0.13 ± 1.49111712
      12. Loose stoolsYIT103472.23 ± 1.581.74 ± 0.97−0.49 ± 1.520.588141960.708
      Placebo2.38 ± 1.501.80 ± 0.97−0.58 ± 1.3418175
      13. Hard stoolsYIT103471.97 ± 1.201.51 ± 0.97−0.46 ± 1.350.633141960.713
      Placebo2.05 ± 1.081.58 ± 0.81−0.48 ± 1.2617194
      14. Urgent need for defecationYIT103472.49 ± 1.801.72 ± 1.00−0.77 ± 1.350.438181740.126
      Placebo2.58 ± 1.662.05 ± 1.18−0.53 ± 1.87171211
      15. Feeling of incomplete evacuationYIT103472.97 ± 1.612.08 ± 1.36−0.90 ± 1.590.927221340.649
      Placebo2.68 ± 1.251.88 ± 0.85−0.80 ± 1.3824106
      1 Data are expressed as the mean ± SD or number of subjects. Subjects consumed 100 mL of milk fermented with Bifidobacterium bifidum YIT 10347 (YIT10347 group) or placebo fermented milk daily for 4 wk. Subjects were asked to report their symptoms about the past week from “before ingestion” (wk 0) and “after ingestion” (wk 4).
      2 Overall score = (sum of each question score)/(number of questions, 15). Upper and lower GI symptom, reflux syndrome (RS), abdominal pain (AP), indigestion syndrome (IS), diarrhea syndrome (DS), and constipation syndrome (CS) scores = (sum of each question score)/(number of questions). Each score is on a 7-point Likert scale.
      3 Relief rate = numbers of participants whose symptoms were alleviated, did not change, or deteriorated according to the “before ingestion” and “after ingestion” scores.
      P < 0.1
      * P < 0.05.

      Secondary Endpoints

      Table 4, Table 5 show changes in mental symptoms and quality of life, evaluated by the POMS-2 and SF-36v2 tools, respectively. Table 6 shows changes in salivary cortisol levels and gastric emptying in the PPS population. We found no significant differences in either the levels or their relief rates between the YIT10347 and placebo groups, and no significant differences were observed for the same parameters in the FIS population (Supplemental Tables S4, S5, and S6; https://doi.org/10.3168/jds.2017-13803).
      Table 4Change in Profile of Mood States second edition (POMS-2) score (per-protocol set)
      Data are expressed as the mean ± SD. Subjects consumed 100 mL of milk fermented with Bifidobacterium bifidum YIT 10347 (YIT10347 group) or placebo fermented milk daily for 4 wk. Subjects were asked to report their symptoms about the past week from “before ingestion” (wk 0) and “after ingestion” (wk 4).
      StateGroupScore changeP-value Wilcoxon
      Wk 0Wk 4Δ (Wk 4 – 0)
      Total mood disturbanceYIT1034747.59 ± 8.6845.51 ± 7.41−2.08 ± 6.930.683
      Placebo47.58 ± 8.0245.43 ± 8.47−2.15 ± 5.48
      Anger–hostilityYIT1034748.90 ± 9.2146.36 ± 7.10−2.54 ± 7.100.921
      Placebo47.10 ± 7.6545.48 ± 7.48−1.63 ± 5.16
      Confusion–bewildermentYIT1034749.41 ± 10.0047.46 ± 8.58−1.95 ± 7.940.546
      Placebo50.00 ± 9.4147.83 ± 9.23−2.18 ± 6.21
      Depression–dejectionYIT1034748.13 ± 7.5347.38 ± 6.94−0.74 ± 6.890.479
      Placebo48.45 ± 6.8646.68 ± 6.69−1.78 ± 5.85
      Fatigue–inertiaYIT1034747.59 ± 7.8945.74 ± 6.85−1.85 ± 7.950.753
      Placebo48.63 ± 8.2147.10 ± 8.79−1.53 ± 6.41
      Tension–anxietyYIT1034748.77 ± 8.2445.72 ± 7.24−3.05 ± 7.120.933
      Placebo50.05 ± 7.6447.20 ± 8.82−2.85 ± 5.36
      Vigor–activityYIT1034754.85 ± 9.6654.49 ± 10.15−0.36 ± 7.280.844
      Placebo55.48 ± 11.7155.78 ± 11.220.30 ± 9.32
      FriendlinessYIT1034754.79 ± 9.9154.79 ± 10.700.00 ± 7.460.356
      Placebo57.73 ± 10.1656.58 ± 9.39−1.15 ± 5.94
      1 Data are expressed as the mean ± SD. Subjects consumed 100 mL of milk fermented with Bifidobacterium bifidum YIT 10347 (YIT10347 group) or placebo fermented milk daily for 4 wk. Subjects were asked to report their symptoms about the past week from “before ingestion” (wk 0) and “after ingestion” (wk 4).
