J Neurogastroenterol Motil 2024; 30(1): 73-86  https://doi.org/10.5056/jnm23036
Efficacy of Quadruple-coated Probiotics in Patients With Irritable Bowel Syndrome: A Randomized, Double-blind, Placebo-controlled, Parallel-group Study
Young Hoon Chang,1 Yoon Jin Choi,1,2 Cheol Min Shin,1* Jin Seok Moon,3 Tae-Yoon Kim,3 Hyuk Yoon,1 Young Soo Park,1 Nayoung Kim,1 and Dong Ho Lee1*
1Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea; 2Department of Internal Medicine, National Cancer Center, Goyang-si, Gyeonggi-do, Korea; and 3Research Laboratories, ILDONG Pharmaceutical Co, Ltd, Hwaseong, Gyeonggi-do, Korea
Correspondence to: *Cheol Min Shin, MD, PhD
Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro 173 Beon-gil, Seongnam, Gyeonggi-do 13620, Korea
Tel: +82-31-787-7057, E-mail: scm6md@gmail.com
Dong Ho Lee, MD, PhD
Department of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173, Beon-gil, Seongnam, Gyeonggi-do 13620, Korea
Tel: +82-31-787-7008, E-mail: dhljohn@yahoo.co.kr

Cheol Min Shin and Dong Ho Lee are equally responsible for this study.
Young Hoon Chang and Yoon Jin Choi contributed equally to this study.
Received: March 8, 2023; Revised: August 17, 2023; Accepted: September 12, 2023; Published online: January 30, 2024
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
To evaluate the efficacy of quadruple-coated probiotics (gQlab) in patients with irritable bowel syndrome (IBS), focusing on sex differences and IBS subtypes.
One hundred and nine Rome III-diagnosed IBS patients were randomized into either a gQlab or placebo group and received either gQlab or a placebo for 4 weeks. Participants replied to questionnaires assessing compliance, symptoms, and safety. Fecal samples were collected at 0 and 4 weeks to measure the probiotic levels using real-time quantitative polymerase chain reaction (qPCR) and to perform metagenomic analysis via 16S ribosomal DNA sequencing. The primary endpoint was the change in the overall IBS symptoms after 4 weeks of treatment.
Ninety-two subjects (47 and 45 in the gQlab and placebo groups, respectively) completed the study protocol. At week 4, there was a higher relief of the overall IBS symptoms in the gQlab group (P = 0.005). The overall IBS symptom improvement was statistically significant (P = 0.017) in female patients of the gQlab group compared with the placebo group. Among the IBS subtypes, constipation-predominant IBS patients showed significant relief of the overall IBS symptoms (P = 0.002). At week 4, the fecal microbiome profiles between the 2 groups did not differ, but the qPCR levels of Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus helveticus, Bifidobacterium longum, and Bifidobacterium breve were increased in the gQlab group (P < 0.05 by repeated measures ANOVA).
gQlab administration can improve the overall IBS symptoms, especially in female and constipation-predominant IBS patients. Further research is necessary to clarify the pathophysiology behind sex-related treatment responses in IBS patients.
Keywords: Irritable bowel syndrome; Microbiota; Probiotics; Sex characteristics

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders seen by primary care physicians.1 Although IBS is not a life-threatening disorder, it negatively affects the quality of life (QoL) and has a high economic cost due to its chronic nature.1,2 Since the worldwide prevalence of IBS is estimated to be over 10%, its treatment is of great importance to global healthcare.2

The pathophysiology of IBS is complicated,3 which makes its diagnosis and treatment challenging. As there is currently no biomarker for IBS, diagnosis is primarily based on the patient’s history. The exclusion of organic diseases such as colorectal cancer and inflammatory bowel disease is necessary because of the complex symptoms of IBS which include abdominal pain associated with changes in the pattern of bowel movements, with no evidence of underlying structural gut damage.2

Of the many factors associated with IBS, sex difference is one of the most prominent areas of investigation. Females are known to be more susceptible to IBS, which has a higher prevalence in the fourth and fifth age decades, after which it decreases with age.4,5 The reasons why IBS occurs more frequently in females are not fully understood, however, it is evident that IBS significantly lowers QoL and leads to a higher level of anxiety in females.5

To date, there have been several studies of gut microbiota composition in IBS patients,6-9 however, these have produced inconsistent results. For example, with regard to microbial diversity, some studies reported no difference between controls and patients,8-10 while others reported lower diversity with IBS patients.11 Possible causes for the discrepancies might be a relatively small sample size or differences in the experimental approaches used.12 Although sex difference is one of the key variables affecting gut microbiota, its association with gut microbiota has not been fully investigated.13 In addition to sex and gut microbiota, there is a range of IBS-associated factors such as depression or anxiety disorders, dietary factors, and medications that are not uniformly considered across analyses. There can also be a high disease heterogeneity within studies, with different dominant symptoms defining the IBS subtypes.

This heterogeneity of IBS makes its treatment modalities diverse. Since targeting the gut microbiota of IBS patients may have therapeutic potential, probiotics have long served as one of the treatment options available. The efficacy of probiotics in improving IBS symptoms is well described in previous studies.14

In this study, we introduce gQlab (Ildong pharmaceutical Co, Ltd, Seoul, Korea) (Supplementary Table 1), a probiotic preparation of 10 strains: Bifidobacterium longum IDCC 4101,15 Bifidobacterium bifidum IDCC 4201,15 Bifidobacterium lactis IDCC 4301,16 Bifidobacterium breve IDCC 4401,17 Enterococcus faecium IDCC 2102, Lactobacillus rhamnosus IDCC 3201,18 Lactobacillus acidophilus IDCC 3302,19 Lactobacillus casei IDCC 3451,20 Lactobacillus plantarum IDCC 3501,21 and Lactobacillus helveticus IDCC 3801.22 The gQlab capsule included a total of 1 × 1010 viable cells (1.0 × 109 viable cells/strain) in lyophilized powder form, weighing 500 mg per capsule. gQlab is a multi-strain probiotic product that incorporates a quadruple-coating technology that prevents probiotics from being killed by external factors. The probiotic strains, manufactured with a quadruple-coating, outperform conventional noncoated, single-coated, dual-coated, and triple-coated strains in terms of acid and bile tolerance.23 Moreover, the strains’ genetic basis of anti-inflammatory potential and adhesive properties to epithelial cells suggest their effective and safe application to gastrointestinal diseases.15,17,22

The aim of this study was to evaluate the symptomatic efficacy of gQlab (a multi-strain probiotic supplementation) for the relief of the overall IBS symptoms and the improvement in the QoL of IBS patients. In addition, we investigated whether the efficacy of gQlab depends on sex and IBS subtypes.

Materials and Methods

Study Participants

This was a single center double-blind randomized study. A total of 109 patients, aged 18-80 years and diagnosed with IBS based on the Rome III questionnaire during the screening period (49 diarrhea-predominant IBS [IBS-D], 28 constipation-predominant IBS [IBS-C], and 23 mixed-type IBS [IBS-M] patients) were consecutively enrolled. Individuals were excluded if they met any of the following exclusion criteria: (1) those who had lactose intolerance, (2) those who had severe systemic illnesses, (3) those with a history of any cancer, (4) those who had a history of a psychiatric disorder, (5) those who were taking probiotic supplements within 2 weeks of the study enrollment, and (6) those with history of any abdominal surgery, other than hernia and appendectomy.

