Abstract
This study aimed to investigate the efficacy and safety of human gut-derived multi-strain probiotics in patients with irritable bowel syndrome (IBS). This was an open-label, prospective, observational study. Patients with IBS were administered human gut-derived multi-strain probiotics for 4 weeks. The primary and secondary outcomes were based on the overall responder rate of the total IBS severity scoring system (IBS-SSS) score (>50-point decrease) and the IBS quality of life (IBS-QOL) score and IBS-SSS1 subscore (>10-point decrease in both scores), respectively. The estimated response rate is 55%. Of 44 patients, the total IBS-SSS score responder rate was 18.2% and 63.6% of patients at 2 and 4 weeks, respectively (P = .018). Compared with baseline, a significant improvement in the IBS-QOL score was observed in 27.3% and 63.6% of patients at 2 and 4 weeks, respectively (P = .001). Overall improvement rates in the IBS-SSS1 subscore were observed in 29.5% and 61.4% of patients at 2 and 4 weeks, respectively (P < .001). Primary and secondary outcomes were higher at 4 weeks (total IBS-SSS score, 63.6%; IBS-QOL score, 63.6%; IBS-SSS1 subscore, 61.4%) than the estimated responder rate (55%). Human gut-derived multi-strain probiotics have the potential to become an effective and safe treatment option for IBS patients.
Keywords: irritable bowel syndrome, multi-strain, probiotics
1. Introduction
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder that accompanies recurrent abdominal pain, bloating, or a change in bowel habits.[1,2] It affects approximately 4% to 10% of the general population, depending on the Rome III or IV criteria.[3,4] IBS reduces a distinct impairment of the patient quality of life (QOL), thereby increasing healthcare costs.[5]
The pathophysiology of IBS is complex and not fully understood, although multifactorial mechanisms, including motility disorders, visceral hypersensitivity, altered intestinal barrier, gut microbiota, and brain-gut axis are proposed.[6–10] The gut microbiota of IBS patients is significantly different from that of healthy individuals, with low diversity and dysbiosis,[10–12] which has also been associated with symptom severity.[13,14] Gut microbiota is considered one of the factors that may play an important role in the pathophysiology of IBS.[14–19] Therefore, therapeutic targeting of the gut microbiota may be a potential treatment for IBS. Probiotics, prebiotics, and microbiome modulation therapy can improve the gut microbiota and limit colonization by pathogenic bacteria.[16,20–23]
As per the recent definition provided by the Food and Agriculture Organization and the World Health Organization, probiotics refer to live microorganisms that provide a health benefit to the host upon administration in appropriate amounts.[24] With regards to the IBS, the probiotics primarily associated are those comprising Lactobacillus and Bifidobacterium species. These probiotics are expected to have a potential to stimulate a beneficial modulation of gut microbiota that has been altered in the context of IBS through several mechanisms. These mechanisms include gut microbiota modulation, inhibition of pathogen adhesion to the gut epithelia, improvement in gut barrier function, anti-inflammatory effects, improvement of gut immunity, and enhancement of the gut-brain axis.[25–31]
However, although numerous randomized controlled trials (RCTs) conducted for the treatment of IBS, their efficacy still remains controversial.[32–39] Few studies have been conducted according to the ROME IV definition.[40,41] Therefore, the aim of our study was to assess the effect of human gut-derived multi-strain probiotics, including Lactobacillus and Bifidobacterium species, on IBS severity and patients’ QOL according to the ROME IV criteria.
2. Patients and methods
2.1. Study design
This study was a prospective, observational, open-label, single-center trial, and was conducted at Kangnam Sacred Heart Hospital, Hallym University of Korea, Seoul, Korea. Patients with IBS were enrolled in the study. This study was conducted in accordance with the Declaration of Helsinki and the study protocol was approved by the Institutional Review Board (HKS202207017002). All the patients provided written informed consent before participating in the study. This study was registered with the International Clinical Trials Registry Platform (KCT0007709).