      Table 5Change in Short Form Health Survey version 2 (SF-36v2) score (per-protocol set)
      Data are expressed as the mean ± SD. Subjects consumed 100 mL of milk fermented with Bifidobacterium bifidum YIT 10347 (YIT10347 group) or placebo fermented milk daily for 4 wk. Subjects were asked to report their symptoms about the past week from “before ingestion” (wk 0) and “after ingestion” (wk 4).
      ItemGroupScore changeP-value Wilcoxon
      Wk 0Wk 4Δ (Wk 4 – 0)
      Physical component summaryYIT1034757.5 ± 7.657.5 ± 5.80.0 ± 5.80.757
      Placebo54.2 ± 7.553.8 ± 6.0−0.4 ± 6.8
      Mental component scoreYIT1034747.5 ± 10.250.5 ± 8.03.0 ± 7.60.600
      Placebo50.2 ± 5.452.0 ± 7.31.7 ± 6.9
      Role–social component scoreYIT1034747.6 ± 9.749.3 ± 9.81.8 ± 9.50.118
      Placebo52.1 ± 6.651.6 ± 6.2−0.4 ± 6.7
      Physical functioningYIT1034755.3 ± 3.655.7 ± 3.00.4 ± 3.10.301
      Placebo53.8 ± 4.853.7 ± 4.9−0.1 ± 5.4
      Role physicalYIT1034753.3 ± 4.353.1 ± 6.5−0.3 ± 6.00.503
      Placebo53.6 ± 4.553.2 ± 4.9−0.3 ± 4.4
      Bodily painYIT1034749.3 ± 10.654.7 ± 7.15.4 ± 11.00.073
      P < 0.1.
      Placebo53.0 ± 8.554.0 ± 7.01.0 ± 9.0
      General healthYIT1034755.2 ± 7.956.0 ± 8.30.8 ± 5.90.862
      Placebo54.2 ± 6.654.4 ± 7.50.2 ± 5.3
      VitalityYIT1034747.0 ± 9.148.8 ± 8.21.8 ± 8.60.960
      Placebo49.0 ± 7.250.8 ± 8.61.8 ± 8.3
      Social functioningYIT1034747.9 ± 10.751.1 ± 9.83.1 ± 11.10.208
      Placebo53.6 ± 6.754.6 ± 4.31.0 ± 6.6
      Role emotionalYIT1034749.6 ± 7.452.5 ± 7.03.0 ± 8.90.055
      P < 0.1.
      Placebo52.4 ± 6.551.8 ± 7.0−0.6 ± 7.3
      Mental healthYIT1034748.4 ± 10.351.3 ± 8.03.0 ± 9.70.337
      Placebo51.6 ± 6.852.6 ± 6.41.0 ± 6.1
      1 Data are expressed as the mean ± SD. Subjects consumed 100 mL of milk fermented with Bifidobacterium bifidum YIT 10347 (YIT10347 group) or placebo fermented milk daily for 4 wk. Subjects were asked to report their symptoms about the past week from “before ingestion” (wk 0) and “after ingestion” (wk 4).
      P < 0.1.
      Table 6Change in salivary cortisol and gastric emptying time (per-protocol set)
      Data are expressed as the mean ± SD. Subjects consumed 100 mL of milk fermented with Bifidobacterium bifidum YIT 10347 (YIT10347 group) or placebo fermented milk daily for 4 wk.
      ItemGroupChangeP-value Wilcoxon
      Wk 0Wk 4Δ (Wk 4 – 0)
      Salivary cortisol, μg/dLYIT103470.29 ± 0.220.32 ± 0.240.03 ± 0.130.404
      Placebo0.22 ± 0.090.23 ± 0.110.01 ± 0.10
      Gastric emptying,
      Tmax was the time at maximal 13CO2 excretion.