During the screening period, each study participant underwent serum laboratory tests including complete blood count, liver function tests, and electrolyte tests. For female participants, we additionally checked serum human chorionic gonadotropin. Exclusion criteria for each laboratory test were as follows: white blood cell > 12.0 × 109/L, hemoglobin < 11.00 g/dL, aspartate transaminase > 3 times upper limit of normal, alanine transferase (ALT) > 3 times upper limit of normal, total bilirubin > 2.5 mg/dL, sodium > 145 mmol/L, potassium > 5.5 mmol/L, chloride > 120 mmol/L, and positive human chorionic gonadotropin. Only patients with no organic problem confirmed by colonoscopy in the last 5 years were enrolled.

We also reviewed medication status of each study participant. There were 4 study participants who had existing medication prescriptions as follows: 1 with finasteride for androgenic alopecia, 2 with hypertension medications, and 1 with arthritis. They continued their medications during the study period. There was no change in their medication status.

One hundred subjects fulfilled the inclusion criteria, without meeting the exclusion criteria (Supplementary Fig. 1).

Study Design

This randomized, double-blind, placebo-controlled, parallel-group study was approved by the Institutional Review Board (IRB) of Seoul National University, Bundang Hospital (IRB No. B-1605-345-003) and conducted from October 2016 through January 2018. After listening to detailed explanations from researchers for approximately 15 minutes, all subjects provided written informed consent. The study was registered at ClinicalTrials.gov (NCT03964103).

Participants were randomized into either a gQlab group or a placebo group using a computer-generated table in blocks of 4. All subjects and investigators, except for the study coordinator, were blinded to the randomization process until study completion. Participants received either gQlab or a placebo for four weeks. One capsule was self-administered orally once a day for 4 weeks. Placebo capsules were identical in all aspects but contained excipients only. All preparations were identical in appearance, color, taste, and consistency. Taking 80-120% of the allocation was considered good compliance with treatment.

All subjects visited the clinic to assess compliance, symptoms, and safety at 0 and 4 weeks (Supplementary Fig. 2). Telephone survey was conducted at week 2. Fecal samples were collected at 0 and 4 weeks. All study subjects were required to complete the Bristol stool scale questionnaire, the visual analogue scale of various gastrointestinal symptoms (a spontaneous complete bowel movement per day, abdominal pain, abdominal discomfort, hard stool, straining, tenesmus, finger enema, obstipation, loose stool, fecal incontinence, abdominal distension, flatulence, and the overall IBS symptom relief), and the IBS-QoL questionnaire (a 34-item self-report measure specific to IBS to assess the impact of IBS on QoL) at the baseline and 4 weeks after treatment. The visual analogue scale ranged from 0 to 10 (0 represents absence of problems and 10 represents very severe problems). All study participants replied to a 72-hour recall questionnaire that contained questionnaires about dietary intake at baseline and 4 weeks after treatment.

During the study period, 3 participants in the gQlab group and 5 subjects in the placebo group dropped out (Supplementary Fig. 1). All subjects who dropped out (n = 8) did not meet the criteria for medication compliance. Since the definition of a responder varied in previous studies24,25 from 30% to 50% symptom improvement, we defined responders as patients who replied to overall relief of IBS symptoms as more than score of 3 out of 10 after 4 weeks of treatment.

Study Endpoints

The primary endpoint was change in the overall IBS symptoms scores at week 4. The secondary endpoints were changes in bowel symptom scores, IBS-QoL scores, and fecal microbiota composition from the baseline to week 4.

Fecal Samples

Enrolled participants provided fecal specimens at the beginning and end of the study. The fecal specimens were collected in sterile containers and brought to the laboratory in a frozen condition. They were stored at –80℃ prior to analysis.

Fecal Probiotics Level Analysis Using Real-time Quantitative PCR

To perform real-time quantitative polymerase chain reaction (qPCR), bacterial genomic DNAs were prepared from fecal samples using a QIAamp DNA Stool Mini Kit (QIAGEN, Hilden, Germany). Real-time quantitative PCR, using a CFX Real-Time PCR Detection System (Bio-Rad Laboratories, Inc, Hercules, CA, USA), was carried out in a 96-well plate with a final PCR reaction volume of 20 μL consisting of 10 μL SYBR Green I master mixture (Roche, Munich, Germany), 1 μL of fecal sample DNA, 0.5 μL of each primer (10 pmol/μL), and 8 μL of water.26 Species-specific primers (synthesized by Bioneer, Daejeon, Korea) used for the PCR are listed in Supplementary Table 2.27,28 The PCR amplification program started with a pre-incubation step at 94℃ for 4 minutes. The following steps consisted of 55 cycles of amplification (denaturation at 94℃ for 15 seconds, annealing at 55℃ for 15 seconds, and extension at 72℃ for 20 seconds). Melting curves were analyzed by heating samples from 50℃ to 90℃ at a transition rate of 5℃/sec.29

Metagenomic Analysis of Fecal Bacterial Microbiota and Extracellular Vesicles Derived From Fecal Samples

To discover whether supplementation with the multi-strain probiotics (gQlab) changed the gut microbiota profile, we analyzed fecal samples from the 2 study groups at the baseline and week 4, using Illumina MiSeq platform targeting 16S rDNA, following the isolation of extracellular vesicles (EVs) from the feces. Fecal samples were placed in 10 mL phosphate-buffered saline for 24 hours and then filtered through a cell strainer. Centrifugation (at 10 000 × g for 10 minutes at 4℃) was applied to separate the EVs from the fecal samples. After centrifugation, the debris pellet contained the bacterial cells while the supernatant contained the EVs. The supernatant was further passed through a 0.22 μm filter and sterilized to remove any remaining bacteria and foreign particles. The filtered bacteria and EVs were boiled at 100℃ for 40 minutes and then centrifuged at 13 000 rpm for 30 minutes at 4℃. The supernatant was collected after centrifugation and DNA was extracted using a PowerSoil DNA Isolation Kit (MO BIO Laboratories, Inc, Carlsbad, CA, USA). The DNA extracted from bacterial cells and the bacterial EVs were quantified by using QIAxpert (QIAGEN, Germany) and analyzed separately. 16S amplicon PCR forward and reverse primers, specific for the V3-V4 hypervariable regions of the 16S rDNA gene, were used for amplification. The amplicons were quantified, combined in equimolar ratio, pooled, and sequenced using the Illumina MiSeq (Illumina, Inc, San Diego, CA, USA) following the manufacturer’s protocols. Cutadapt version 1.1.6 was used to trim paired-end sequencing that match adapter sequences.30 The trimmed paired-end reads were merged with context-aware scheme for paired-end reads (CASPER) and then filtered with Phred (Q) score criteria as described by Bokulich et al.31,32 Base pair reads shorter than 350 base pairs or longer than 550 base pairs were discarded. Using the VSEARCH tool with the SILVA gold database, chimeric sequences and clustered sequence reads were identified and organized into operational taxonomic units (OTUs) under a similarity threshold of 97%.33,34 The UCLUST algorithm was used to classify representative sequences of OTUs.35 Rare OTU clusters with mean relative abundances of less than 0.1% were discarded. OTU counts with a shared taxonomy at all taxonomic ranks, from phylum to genus, were agglomerated using the “tax_glom” function in the “phyloseq” package using R.36

Data Availability

The raw reads were deposited in the NCBI Sequence Read Archive SRA database (Accession No. SRR15244359-SRR15244253 [stool bacteria] and SRR15245249-SRR15245239 [stool extracellular vesicle]).

Statistical Methods

For sample size calculation, we referred to the sample size calculation described by Shin et al.29 We expected a 20% difference in the overall IBS symptom improvement at week 4 between gQlab and placebo groups. The estimated standardized deviation was 30%. For a statistical power of 0.80 with a one-sided significance level of 0.05, the number of subjects in each group was calculated as 36. Considering a 30% dropout rate later in the study, we estimated that 100 patients would be required for completing the entire study (50 in each group). Our statistical sample size calculation proposal was approved by IRB before initiating the trial.