2.2. Study participants
Participants were prospectively enrolled between September 2022 and December 2022. We included patients aged >19 years diagnosed with IBS according to the ROME IV criteria. Patients had recurrent abdominal pain, on average, at least 1 day/week in the last 3 months, associated with 2 or more of the following criteria: abdominal pain related to defecation; abdominal pain associated with change in stool frequency; and abdominal pain associated with change in stool appearance. IBS criteria were fulfilled in the last 3 months, with symptom onset at least 6 months prior to diagnosis. The exclusion criteria were: treatment with antibiotics, prebiotics, probiotics, microbiome treatments, or fecal microbiota transplantation (FMT) within 2 weeks from inclusion; patients with a history of abdominal surgery (except for appendectomy or cesarean section); patients with inflammatory bowel disease, major psychiatric disease, or depressive disease with medication; and patients with severe cardiopulmonary disease or malignancy. The participants consumed the assigned study product orally, once daily before a meal, with a glass of water throughout the 4 weeks study period. The daily dose was 1 × 1010 colony-forming units (CFU).
2.3. Human gut-derived multi-strain probiotics
The multi-strain probiotic contained 6 strains of Lactobacillus gasseri, Lactobacillus rhamnosus, Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium bifidum, and Bifidobacterium lactis at a dose of 1 × 1010 CFU. Lactobacillus and Bifidobacterium were obtained from healthy human gut.
2.4. Questionnaires
2.4.1. IBS severity scoring system (IBS-SSS).
The IBS-severity scoring system (SSS) includes 5 subscore visual analog scales related to abdominal pain severity (IBS-SSS1), abdominal pain frequency (IBS-SSS2), abdominal discomfort severity (IBS-SSS3), dissatisfaction with bowel habits (IBS-SSS4), and life interference in general (IBS-SSS5).[42] The total score ranges from 0 to 500. Patients with a score of <75 were classified as in remission, 75 to 175 as mild disease, 175 to 300 as moderate disease, and 300 or more as severe disease.
3. IBS-QOL
The IBS-QOL assesses 8 subscales of health, graded on a 5-point scale, with total scores ranging from 0 to 100.[43]
3.1. Outcome parameters
The primary outcome was the proportion of responders with a decrease of >50 points in the total IBS-SSS score. The possible range is 0 to 500. The mean values at baseline, weeks 2 and 4 were calculated for individual symptoms and overall IBS-SSS score. Secondary outcomes were the proportion of responders who had a decrease of >10 points in the IBS-SSS1 subscore and IBS-QOL scores. IBS-SSS1 subscore and IBS-QOL scores were calculated for baseline, weeks 2 and 4.
All patients were scheduled to visit our outpatient clinic at weeks 2 and 4 to check for any adverse events after receiving multi-strain probiotics. They were also asked whether they had experienced abdominal pain, constipation, diarrhea, nausea, bloating, or vomiting, and other adverse events.
3.2. Sample size calculation
Based on a systematic review and meta-analysis, the placebo response rate across all RCTs was estimated to be up to 25%.[44–46] In our preliminary experience with the human gut-derived multi-strain probiotics for IBS patients, we assumed a response rate of 55% in the human gut-derived multi-strain probiotics group. Therefore, a sample size of 38 patients per group was required, with an alpha level of 5% and a power of 80%, to show superiority. Thus, the required sample size was 44 patients, with a dropout rate of 13%.
3.3. Statistics
Descriptive statistics were reported as mean for continuous variables or as a percentage for categorical variables. The mean values are reported as standard deviations. Continuous variables were analyzed and compared using the paired t test. Categorical variables were compared using the chi-squared test or Fisher exact test. Statistical significance was set at P < .05 (two-sided). All statistical analyses were performed using the SPSS statistical software (version 21.0; SPSS Inc., Chicago, IL).
4. Results
4.1. Patient characteristics
A total of 55 patients were enrolled in the study. Among them, 11 patients were excluded because they had undergone previous treatment with antibiotics, prebiotics, probiotics, microbiome treatments, or FMT within 2 weeks of inclusion (n = 9), had a history of abdominal surgery (n = 1), or had a psychiatric disorder (n = 1). Finally, 44 patients were included in this study. Forty-four patients completed the study according to the protocol and no follow up loss occurred.
Table 1 presents the baseline patient characteristics. Patients were predominantly female with a mean age of 57. Body mass index was classified as normal in 63.6% of patients. In addition, 68.2% of the patients received at least one previous IBS treatment, which was unlikely to interfere with the study treatment. According to the ROME IV criteria, the majority of patients were diagnosed with IBS-D (70.5%), followed by IBS-M (27.2%) and IBS-C subtypes (2.3%). At baseline, the mean IBS-SSS and IBS-QOL score were 326.3 and 64.8, respectively. Among these patients, 59.1% had severe disease and 40.9% had moderate disease.
Table 1.