      13CO2-Tmax, min
      YIT1034748.72 ± 9.7851.79 ± 10.733.08 ± 9.220.259
      Placebo50.77 ± 12.6551.03 ± 11.420.26 ± 12.46
      1 Data are expressed as the mean ± SD. Subjects consumed 100 mL of milk fermented with Bifidobacterium bifidum YIT 10347 (YIT10347 group) or placebo fermented milk daily for 4 wk.
      2 Tmax was the time at maximal 13CO2 excretion.

      Adverse Events

      During the trial, 7 and 12 adverse events occurred in the YIT10347 and placebo groups, respectively, with no significant difference in the number of events between the 2 groups. In the YIT10347 group, the 7 adverse events comprised mild symptoms such as headache (1 case), cold (3 cases), injury in a fall (1 case), stomatitis (1 case), and hard stool (1 case). In the placebo group, the 12 adverse events comprised the following mild symptoms: fatigue (1 case), abdominal pain (3 cases), cold (4 cases), stomatitis (1 case), suppuration of gums (1 case), gastric distention (1 case), and cystitis (1 case). These adverse events were not considered serious or associated with daily consumption of the test beverages.
      No abnormal changes were detected in the general blood biochemical parameters in either group after daily consumption for 4 wk. These findings suggested that both beverages were safe.

      DISCUSSION

      This prospective randomized, double-blind, placebo-controlled, parallel comparative trial investigated the beneficial effects of YIT10347 on the temporary gastric symptoms of healthy Japanese adults. The results showed that the YIT10347 group achieved significantly better relief from some upper GI symptoms, such as postprandial discomfort and postprandial epigastric pain, compared with the placebo group.
      Although there was a higher relief rate of postprandial discomfort, the average score change did not differ between YIT10347 and placebo in the m-FSSG evaluation. Additionally, there was a higher score change for postprandial epigastric pain but no difference in the relief rate between YIT10347 and placebo in the m-FSSG evaluation. Relief rate was greatly influenced by the number of participants with GI symptoms in the “before ingestion” period. For example, 17 and 13 participants had postprandial epigastric pain symptoms in the YIT10347 and placebo groups, respectively. Many of the participants scored zero for this symptom in the “before ingestion” period, making it difficult to detect a difference in relief rate. However, the average score of the 17 participants with postprandial epigastric pain symptoms in the YIT10347 group changed drastically from 1.18 to 0.18. On the other hand, 32 and 33 participants had postprandial discomfort symptoms in the YIT10347 and placebo groups, respectively. Because over 80% of all participants had felt this symptom in the “before ingestion” period, the difference in the relief rate was clear.
      This study enrolled healthy adults who had temporary upper GI symptoms. A score of 8 on the m-FSSG is often used as a cutoff for screening participants with upper GI symptoms (
      • Kusano M.
      • Hosaka H.
      • Kawada A.
      • Kuribayashi S.
      • Shimoyama Y.
      • Kawamura O.
      • Moki F.
      Development and evaluation of a modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease to distinguish functional dyspepsia from non-erosive reflux disease.
      ;
      • Tominaga K.
      • Kato M.
      • Takeda H.
      • Shimoyama Y.
      • Umegaki E.
      • Iwakiri R.
      • Furuta K.
      • Sakurai K.
      • Odaka T.
      • Kusunoki H.
      • Nagahara A.
      • Iwakiri K.
      • Furuta T.
      • Murakami K.
      • Miwa H.
      • Kinoshita Y.
      • Haruma K.
      • Takahashi S.
      • Watanabe S.
      • Higuchi K.
      • Kusano M.
      • Fujimoto K.
      • Arakawa T.
      • Pride G.
      • Study Group
      A randomized, placebo-controlled, double-blind clinical trial of rikkunshito for patients with non-erosive reflux disease refractory to proton-pump inhibitor: The G-PRIDE study.
      ). However, to exclude participants with chronic symptoms, the Rome IV classification was used, which comprises bothersome postprandial fullness, bothersome early satiety, bothersome epigastric pain, and bothersome epigastric burning during the preceding 6-mo period (or more), with such symptoms occurring regularly during the last 3-mo period.