The baseline characteristics and clinical data of all subjects are reported as n (%) and the standard error of the mean (SEM). Relief of the overall IBS symptoms and changes in IBS-QoL scores from the baseline to week 4 were compared using a paired t test. To compare the quantitative changes of probiotics in fecal samples between the gQlab and placebo groups, before and after the study period, both the paired t test and repeated measures of ANOVA were used.

For metagenomic analysis, rarefication to an even depth was done on the OTU table. Diversity indices of the total, male, and female groups according to IBS subtypes were calculated using rarefied OTU tables and tested for significant differences using the Student’s t test. The relative abundance of each taxon was log-transformed and compared within the total number of participants by IBS subtypes. In addition, a comparison between the gQlab and placebo groups, before and after treatment, using the Student’s t test with the false discovery rate (FDR), was conducted. For diversity analyses, both the “phyloseq” package in R and Quantitative Insights Into Microbial Ecology (QIIME) were used.36 Permutational multivariate analysis of variance (PERMANOVA) was calculated using the “adonis” function implemented in the “vegan” R package.37

All statistical data were analyzed using R V.4.0.2 software and IBM SPSS Statistics version 22.0 for Windows (IBM Corp, Armonk, NY, USA).


Baseline Characteristics of the Study Participants

From January 2017 to November 2017, a total of 109 study participants were consecutively enrolled. Among them, 92 subjects (47 in the gQlab group and 45 in the placebo group) completed the entire study protocol. The baseline characteristics of the two study groups are summarized in Table 1. The total mean age was 46.95 years (SEM, 1.47 years). Of the total 92 patients, 57.6% were female. All the participants in the placebo group were nonsmokers while 5 (10.6%) of the 47 participants were smokers in the gQlab group. The proportion of alcohol drinkers was comparable between the 2 groups. However, the sex ratio was imbalanced between the 2 study groups since the male proportion was only 28.9% in the placebo group and 55.3% in the gQlab group (P = 0.031). Also, the proportion of IBS-C participants was higher in the placebo group than in the gQlab group (37.8% vs 17.0%), which is largely attributed to the female predominance in the placebo group. Furthermore, the bowel symptom scores for abdominal discomfort and abdominal distension were markedly higher in the placebo group (P < 0.05). In contrast, neither baseline dietary intake nor IBS-QoL scores between the treatment groups showed any statistical significance.

Table 1 . Baseline Characteristics of the Study Participants

VariablegQlab group (n = 47)Placebo group (n = 45)P-value
Age (yr)48.3 ± 1.9645.4 ± 2.210.321
Male26 (55.3)13 (28.9)0.031
Smoker5 (10.6)0 (0.0)0.073
Drinker22 (46.8)18 (40.0)0.654
Body mass index (kg/m2)23.51 ± 0.4422.45 ± 0.480.107
Stool form (BSFS)5.14 ± 0.224.06 ± 0.300.005
IBS subtype0.067
IBS-D28 (59.6)18 (40.0)
IBS-C8 (17.0)17 (37.8)
IBS-M11 (23.4)10 (22.2)
Bowel symptom score
SCBM per week15.45 ± 1.6311.99 ± 1.710.146
Abdominal pain2.40 ± 0.182.96 ± 0.280.095
Abdominal discomfort2.42 ± 0.193.27 ± 0.280.013
Hard stool1.72 ± 0.332.47 ± 0.380.138
Straining2.21 ± 0.322.88 ± 0.360.160
Loose stool0.51 ± 0.160.22 ± 0.130.164
Abdominal distension3.49 ± 0.264.40 ± 0.330.030
Flatulence3.61 ± 0.264.40 ± 0.340.070
Dietary intakes
Calories (kcal/day)1803.07 ± 76.371732.50 ± 60.900.645
Carbohydrate (g/day)259.61 ± 11.16257.02 ± 9.950.905
Fat (g/day)51.72 ± 3.1848.03 ± 2.290.429
Protein (g/day)68.21 ± 2.9263.20 ± 2.720.281
Dietary fiber (g/day)20.70 ± 1.2120.64 ± 1.270.805
Folate (μg/day)419.67 ± 22.81423.90 ± 27.870.673
Calcium (mg/day)460.62 ± 29.66430.85 ± 28.330.705
IBS-QoL total scores54.38 ± 2.7456.33 ± 3.200.643
IBS-QoL domains
Dysphoria12.53 ± 0.7613.60 ± 0.900.365
Interference with daily activities11.08 ± 0.5811.53 ± 0.730.632
Body image7.00 ± 0.386.76 ± 0.360.645
Health worries5.72 ± 0.355.53 ± 0.380.717
Food avoidance5.70 ± 0.386.00 ± 0.400.594
Social reaction5.96 ± 0.316.00 ± 0.420.934
Sexual function2.26 ± 0.072.49 ± 0.150.181
Impact on relations4.13 ± 0.244.42 ± 0.340.485

BSFS, Bristol stool form scale; IBS, irritable bowel syndrome; IBS-D, diarrhea predominant IBS; IBS-C, constipation predominant IBS; IBS-M, mixed-type IBS; SCBM, spontaneous complete bowel movement; QoL, quality of life.

Data were presented as mean ± SEM or n (%).

P-value: comparison between groups (Student’s t test or χ2 test. P < 0.05 was considered statistically significant.

Differences in baseline characteristics according to sex were examined. In male subjects, there was no significant difference between the two groups except for the number of spontaneous complete bowel movements per week (P = 0.049, Supplementary Table 3). In female subjects, there was no significant difference between the 2 groups except for the Bristol stool form scale scores and the abdominal distension symptom score (P = 0.017 and 0.039, respectively; Supplementary Table 4). When checking whether there were differences in baseline characteristics according to IBS subtype, there was no significant difference between the 2 groups except for significantly higher abdominal distension symptom scores in the placebo participants of IBS-M group and higher abdominal discomfort scores in the placebo participants of IBS-D group (P < 0.05, Supplementary Tables 5-7).

Improvement of Overall Irritable Bowel Syndrome and Specific Bowel Movement Symptoms at Week 4

At week 4, there was a higher relief of the overall IBS symptoms in the gQlab group compared with the placebo group (P = 0.004 and 0.005, intention-to-treat and per-protocol analyses, respectively; Fig. 1). Because the sex distribution of the gQlab and placebo groups were significantly different, a stratified analysis was performed according to sex (Table 2). The overall IBS symptom improvement was statistically significant only in female patients of the gQlab group (P = 0.017, Table 2). In terms of individual IBS symptoms, however, no significant difference was observed between the treatment groups across the total, male, and female patients (Table 2).

Figure 1. Comparison of relief of overall irritable bowel syndrome (IBS) symptoms in the gQlab and placebo groups after 4 weeks of treatment. (A) Intention-to-treat analysis (n = 100). (B) Per protocol analysis (n = 92). P-values were calculated using the Student’s t test.

Table 2 . Comparison of Changes in Bowel Symptom Score, Irritable Bowel Syndrome–Quality of Life Total Scores, and Scores in the 8 Domains of the Irritable Bowel Syndrome–Quality of Life Scale From Baseline to Week 4 Between the 2 Groups in Total, Male, and Female Participants

Item or domainTotalMaleFemale
(n = 47)
(n = 45)
(n = 26)
(n = 13)
(n = 21)
(n = 32)
Overall IBS symptom relief3.51 ± 0.272.51 ± 0.240.0053.54 ± 0.422.69 ± 0.440.2133.48 ± 0.322.40 ± 0.280.017
SCBM per week–4.30 ± 1.67–4.05 ± 1.500.911–4.44 ± 2.17–5.78 ± 3.900.748–4.12 ± 2.64–3.34 + 1.430.781
Abdominal pain–1.17 ± 0.20–0.95 ± 0.240.487–1.23 ± 0.28–0.85 ± 0.390.435–1.10 ± 0.28–1.00 ± 0.290.826
Abdominal discomfort–1.13 ± 0.20–1.31 ± 0.270.583–1.15 ± 0.25–1.61 ± 0.410.324–1.10 ± 0.32–1.19 ± 0.340.853
Hard stool–0.98 ± 0.30–0.51 ± 0.290.267–0.88 ± 0.320.23 ± 0.590.080–1.10 ± 0.54–0.81 ± 0.330.637
Straining–1.25 ± 0.30–1.04 ± 0.340.640–1.08 ± 0.41–1.15 ± 0.630.916–1.48 ± 0.43–1.00 ± 0.410.445
Loose stool–0.28 ± 0.17–0.18 ± 0.110.625–0.23 ± 0.130.08 ± 0.080.113–0.33 ± 0.34–0.28 ± 0.150.876
Abdominal distension–2.28 ± 0.30–1.91 ± 0.290.385–2.30 ± 0.29–1.38 ± 0.560.115–2.24 ± 0.58–2.13 ± 0.340.857
Flatulence–2.12 ± 0.28–2.04 ± 0.300.839–2.00 ± 0.34–2.08 ± 0.560.903–2.29 ± 0.47–2.03 ± 0.360.664
IBS-QoL total score–7.38 ± 3.363.53 ± 0.88< 0.001–4.96 ± 2.824.62 ± 1.930.030–10.14 ± 3.473.16 ± 0.950.001
Dysphoria–1.80 ± 1.081.71 ± 0.36< 0.001–1.15 ± 0.891.69 ± 0.700.016–2.62 ± 1.071.72 ± 0.430.001
Interference with daily activities–0.96 ± 0.940.13 ± 0.300.107–0.27 ± 0.770.07 ± 0.480.700–1.80 ± 0.920.16 ± 0.370.060
Body image–1.34 ± 0.400.11 ± 0.23< 0.001–0.85 ± 0.35–0.30 ± 0.550.390–1.95 ± 0.490.28 ± 0.23< 0.001
Health worries–1.15 ± 0.390.48 ± 0.20< 0.001–0.85 ± 0.330.92 ± 0.380.002–1.52 ± 0.450.31 ± 0.240.001
Food avoidance–0.36 ± 0.380.15 ± 0.240.210–0.42 ± 0.470.53 ± 0.420.136−0.29 ± 0.480.00 ± 0.290.590
Social reaction–1.15 ± 0.340.49 ± 0.23< 0.001–1.03 ± 0.371.00 ± 0.370.001–1.29 ± 0.400.28 ± 0.280.002
Sexual function–0.12 ± 0.06–0.09 ± 0.120.154–0.08 ± 0.130.23 ± 0.200.201–0.19 ± 0.110.03 ± 0.150.250
Impact on relations–0.49 ± 0.210.35 ± 0.15< 0.001–0.31 ± 0.250.46 ± 0.330.080–0.71 ± 0.280.31 ± 0.170.002

IBS, irritable bowel syndrome; SCBM, spontaneous complete bowel movement; QoL, quality of life.

Per protocol analysis. P-values were calculated using Student’s t test. P < 0.05 was considered statistically significant.

Data were presented as mean ± SEM.

Among IBS subtypes, IBS-C patients in the gQlab group had a higher relief of overall IBS symptoms than those in the placebo group (4.50 ± 0.73 vs 1.88 ± 0.37, P = 0.002; Table 3). In contrast, overall IBS symptoms showed no statistical difference in IBS-M or IBS-D patients between the gQlab group and the placebo group (P > 0.05, Table 3). In terms of individual IBS symptoms, only hard stool frequencies reported by IBS-C patients were significantly improved in the gQlab group compared with the placebo group (–3.88 ± 1.04 vs –1.17 ± 0.53, P = 0.018; Table 3). Likewise, abdominal distension was the single bowel habit that improved in the IBS-D patients from the gQlab group. It was interesting to note that IBS-M patients from the placebo group showed a greater improvement in abdominal discomfort (P = 0.035).

Table 3 . Comparison of Changes in Bowel Symptom Score, Irritable Bowel Syndrome–Quality of Life Total Scores and Scores in the 8 Domains of the Irritable Bowel Syndrome–Quality of Life Scale From Baseline to Week 4 Between the 2 Groups According to Irritable Bowel Syndrome Subtypes

Item or domainIBS-DIBS-CIBS-M
(n = 27)
(n = 18)
(n = 8)
(n = 17)
(n = 11)
(n = 10)
Overall IBS symptom relief2.93 ± 0.252.61 ± 0.340.4514.50 ± 0.731.88 ± 0.370.0024.27 ± 0.713.30 ± 0.470.280
SCBM per week–7.50 ± 2.25–6.42 ± 2.080.7424.31 ± 1.151.06 ± 1.440.163–2.41 ± 3.25–6.76 ± 5.170.477
Abdominal pain–1.07 ± 0.21–0.89 ± 0.270.594–1.88 ± 0.67–0.82 ± 0.420.183–0.91 ± 0.46–1.30 ± 0.650.623
Abdominal discomfort–1.04 ± 0.22–1.11 ± 0.350.849–1.75 ± 0.59–0.76 ± 0.440.209–0.91 ± 0.04–2.60 ± 0.600.035
Hard stool–0.39 ± 0.160.17 ± 0.330.093–3.88 ± 1.04–1.17 ± 0.530.018–0.36 ± 0.54–0.60 ± 0.690.788
Straining–0.89 ± 0.27–0.61 ± 0.480.586–3.13 ± 1.09–1.59 ± 0.580.183–0.82 ± 0.53–0.90 ± 0.820.933
Loose stool–0.21 ± 0.09–0.28 ± 0.250.7870.25 ± 0.41–0.06 ± 0.060.296–0.82 ± 0.58–0.20 ± 0.200.350
Abdominal distension–2.54 ± 0.36–1.38 ± 0.370.040–2.38 ± 0.65–1.94 ± 0.470.600–1.55 ± 0.78–2.80 ± 0.750.264
Flatulence–2.14 ± 0.37–1.67 ± 0.410.409–2.50 ± 0.76–2.29 ± 0.450.808–1.82 ± 0.52–2.30 ± 0.840.625
IBS-QoL total score–4.86 ± 2.192.00 ± 1.310.010–11.75 ± 5.734.00 ± 1.470.029–10.64 ± 6.625.50 ± 1.960.038
Dysphoria–1.07 ± 0.731.05 ± 0.450.018–2.38 ± 1.831.76 ± 0.630.062–3.27 ± 1.852.80 ± 0.850.010
Interference with daily activities–0.43 ± 0.55–0.55 ± 0.440.881–1.75 ± 1.42–0.24 ± 0.390.216–1.73 ± 1.501.20 ± 0.800.110
Body image–1.07 ± 0.310.28 ± 0.300.005–2.75 ± 0.70–0.41 ± 0.290.002–1.00 ± 0.82–0.70 ± 0.680.782
Health worries–0.57 ± 0.250.55 ± 0.350.010–2.50 ± 0.800.06 ± 0.280.015–1.63 ± 0.661.10 ± 0.430.003
Food avoidance–0.39 ± 0.300.17 ± 0.400.267–0.75 ± 0.730.41 ± 0.240.1650.00 ± 1.12–0.30 ± 0.730.825
Social reaction–1.14 ± 0.350.28 ± 0.350.009–0.50 ± 0.420.59 ± 0.430.136–1.63 ± 0.650.70 ± 0.430.008
Sexual function0.04 ± 0.080.00 ± 0.200.869–0.38 ± 0.260.06 ± 0.180.188–0.36 ± 0.240.30 ± 0.300.100
Impact on relations–0.21 ± 0.240.22 ± 0.250.229–0.75 ± 0.450.47 ± 0.170.005–1.00 ± 0.380.40 ± 0.480.032

IBS, irritable bowel syndrome; IBS-D, diarrhea predominant IBS; IBS-C, constipation predominant IBS; IBS-M, mixed-type IBS; SCBM, spontaneous complete bowel movement; QoL, quality of life.