      A previous double-blinded, placebo-controlled, parallel trial found that daily consumption of YIT10347 helps to improve upper GI symptoms in patients with H. pylori-associated gastritis (
      • Miki K.
      • Urita Y.
      • Ishikawa F.
      • Iino T.
      • Shibahara-Sone H.
      • Akahoshi R.
      • Mizusawa S.
      • Nose A.
      • Nozaki D.
      • Hirano K.
      • Nonaka C.
      • Yokokura T.
      Effect of Bifidobacterium bifidum fermented milk on Helicobacter pylori and serum pepsinogen levels in humans.
      ). Additionally, an open-label trial found beneficial effects on serious FGID (
      • Urita Y.
      • Goto M.
      • Watanabe T.
      • Matsuzaki M.
      • Gomi A.
      • Kano M.
      • Miyazaki K.
      • Kaneko H.
      Continuous consumption of fermented milk containing Bifidobacterium bifidum YIT 10347 improves gastrointestinal and psychological symptoms in patients with functional gastrointestinal disorders.
      ) and a double-blind, placebo-controlled, crossover trial found positive effects in healthy adults (
      • Gomi A.
      • Iino T.
      • Nonaka C.
      • Miyazaki K.
      • Ishikawa F.
      Health benefits of fermented milk containing Bifidobacterium bifidum YIT 10347 on gastric symptoms in adults.
      ). However, these trials used YIT10347-fermented milk containing YIT10347 and S. thermophilus YIT 2021 and placebo milk without either strain as test beverages, meaning that the effects of S. thermophilus YIT 2021 in the active milk could not be completely excluded. In contrast, our study used S. thermophilus YIT 2021-fermented milk as the milk to distinguish the effects of YIT10347 in the active milk. We used S. thermophilus YIT 2021-fermented milk as the placebo because we found that S. thermophilus YIT 2021 had no beneficial probiotic effects in a previous study (
      • Miki K.
      • Urita Y.
      • Ishikawa F.
      • Iino T.
      • Shibahara-Sone H.
      • Akahoshi R.
      • Mizusawa S.
      • Nose A.
      • Nozaki D.
      • Hirano K.
      • Nonaka C.
      • Yokokura T.
      Effect of Bifidobacterium bifidum fermented milk on Helicobacter pylori and serum pepsinogen levels in humans.
      ;
      • Gomi A.
      • Harima-Mizusawa N.
      • Shibahara-Sone H.
      • Kano M.
      • Miyazaki K.
      • Ishikawa F.
      Effect of Bifidobacterium bifidum BF-1 on gastric protection and mucin production in an acute gastric injury rat model.
      ) but also did not aggravate GI symptoms. Hence, our findings clarify that daily consumption of YIT10347 has benefits in healthy Japanese adults with temporary gastric symptoms.
      Our previous studies have shown that YIT10347 suppresses inflammation by regulating the nuclear factor-κB signaling pathway in human gastric epithelial cells in vitro (
      • Shirasawa Y.
      • Shibahara-Sone H.
      • Iino T.
      • Ishikawa F.
      Bifidobacterium bifidum BF-1 suppresses Helicobacter pylori-induced genes in human epithelial cells.
      ), alleviates drug-induced acute gastric injury via stimulated production of gastric mucin in an animal model (
      • Gomi A.
      • Harima-Mizusawa N.
      • Shibahara-Sone H.
      • Kano M.
      • Miyazaki K.
      • Ishikawa F.
      Effect of Bifidobacterium bifidum BF-1 on gastric protection and mucin production in an acute gastric injury rat model.
      ), and survives in a live state on the human gastric mucosa for 2 h after a single consumption via strong adherence to the gastric mucosa (
      • Shibahara-Sone H.
      • Gomi A.
      • Iino T.
      • Kano M.
      • Nonaka C.
      • Watanabe O.
      • Miyazaki K.
      • Ohkusa T.
      Living cells of probiotic Bifidobacterium bifidum YIT 10347 detected on gastric mucosa in humans.