Per protocol analysis. P-values were calculated using Student’s t test. P < 0.05 was considered statistically significant.

Data were presented as mean ± SEM.

Improvement of Irritable Bowel Syndrome–Quality of Life at Week 4

The total IBS-QoL scores significantly improved at week 4 in the gQlab group (P < 0.001, Table 2). The administration of gQlab resulted in not only higher improvement in total IBS-QoL scores but also higher improvement in individual IBS-QoL domain scores such as dysphoria (–1.80 ± 1.08 vs 1.71 ± 0.36, P < 0.001), body image (–1.34 ± 0.40 vs 0.11 ± 0.23, P < 0.001), health worries (–1.15 ± 0.39 vs 0.48 ± 0.20, P < 0.001), social reaction (–1.15 ± 0.34 vs 0.49 ± 0.23, P < 0.001), and impact on relations (–0.49 ± 0.21 vs 0.35 ± 0.15, P < 0.001).

Both male and female patients in the gQlab group showed an improvement in IBS-QoL scores (Table 2). However, there was a sex difference in the types of IBS-QoL domains which improved since female patients reported improvements in more domain areas. The domains which showed improvements for male patients included dysphoria (–1.15 ± 0.89 vs –1.69 ± 0.70, P =0.016), health worries (–0.85 ± 0.33 vs 0.92 ± 0.38, P = 0.002), and social reactions (–1.03 ± 0.37 vs 1.00 ± 0.37, P = 0.001). Female patients improved in domains such as dysphoria (–2.62 ± 1.07 vs 1.72 ± 0.43, P = 0.001), body image (–1.95 ± 0.49 vs 0.28 ± 0.23, P < 0.001), health worries (–1.52 ± 0.45 vs 0.31 ± 0.24, P = 0.001), social reaction (–1.29 ± 0.40 vs 0.28 ± 0.28, P = 0.002), and impact on relations (–0.71 ± 0.28 vs 0.31 ± 0.17, P = 0.002).

Furthermore, all IBS subtypes showed an improvement in IBS-QoL scores (Table 3). IBS-D patients reported an improvement in dysphoria, body image, health worries, and social reaction while IBS-C patients revealed an improvement in body image, health worries, and impact on relations. Improvement in domains such as dysphoria, health worries, and impact on relations was observed in IBC-M patients.

Quantitative Changes of Probiotics in Feces From the Baseline to Week 4 by Real-time Quantitative PCR

The qPCR assay for probiotics in the feces showed that quantities of L. plantarum, L. acidophilus, L. helveticus, B. longum, and B. breve significantly increased in the gQlab group after 4 weeks of treatment (P < 0.05 by repeated measure ANOVA, Fig. 2). The quantities of L.s plantarum, L. acidophilus, L. helveticus, B. longum, and B. breve were increased in the male patients (Supplementary Fig. 3) while the levels of L. plantarum, L. acidophilus, and L. helveticus were increased in the female patients (Supplementary Fig. 4). The levels of L.s plantarum, L. acidophilus, L. helveticus, B. longum, and B. breve were significantly increased in the IBS-D group (Supplementary Fig. 5). A rise in quantities of L. plantarum, L. acidophilus, L. helveticus, and B. breve was observed in the IBS-C group (Supplementary Fig. 6). Feces from the IBS-M group showed a rise in the quantities of L.s plantarum, L. acidophilus, L. helveticus, and B. longum (Supplementary Fig. 7).

Figure 2. Quantitative changes in the probiotic fecal strains before and after the study period. Quantitative changes in fecal probiotic levels at the baseline and week 4. The levels of Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus helveticus, Bifidobacterium longum, and Bifidobacterium breve were significantly increased in the gQlab group (P < 0.05 by repeated measure analysis of variance). P-values within the group were calculated using the paired t test; P-values between the 2 groups were calculated using repeated measure analysis of variance. Means and standardized errors are shown. *P < 0.05, **P < 0.001. NS, not significant.

Furthermore, we checked whether there were differences in quantities of probiotics in feces of responders and non-responders of both gQlab and placebo groups. A total of 33 responders were identified in the gQlab group while 20 responders were identified in the placebo group (P = 0.022, Supplementary Fig. 8). Changes in levels of fecal probiotics before and after treatment in both gQlab and placebo groups were analyzed between responders and non-responders. Significant differences were mainly observed in responders of the gQlab group. Levels of L. plantarum, L. acidophilus, L. helveticus, B. longum, and B. breve were significantly increased in responders of the gQlab group (Supplementary Fig. 9). When we analyzed responders and non-responders in each group separately, only levels of L. rhamnosus, B. lactis, and B. breve were significantly increased in responders of the gQlab group (Supplementary Fig. 10 and 11). Additionally, levels of L. plantarum and L. acidophilus were significantly increased in responders than in non-responders (Supplementary Fig. 12).

Metagenomic Analyses of Feces in the Study Participants

The baseline fecal microbiome derived from the bacterial cells was similar between the gQlab and the placebo groups (data not shown). Next, we calculated the microbial diversity of the total, male, and female study participants according to the IBS subtypes. Among the 3 groups, α-diversity was slightly higher in the IBS-D subtype, but without statistical significance (Supplementary Fig. 13A, 14A, and 15A). For β-diversity, there were statistically significant differences between the IBS subtypes in the total and male participants (PERMANOVA P = 0.005 [Supplementary Fig. 13B], and P = 0.019 [Supplementary Fig. 14B], respectively), while no statistically significant difference in β-diversity was observed between IBS subtypes in female participants (PERMANOVA P = 0.080, Bray-Curtis distance; Supplementary Fig. 15B). The baseline compositions of microbiota in the feces show that the relative abundances of taxa, including Parabacteriodes and Alistipes, in the bacterial cell microbiome were found to have statistically significant differences by IBS subtypes (FDR q-value < 0.05, Supplementary Table 8). The compositions of fecal microbiota at phylum and family levels in overall, male, and female subjects were summarized in Supplementary Figures 13C, 13D, 14C, 14D, 15C, and 15D.

Baseline fecal microbiome profiles, derived from bacterial EVs (Supplementary Fig. 16-18), were also analyzed. Both microbial diversity and β-diversity showed no statistically significant differences according to sex and IBS subtype (all P > 0.05). Analysis of the relative abundances of taxa showed no statistical significance at a level of FDR q < 0.05 (Supplementary Table 9).

There was a significant difference, according to sex, in microbiome originating from bacterial cells (PERMANOVA P = 0.016), but there was no difference in cases of microbiome originating from bacterial EVs (P > 0.05, Supplementary Fig. 19 and 20). When evaluating whether there was a difference according to sex for each IBS subtype, only IBS-M, in the microbiome originating from bacterial cells, showed a significant difference (PERMANOVA P = 0.013).