      ). Functional dyspepsia is characterized by chronic abdominal complaints without a structural or biochemical cause that could explain the symptoms. In addition, gastric pain in functional dyspepsia may be associated with hyperesthesia. It has been hypothesized that, in healthy adults, YIT10347 exerts beneficial effects on gastric symptoms such as postprandial discomfort and postprandial epigastric pain by stimulating the production of gastric mucin and other gastrointestinal or neuropeptide hormones to improve gastroduodenal function and relieve visceral hypersensitivity via signaling induced by its adherence to the gastric mucosa. In other words, YIT10347 is thought to maintain normal gastric function.
      A previous open-label trial found that daily consumption of YIT10347 improves some subjective psychological symptoms and POMS scores (decreasing “anger–hostility” subscale scores and increasing “vigor” subscale scores) and reduces salivary cortisol levels (
      • Urita Y.
      • Goto M.
      • Watanabe T.
      • Matsuzaki M.
      • Gomi A.
      • Kano M.
      • Miyazaki K.
      • Kaneko H.
      Continuous consumption of fermented milk containing Bifidobacterium bifidum YIT 10347 improves gastrointestinal and psychological symptoms in patients with functional gastrointestinal disorders.
      ). However, we detected no significant differences in the levels or relief rates of these parameters or gastric emptying in this trial. One reasonable explanation for the differences in results between the 2 trials is that the participants in this trial—all healthy adults—had normal levels of these parameters. Further study is necessary to clarify the effects of YIT10347 on mental parameters and gastric emptying in patients with FGID in a randomized, double-blind, placebo-controlled, parallel comparative trial.
      To better understand the effects of YIT10347 on temporary gastric symptoms in healthy adults, subgroup analyses were conducted based on the baseline scores of the m-FSSG (Table 7) and GSRS (Table 8) in the PPS population. Interestingly, we detected no significant differences in changes in scores of all symptoms between the 2 groups in participants who had higher-than-median GSRS symptom scores at baseline. However, the YIT10347 group had significantly greater relief in overall, upper GI symptoms, abdominal pain, and indigestion scores of the GSRS compared with the placebo group in participants who had lower-than-median scores for the GSRS at baseline. In contrast, subgroup analysis based on the baseline score of the m-FSSG did not detect clear differences between the 2 groups, although the YIT10347 group had a tendency for relief in the total m-FSSG score compared with the placebo group (P = 0.051). Additionally, the YIT10347 group had significantly greater relief rates for overall and upper GI symptoms and for abdominal pain of the GSRS than the placebo group in participants who had a lower-than-median score for each symptom in the GSRS at baseline (data not shown).
      Table 7Subgroup analysis: Score change of modified Frequency Scale for Symptoms of Gastroesophageal Reflux Disease (m-FSSG) (per-protocol set)
      Data are expressed as the mean ± SD. Subjects consumed 100 mL of milk fermented with Bifidobacterium bifidum YIT 10347 (YIT10347 group) or placebo fermented milk daily for 4 wk. Subjects were asked to report their symptoms about the past week from “before ingestion” (wk 0) and “after ingestion” (wk 4).
      Item
      Total, reflux syndrome, and acid-related dyspepsia score = sum of the score of each question (never = 0; occasionally = 1; sometimes = 2; often = 3; and always = 4).
      GroupParticipants with low m-FSSG score (<15) at wk 0 (YIT10347, n = 20; placebo, n = 19)Participants with high m-FSSG score (≥15) at wk 0 (YIT10347, n = 20; placebo, n = 19)
      Wk 0Wk 4Δ (Wk 4 – 0)P-value WilcoxonWk 0Wk 4Δ (Wk 4 – 0)P-value Wilcoxon
      TotalYIT1034711.55 ± 1.797.80 ± 4.12−3.75 ± 3.770.051
      P < 0.1.
      19.37 ± 3.3211.58 ± 5.91−7.79 ± 6.070.713
      Placebo11.00 ± 2.119.21 ± 3.26−1.79 ± 3.3118.62 ± 2.9911.81 ± 6.50−6.81 ± 6.56
      Reflux syndromeYIT103474.80 ± 2.143.25 ± 2.92−1.55 ± 2.420.2538.32 ± 2.004.95 ± 3.46−3.37 ± 3.480.786
      Placebo4.21 ± 1.443.47 ± 1.58−0.74 ± 2.108.14 ± 2.945.10 ± 3.39−3.05 ± 3.20
      Acid-related dyspepsiaYIT103476.75 ± 1.894.55 ± 1.88−2.20 ± 2.690.16411.05 ± 1.996.63 ± 2.97−4.42 ± 2.990.586
      Placebo6.79 ± 1.555.74 ± 2.23−1.05 ± 1.9010.48 ± 2.186.71 ± 3.73−3.76 ± 3.91
      1 Data are expressed as the mean ± SD. Subjects consumed 100 mL of milk fermented with Bifidobacterium bifidum YIT 10347 (YIT10347 group) or placebo fermented milk daily for 4 wk. Subjects were asked to report their symptoms about the past week from “before ingestion” (wk 0) and “after ingestion” (wk 4).