After 4 weeks, neither microbial diversity nor β-diversity was different between the gQlab and placebo groups (Fig. 3). Furthermore, the fecal microbiome profiles did not differ in the gQlab group or placebo group, when comparing profiles between the baseline and week 4 in either microbiome originating from bacterial cells or bacteria-derived EVs (PERMANOVA P > 0.05, Supplementary Fig. 21). No taxa were statistically different between the 2 groups (FDR q > 0.05, data not shown).

Figure 3. Summary of metagenomic analyses of the fecal microbiome from the gQlab and placebo group. At week 4, the microbial diversity of bacterial cells (A) and bacteria-derived extracellular vesicles (EVs) (B) was not different between the 2 groups (Shannon index, P > 0.05). When fecal microbiome profiles were compared between the gQlab and placebo groups at week 4, no significant differences in the β-diversity index were observed in the 2 groups (bacterial cells [C], bacteria-derived EVs [D]; PERMANOVA P > 0.05, Bray-Curtis distance). Relative abundances were compared between the 2 groups at the phylum level (bacterial cells [E], bacteria-derived EVs [F]).

Finally, we investigated whether there were differences in fecal microbiome profile before and after treatment between responders and non-responders. In microbiome originating from both bacterial cells and bacteria-derived EVs, there were no significant differences in α- or β-diversity indices after four weeks of treatment (Supplementary Fig. 22 and 23). No taxa showed significant difference in relative abundance between responders and non-responders (all FDR q > 0.05). Also, when we performed microbiome analysis of the fecal microbiome at baseline to identify fecal microbiome profiles which could predict gQlab treatment response, no significant results were drawn (Supplementary Fig. 24).

Adverse Events and Drug Safety

No serious adverse side effects were reported during the study period. Criteria for adverse events of each laboratory test were the same as the exclusion criteria. One patient from the gQlab group developed mild elevation of serum sodium level after 4 weeks of treatment.


This randomized, double-blind, placebo-controlled, parallel-group study found that gQlab, a multi-strain probiotic, substantially improved the overall relief of IBS symptoms. Although there was no significant difference in fecal microbiota diversity between the gQlab and placebo group after 4 weeks of treatment, QoL was significantly improved in the gQlab group. Despite our randomization process, the sex ratio was imbalanced between the 2 treatment groups. Therefore, we conducted subgroup analysis according to sex and IBS subtypes and found greater treatment responses from female and IBS-C type participants.

Although both male and female participants in the gQlab group showed a higher relief of the overall IBS symptoms, statistical significance was only found in females. While a sex difference is well noted among IBS patients, previous studies have mostly focused on the therapeutic outcomes of probiotics in either male or female patients homogeneously.38 Sex-dependent treatment efficacy of gQlab may have contributed to our findings, however, the results must be interpreted with caution because there was a lower number of male participants in the placebo group.

Among the IBS subtypes, only IBS-C subtype patients showed an improvement in the overall relief of IBS symptoms. A systematic review of 70 randomized controlled studies on probiotics in the management of lower gastrointestinal symptoms by Hungin et al39 stated that specific probiotics are known to reduce constipation in some IBS patients, but diarrhea has not been significantly alleviated by probiotics. Therefore, our heterogeneous results are consistent with those of previous studies. It is unclear if specific strains of probiotics are effective for particular IBS subtypes, therefore, our results may suggest a potential benefit for the IBS-C subtype.40 However, given that in our study most IBS-C patients were females and most of the IBS-D patients were males, it is not evident whether a sex difference or the IBS subtype is a key factor related to treatment response.

Unlike the overall relief of IBS symptoms, individual bowel symptoms were not significantly improved at the end of the trial. The improvement in abdominal distension of the IBS-D patients from the gQlab group is somewhat consistent with the previous systemic review on the effect of probiotics.39 The reason why individual IBS symptoms did not significantly improve is unclear. Because our primary goal was to examine the overall relief of IBS symptoms, the sample size calculation might have been insufficient for the comparison of individual IBS symptoms. Furthermore, we assume that the relief of the overall IBS symptoms was primarily due to improvement in the IBS-QoL scores. This raises the question of the relationship between the overall IBS symptom improvement and the IBS-QoL score changes. To date, this discrepancy between IBS symptoms and QoL has not been examined widely. According to Weerts et al41 the severity of GI symptoms in IBS patients does not correlate with long-term IBS QoL improvement.

Regarding IBS-QoL, higher improvements were observed in the total IBS-QoL scores and individual IBS-QoL domains across all subgroups in the gQlab group. Since gut microbiota are known to affect mood and behavior in humans,40 it is notable that the IBS-QoL scores of the study patients significantly improved after treatment, and a sex difference was once again observed in the IBS-QoL domains, with female patients showing the highest improvement. In males, only the health worries and social reaction domains showed a statistically significant difference but in females, differences were pronounced in most of the domains. IBS is known to be more prevalent in females and lowers their quality of life more frequently than in males.42 Considering the higher psychological distress experienced by the general female IBS population,5 it was noteworthy to observe higher QoL score changes reported by the females in our study. We assume that the potential role of multi-strain probiotics in modulating gut microbiota may be different according to sex. Although not always consistent, many animal and human studies report sex differences in gut microbiota.13 Therefore, by modulating gut microbiota differently according to sex, gQlab might have proven its effect in the IBS-QoL domains in females.

To further investigate the effect of gQlab on gut microbiota modulation, we analyzed the fecal samples of the participants before and after the study period. The changes in the levels of probiotics in the feces samples, from the baseline to week 4, were significant (Supplementary Fig. 3-7). Furthermore, significant increases of L. plantarum, L. acidophilus, L. helveticus, B. longum, and B. breve were observed in responders of the gQlab group (Supplementary Fig. 9). In contrast, fecal microbiota profiles were not significantly different between the 2 groups from the start to the end of the study. There was no significant difference in fecal microbiome between male and female participants. There were no significant differences in fecal microbiome between responders and non-responders before or after gQlab administration (Supplementary Fig. 22 and 23). Moreover, we could not find any fecal microbiome marker for predicting treatment response (Supplementary Fig. 24). However, since our study included patients with all three IBS subtypes and the sample size was relatively small to draw a conclusion on the relationship between fecal microbiome and gQlab response, further microbiome study that could predict treatment response according to IBS subtype should be considered.

The administration of gQlab resulted in an overall symptomatic relief of IBS symptoms and quality of life yet changes in the microbiome environment were not significant. This might be due to the relatively short duration of the ingestion period. Previous studies have also shown that probiotic administration did not significantly alter the microbiome.43 A recent study by Shin et al,29 which investigated the microbiota of fecal samples derived from EV and non-EV separately after ingestion of multi-strain probiotics, showed that microbial diversity did not differ significantly between their treatment groups. Because gut microbiota is greatly affected by host genetic factors, diet, comorbidity, etc, it is difficult to see a dramatic change in the microbiome structure with short-term administration of probiotics.

The underlying biological mechanism behind sex-dependent treatment responses in IBS is unclear. Sex hormones, pelvic area anatomy, and intestinal microbiota are all known to cause sex-dependent susceptibility in IBS.44 In addition, males and females may respond differently to drugs due to physiological differences. Tack et al45 demonstrated the effectiveness of ibodutant treatment in female IBS patients. Likewise, Mangel et al46 showed that treatment with crofelemer resulted in a higher improvement of IBS-related pain in female IBS-D patients. Although several animal studies have addressed the issue of sex differences in the modulation effect of probiotics,47,48 there is a lack of extensive clinical studies on finding sex differences in IBS symptom relief after the administration of probiotics. Multi-strain probiotics are known to exert their effects through interactions with host cells and immune system modulation.49 Further research on how males and females interact differently with multi-strain probiotics is needed to understand gut microbiota modulation at the cellular and tissue levels.