      2 Total, reflux syndrome, and acid-related dyspepsia score = sum of the score of each question (never = 0; occasionally = 1; sometimes = 2; often = 3; and always = 4).
      P < 0.1.
      Table 8Subgroup analysis: Score change of Gastrointestinal Symptom Rating Scale (GSRS) (per-protocol set)
      Data are expressed as the mean ± SD. Subjects consumed 100 mL of milk fermented with Bifidobacterium bifidum YIT 10347 (YIT10347 group) or placebo fermented milk daily for 4 wk. Subjects were asked to report their symptoms about the past week from “before ingestion” (wk 0) and “after ingestion” (wk 4).
      Item
      Overall, upper and lower gastrointestinal (GI) symptoms, reflux syndrome (RS), abdominal pain (AP), indigestion syndrome (IS), diarrhea syndrome (DS), and constipation syndrome (CS) scores = (sum of each question score)/(number of questions). Each score is on a 7-point Likert scale.
      GroupParticipants with low GSRS score (<34) at wk 0 (YIT10347, n = 21; placebo, n = 17)Participants with high GSRS score (≥34) at wk 0 (YIT10347, n = 18; placebo, n = 23)
      Wk 0Wk 4Δ (Wk 4 – 0)P-value WilcoxonWk 0Wk 4Δ (Wk 4 – 0)P-value Wilcoxon
      OverallYIT103471.90 ± 0.221.51 ± 0.21−0.39 ± 0.300.003
      P < 0.01.
      3.08 ± 0.662.08 ± 0.57−1.00 ± 0.790.772
      Placebo1.78 ± 0.251.84 ± 0.630.05 ± 0.612.83 ± 0.511.99 ± 0.45−0.84 ± 0.69
      Upper GI symptomsYIT103472.12 ± 0.311.62 ± 0.29−0.50 ± 0.32<0.001
      P < 0.01.
      3.04 ± 0.582.08 ± 0.54−0.96 ± 0.630.616
      Placebo1.88 ± 0.331.94 ± 0.750.07 ± 0.612.87 ± 0.572.07 ± 0.59−0.80 ± 0.74
       RSYIT103471.95 ± 0.661.45 ± 0.51−0.50 ± 0.770.1192.97 ± 0.841.79 ± 0.51−1.18 ± 0.770.141
      Placebo1.63 ± 0.711.72 ± 0.810.09 ± 1.102.54 ± 0.901.73 ± 0.85−0.81 ± 1.09
       APYIT103471.90 ± 0.581.32 ± 0.35−0.58 ± 0.520.001
      P < 0.01.
      2.61 ± 0.621.82 ± 0.49−0.79 ± 0.810.946
      Placebo1.65 ± 0.461.83 ± 1.250.19 ± 1.032.44 ± 0.781.81 ± 0.76−0.64 ± 0.79
       ISYIT103472.38 ± 0.481.94 ± 0.47−0.44 ± 0.550.020
      P < 0.05
      3.38 ± 0.772.41 ± 1.05−0.97 ± 0.840.596
      Placebo2.17 ± 0.612.14 ± 0.79−0.03 ± 0.463.35 ± 0.892.44 ± 0.80−0.92 ± 0.91
      Lower GI symptomsYIT103471.53 ± 0.401.37 ± 0.34−0.16 ± 0.440.3843.03 ± 1.241.99 ± 0.76−1.04 ± 1.360.762
      Placebo1.58 ± 0.361.73 ± 0.590.15 ± 0.792.71 ± 0.961.83 ± 0.58−0.88 ± 0.94
       DSYIT103471.47 ± 0.541.33 ± 0.43−0.13 ± 0.570.4643.04 ± 1.861.95 ± 0.97−1.09 ± 1.520.626
      Placebo1.46 ± 0.521.67 ± 0.770.21 ± 0.832.86 ± 1.332.04 ± 1.04−0.82 ± 1.39
       CSYIT103471.58 ± 0.631.40 ± 0.66−0.18 ± 0.680.6443.02 ± 1.102.04 ± 1.03−0.98 ± 1.550.958
      Placebo1.71 ± 0.521.79 ± 0.630.08 ± 0.882.56 ± 1.031.63 ± 0.53−0.93 ± 0.92
      1 Data are expressed as the mean ± SD. Subjects consumed 100 mL of milk fermented with Bifidobacterium bifidum YIT 10347 (YIT10347 group) or placebo fermented milk daily for 4 wk. Subjects were asked to report their symptoms about the past week from “before ingestion” (wk 0) and “after ingestion” (wk 4).
      2 Overall, upper and lower gastrointestinal (GI) symptoms, reflux syndrome (RS), abdominal pain (AP), indigestion syndrome (IS), diarrhea syndrome (DS), and constipation syndrome (CS) scores = (sum of each question score)/(number of questions). Each score is on a 7-point Likert scale.
      * P < 0.05
      ** P < 0.01.
      Placebo effects are frequently observed in clinical trials of functional dyspepsia patients. These observations suggest that participants with mild gastric symptoms at baseline had a lesser placebo effect in this trial and were suitable responders to YIT10347, with both preventive and relief benefits. However, this does not mean that YIT10347 has no effect on subjects with severe symptoms. Indeed, the score change of the severe symptom group was higher than that of the mild symptom group. In the severe symptom group, the score change of the placebo group was similarly high, so there were no significant differences between the YIT10347 and placebo groups. This indicates that subjects with severe symptoms might more readily show psychological placebo effects. In a previous study (
      • Urita Y.
      • Goto M.
      • Watanabe T.
      • Matsuzaki M.
      • Gomi A.
      • Kano M.
      • Miyazaki K.
      • Kaneko H.
      Continuous consumption of fermented milk containing Bifidobacterium bifidum YIT 10347 improves gastrointestinal and psychological symptoms in patients with functional gastrointestinal disorders.
      ), continuous consumption of fermented milk containing YIT10347 improved gastrointestinal symptoms in FGID patients, even though all participants with repeated medical care had seen no improvement. Thus, we consider that YIT10347 has potential for upper GI symptom improvement regardless of the presence or absence of a placebo effect.
      One limitation of this study is that, even though we found that daily consumption of YIT10347-fermented milk helped to relieve lower GI symptoms such as flatus and diarrhea in a GSRS evaluation, subgroup analyses of the GSRS and m-FSSG showed that beneficial effects were obtained for upper GI symptoms and not lower GI symptoms. In fact, evidence for the beneficial effect of YIT10347 on lower GI symptoms in clinical trials remains poor. Therefore, further clinical trials with larger numbers of suitable participants are necessary to clarify the beneficial effects of YIT10347 on both upper and lower GI symptoms. Moreover, further studies are necessary to understand the detailed mechanism of action of YIT10347 in both upper and lower GI symptoms.

      CONCLUSIONS

      These findings suggest that daily consumption of milk fermented with B. bifidum YIT 10347 helps to relieve GI discomfort and symptoms such as postprandial discomfort and epigastric pain in healthy adults, with no risk of side effects. The approach is less burdensome and less expensive than medical treatment.

      ACKNOWLEDGMENTS

      We thank all participants in this trial. We also thank Daisuke Nozaki and Yuki Kataoka of Yakult Honsha Co. Ltd. (Tokyo, Japan) for the production of the test beverages and the staff of KSO Corporation (Tokyo, Japan) for managing this trial and its participants and analyzing the data. The clinical trials, designed by authors, were performed under the management of KSO Corporation with the sponsorship and provision of test beverages from Yakult Honsha Co. Ltd. The sponsor provided salaries for A. Gomi, K. Yamaji, O. Watanabe, M. Yoshioka, and K. Miyazaki but did not have any additional role in data collection or interpretation. The remaining authors declare no potential conflicts of interest with respect to the authorship and publication of this article.

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