This study has strengths in its attempt to compare treatment responses between male and female participants. To the best of our knowledge, there has been a lack of studies analyzing the efficacy of probiotics based on sex differences. To date, most of the previous probiotic studies mostly analyzed the efficacy of their probiotics between treatment and placebo groups. To overcome our sex ratio imbalance between the treatment groups, we analyzed female and male IBS patients separately. Thereby, we created a potential for sex-tailored probiotics for the future treatment of IBS.

Our study has several limitations. First, IBS is a heterogeneous disease. Our study had small sample sizes for both sex and IBS subtypes. Second, the number of IBS subtype participants for each subgroup was insufficient. In addition, female and male patients were not balanced evenly. The lack of sample size also resulted in difficulties in interpreting changes in individual IBS symptoms. More reliable results would have been possible if the research had focused on enrolling patients based on a specific subtype or sex. Third, we cannot be sure whether the participants only adhered to provided medications. Fourth, both IBS symptoms and fecal microbiome analysis may be affected by diet. Although all participants were asked to maintain their usual dietary practices throughout the study period, not every detail of their diet was monitored. Fifth, it is not certain whether the female patients responded more to the multi-strain preparation or a particular strain of gQlab. Sixth, the changes in stool properties of IBS-C and IBS-D patients need to be analyzed separately as it was inappropriate to evaluate IBS-D patients in terms of hard stools. Likewise, the comparison of loose stools in IBS-C patients was not appropriate. However, the interpretation of stool form changes is limited due to the small sample size of each IBS subtype. Seventh, the duration of IBS symptoms suffered by the participants before the study entry was not given enough consideration. The longer the period of IBS, the higher the chances of various medical interventions the patients might have gone through. We are not sure whether these interventions may have interfered with the efficacy of gQlab. Eighth, dietary information from the participants may be inaccurate due to recall bias. Since diet and nutrition affect IBS pathophysiology, our limited validity of dietary intake information may have missed important dietary interpretations. Lastly, the duration of the therapy was limited to 4 weeks which is a relatively short time to evaluate IBS symptoms and QoL considering IBS’s lifelong nature. Furthermore, four weeks is not sufficient time for probiotic strains to successfully colonize the patients’ intestines.

In conclusion, our study demonstrates that daily consumption of gQlab can improve the overall relief of IBS symptoms and quality of life, especially in female and IBS-C patients. Although the underlying pathophysiology behind the female dominant features of IBS is still elusive, sex-specific treatment may provide better responses in IBS patients. Further research is necessary to achieve a clear understanding of sex-different outcomes with multi-strain probiotic-treated IBS patients.

Supplementary Materials

Note: To access the supplementary tables and figures mentioned in this article, visit the online version of Journal of Neurogastroenterology and Motility at http://www.jnmjournal.org/, and at https://doi.org/10.5056/jnm23036.

Financial support

This work was supported by ILDONG Pharmaceutical Co, Ltd, Seoul, Korea. Also, the study was supported by the Technology Innovation Program (20018499) funded by the Ministry of Trade, Industry and Energy (MOTIE, Korea).

Conflicts of interest


Author contributions

Guarantor of the article: Cheol Min Shin and Dong Ho Lee; Young Hoon Chang: drafted the article; Yoon Jin Choi: designed this study protocol and revised the manuscript; Cheol Min Shin: performed microbiome data analysis, supervised the draft, and revised the manuscript; Jin Seok Moon: performed clinical data handling and statistical analysis; Tae-Yoon Kim: supervised the data analysis; Hyuk Yoon, Young Soo Park, and Nayoung Kim: revised the manuscript; and Dong Ho Lee: conceptualized the study, enrolled the study participants, and revised the manuscript. All authors approved the final version of the manuscript before submission.

  1. Canavan C, West J, Card T. The epidemiology of irritable bowel syndrome. Clin Epidemiol 2014;6:71-80.
    Pubmed KoreaMed CrossRef
  2. Ford AC, Lacy BE, Talley NJ. Irritable bowel syndrome. N Engl J Med 2017;376:2566-2578.
    Pubmed CrossRef
  3. Holtmann GJ, Ford AC, Talley NJ. Pathophysiology of irritable bowel syndrome. Lancet Gastroenterol Hepatol 2016;1:133-146.
    Pubmed CrossRef
  4. Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol 2012;10:712-721, e4.
    Pubmed CrossRef
  5. Kim YS, Kim N. Sex-gender differences in irritable bowel syndrome. J Neurogastroenterol Motil 2018;24:544-558.
    Pubmed KoreaMed CrossRef
  6. Bhattarai Y, Muniz Pedrogo DA, Kashyap PC. Irritable bowel syndrome: a gut microbiota-related disorder?. Am J Physiol Gastrointest Liver Physiol 2017;312:G52-G62.
    Pubmed KoreaMed CrossRef
  7. Jeffery IB, O'Toole PW, Öhman L, et al. An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota. Gut 2012;61:997-1006.
    Pubmed CrossRef
  8. Rajilić-Stojanović M, Biagi E, Heilig HG, et al. Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology 2011;141:1792-1801.
    Pubmed CrossRef
  9. Tap J, Derrien M, Törnblom H, et al. Identification of an intestinal microbiota signature associated with severity of irritable bowel syndrome. Gastroenterology 2017;152:111-123, e8.
    Pubmed CrossRef
  10. Dlugosz A, Winckler B, Lundin E, et al. No difference in small bowel microbiota between patients with irritable bowel syndrome and healthy controls. Sci Rep 2015;5:8508.
    Pubmed KoreaMed CrossRef
  11. Pozuelo M, Panda S, Santiago A, et al. Reduction of butyrate- and methane-producing microorganisms in patients with irritable bowel syndrome. Sci Rep 2015;5:12693.
    Pubmed KoreaMed CrossRef
  12. Pittayanon R, Lau JT, Yuan Y, et al. Gut microbiota in patients with irritable bowel syndrome-a systematic review. Gastroenterology 2019;157:97-108.
    Pubmed CrossRef
  13. Kim YS, Unno T, Kim BY, Park MS. Sex differences in gut microbiota. World J Mens Health 2020;38:48-60.
    Pubmed KoreaMed CrossRef
  14. Moayyedi P, Ford AC, Talley NJ, et al. The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut 2010;59:325-332.
    Pubmed CrossRef
  15. Kim H, Chae SA, Lee M, et al. Genomic and toxicity studies on Bifidobacterium bifidum IDCC 4201 and Bifidobacterium longum IDCC 4101 isolated from feces of breast-red infants. Food Suppl Biomater Health 2021;1:e37.
  16. Kim TY, Kim MG, Moon JS, Kwon HS, Choi S. Complete genome sequence of anti-inflammatory properties Bifidobacterium animalis subsp. lactis IDCC4301 isolated from infant feces. Korean J Microbiol 2020;56:62-64.
  17. Choi IY, Kim J, Kim SH, Ban OH, Yang J, Park MK. Safety evaluation of Bifidobacterium breve IDCC4401 isolated from infant eeces for use as a commercial probiotic. J Microbiol Biotechnol 2021;31:949-955.
    Pubmed KoreaMed CrossRef
  18. Jeong K, Kim M, Jeon SA, Kim YH, Lee S. A randomized trial of Lactobacillus rhamnosus IDCC 3201 tyndallizate (RHT3201) for treating atopic dermatitis. Pediatr Allergy Immunol 2020;31:783-792.
    Pubmed CrossRef
  19. Bang WY, Chae SA, Ban OH, et al. The in vitro and in vivo safety evaluation of Lactobacillus acidophilus IDCC 3302. Microbiol Biotechnol Lett 2021;49:39-44.
  20. Shin M, Ban OH, Jung YH, Yang J, Kim Y. Genomic characterization and probiotic potential of Lactobacillus casei IDCC 3451 isolated from infant faeces. Lett Appl Microbiol 2021;72:578-588.
    Pubmed CrossRef
  21. Yang SY, Chae SA, Bang WY, et al. Anti-inflammatory potential of Lactiplantibacillus plantarum IDCC 3501 and its safety evaluation. Braz J Microbiol 2021;52:2299-2306.
    Pubmed KoreaMed CrossRef
  22. Kim TY, Eun SH, Moon JS, Kwon HS, Choi S. Complete genome sequence of probiotic Lactobacillus helveticus IDCC3801 isolated from infant feces. Korean J Microbiol 2020;56:83-85.
  23. Kim MC, Moon JS, Kim YH, Kim MG, Kim TY, Park HY. Analysis of quadruple coating for improvement in improving gastrointestinal stability and survivability of probiotics. KSBB J 2019;34:107-113.
  24. Shin SY, Park S, Moon JM, et al. Compositional changes in the gut microbiota of responders and non-responders to probiotic treatment among patients with diarrhea-predominant irritable bowel syndrome: a post hoc analysis of a randomized clinical trial. J Neurogastroenterol Motil 2022;28:642-654.
    Pubmed KoreaMed CrossRef
  25. Marchix J, Quénéhervé L, Bordron P, et al. Could the microbiota be a predictive factor for the clinical response to probiotic supplementation in IBS-D? a cohort study. Microorganisms 2023;11:277.
    Pubmed KoreaMed CrossRef
  26. Yang HJ, Min TK, Lee HW, Pyun BY. Efficacy of probiotic therapy on atopic dermatitis in children: a randomized, double-blind, placebo-controlled trial. Allergy Asthma Immunol Res 2014;6:208-215.
    Pubmed KoreaMed CrossRef
  27. Furet JP, Quénée P, Tailliez P. Molecular quantification of lactic acid bacteria in fermented milk products using real-time quantitative PCR. Int J Food Microbiol 2004;97:197-207.
    Pubmed CrossRef
  28. Mezzasalma V, Manfrini E, Ferri E, et al. A randomized, double-blind, placebo-controlled trial: the efficacy of multispecies probiotic supplementation in alleviating symptoms of irritable bowel syndrome associated with constipation. Biomed Res Int 2016;2016:4740907.
    Pubmed KoreaMed CrossRef
  29. Shin CM, Choi YJ, Lee DH, et al. Validity and safety of ID-JPL934 in lower gastrointestinal symptom improvement. Sci Rep 2021;11:13046.
    Pubmed KoreaMed CrossRef
  30. Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J 2011;17:10-12.
  31. Kwon S, Lee B, Yoon S. CASPER: context-aware scheme for paired-end reads from high-throughput amplicon sequencing. BMC Bioinformatics 2014;15(suppl 9):S10.
    Pubmed KoreaMed CrossRef
  32. Bokulich NA, Subramanian S, Faith JJ, et al. Quality-filtering vastly improves diversity estimates from Illumina amplicon sequencing. Nat Methods 2013;10:57-59.
    Pubmed KoreaMed CrossRef
  33. Rognes T, Flouri T, Nichols B, Quince C, Mahé F. VSEARCH: a versatile open source tool for metagenomics. PeerJ 2016;4:e2584.
    Pubmed KoreaMed CrossRef
  34. Quast C, Pruesse E, Yilmaz P, et al. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res 2013;41:D590-D596.
    Pubmed KoreaMed CrossRef
  35. Caporaso JG, Kuczynski J, Stombaugh J, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods 2010;7:335-336.
    Pubmed KoreaMed CrossRef
  36. McMurdie PJ, Holmes S. phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PLoS One 2013;8:e61217.
    Pubmed KoreaMed CrossRef
  37. Dixon P. VEGAN, a package of R functions for community ecology. J Veg Sci 2003;14:927-930.
  38. Hod K, Sperber AD, Ron Y, et al. A double-blind, placebo-controlled study to assess the effect of a probiotic mixture on symptoms and inflammatory markers in women with diarrhea-predominant IBS. Neurogastroenterol Motil 2017;29:e13037.
    Pubmed CrossRef
  39. Hungin APS, Mitchell CR, Whorwell P, et al. Systematic review: probiotics in the management of lower gastrointestinal symptoms - an updated evidence-based international consensus. Aliment Pharmacol Ther 2018;47:1054-1070.
    Pubmed KoreaMed CrossRef
  40. Benjak Horvat I, Gobin I, Kresović A, Hauser G. How can probiotic improve irritable bowel syndrome symptoms?. World J Gastrointest Surg 2021;13:923-940.
    Pubmed KoreaMed CrossRef
  41. Weerts Z, Vork L, Mujagic Z, et al. Reduction in IBS symptom severity is not paralleled by improvement in quality of life in patients with irritable bowel syndrome. Neurogastroenterol Motil 2019;31:e13629.
    Pubmed KoreaMed CrossRef
  42. Kim N. Irritable bowel syndrome. In: Kim N, ed. Sex/gender-specific medicine in the gastrointestinal diseases. Singapore: Springer Nature Singapore 2022:237-258.
  43. Kristensen NB, Bryrup T, Allin KH, Nielsen T, Hansen TH, Pedersen O. Alterations in fecal microbiota composition by probiotic supplementation in healthy adults: a systematic review of randomized controlled trials. Genome Med 2016;8:52.
    Pubmed KoreaMed CrossRef
  44. van Kessel L, Teunissen D, Lagro-Janssen T. Sex-gender differences in the effectiveness of treatment of irritable bowel syndrome: a systematic review. Int J Gen Med 2021;14:867-884.
    Pubmed KoreaMed CrossRef
  45. Tack J, Schumacher K, Tonini G, Scartoni S, Capriati A, Maggi CA; Iris-2 investigators. The neurokinin-2 receptor antagonist ibodutant improves overall symptoms, abdominal pain and stool pattern in female patients in a phase II study of diarrhoea-predominant IBS. Gut 2017;66:1403-1413.
    Pubmed CrossRef
  46. Mangel AW, Chaturvedi P. Evaluation of crofelemer in the treatment of diarrhea-predominant irritable bowel syndrome patients. Digestion 2008;78:180-186.
    Pubmed CrossRef
  47. Lee JY, Kim N, Nam RH, et al. Probiotics reduce repeated water avoidance stress-induced colonic microinflammation in Wistar rats in a sex-specific manner. PLoS One 2017;12:e0188992.
    Pubmed KoreaMed CrossRef
  48. Miao J, Lang C, Kang Z, Zhu H, Wang S, Li M. Oral administration of fermented milk supplemented with synbiotics can influence the physiological condition of Wistar rats in a dose-sensitive and sex-specific manner. Biosci Microbiota Food Health 2016;35:89-96.
    Pubmed KoreaMed CrossRef
  49. Kwoji ID, Aiyegoro OA, Okpeku M, Adeleke MA. Multi-strain probiotics: synergy among isolates enhances biological activities. Biology (Basel) 2021;10:322.
    Pubmed KoreaMed CrossRef

This Article



Aims and Scope