Baseline characteristics of the patients.
| Characteristics | IBS patients (n = 44) |
|---|---|
| Age, mean (SD), yr | 57 (17.4) |
| Sex, male, n (%) | 17 (38.6) |
| BMI class, n (%) | 24.3 (4.3) |
| Normal | 28 (63.6) |
| Underweight | 2 (4.5) |
| Overweight | 8 (18.2) |
| Obese | 6 (13.6) |
| Type of IBS, n (%) | |
| IBS-D | 31 (70.5) |
| IBS-M | 12 (27.2) |
| IBS-C | 1 (2.3) |
| IBS-SSS class, n (%) | |
| Moderate | 18 (40.9) |
| Severe | 26 (59.1) |
| IBS-SSS score, mean, (SD) | |
| Total | 326.3 (30.2) |
| Abdominal pain severity (IBS-SSS1) | 71.2 (5.1) |
| Abdominal pain frequency (IBS-SSS2) | 61.6 (8.6) |
| Abdominal discomfort severity (IBS-SSS3) | 67.0 (6.9) |
| Bowel habit dissatisfaction (IBS-SSS4) | 61.2 (7.9) |
| Life interference in general (IBS-SSS5) | 65.3 (7.9) |
| IBS-QOL score, mean, (SD) | 64.8 (6.6) |
| Previous medication use, n (%) | 30 (68.2) |
| Previous FMT or probiotics use within 4 wk, n (%) | 0 (0) |
BMI = body mass index, FMT = fecal microbiota transplantation, IBS = irritable bowel syndrome, QOL = quality of life, SD = standard deviation, SSS = severity scoring system.
4.2. Outcomes
The primary outcome was the rate of significant responders in the total IBS-SSS score (>50-point decrease). Of the 44 patients, 28 were responders (63.6%) at 4 weeks, which was higher than the estimated response rate (55%) in the total IBS-SSS score (Fig. 1). However, the rate of responders fell short of the estimated response rate at 2 weeks (18.2% vs estimated response rate of 55%).
Figure 1.
The percentage of patients reported as responder for primary and secondary outcomes: (A) total IBS-SSS score; (B) IBS-SSS1 score (abdominal pain severity); (C) IBS-QOL score. IBS = irritable bowel syndrome, QOL = quality of life, SSS = severity scoring system.
Secondary outcomes were the rate of significant responders in the IBS-QOL and IBS-SSS1 subscores (>10-point decrease in both scores). Compared with baseline, a significant improvement in the IBS-QOL score was observed in 27.3% and 63.6% of patients at 2 and 4 weeks, respectively. Improvement rates in the IBS-SSS1 subscore were observed in 29.5% and 61.4% of patients at 2 and 4 weeks, respectively (Fig. 1). The significant response rate (IBS-QOL, 63.6%; IBS-SSS1 subscore, 61.4%) was higher than the estimated response rate (55%) at 4 weeks.
The IBS-SSS score significantly improved after 2 and 4 weeks compared with baseline in the human gut-derived multi-strain probiotics group (−27.1 ± 32.8 and −101.8 ± 76.9, respectively; P < .001) (Table 2). Furthermore, all IBS-SSS and IBS-QOL scores significantly improved after 2 and 4 weeks compared to baseline (Table 2). In the univariate analysis, no significant factors were associated with the respondents (Table 3).
Table 2.
Change of irritable bowel syndrome-severity scoring system score and irritable bowel syndrome-quality of life score from baseline to 2 wk and 4 wk.
| 2 wk | 4 wk | P | |
|---|---|---|---|
| IBS-SSS score, mean, (SD) | |||
| Total | −27.1 (32.8) | −101.8 (76.9) | <.001 |
| Abdominal pain severity (IBS-SSS1) | −6.8 (6.7) | −24.3 (18.5) | <.001 |
| Abdominal pain frequency (IBS-SSS2) | −4.3 (7.3) | −20.9 (15.4) | <.001 |
| Abdominal discomfort severity (IBS-SSS3) | −6.6 (7.5) | −20.0 (14.8) | <.001 |
| Bowel habit dissatisfaction (IBS-SSS4) | −3.9 (8.1) | −16.0 (15.1) | <.001 |
| Life interference in general (IBS-SSS5) | −5.4 (7.3) | −20.6 (17.8) | <.001 |
| IBS-QOL score, mean, (SD) | −6.0 (6.5) | −19.7 (16.2) | <.001 |
IBS-QOL = irritable bowel syndrome-quality of life, IBS-SSS = irritable bowel syndrome-severity scoring system, SD = standard deviation.
Table 3.
Univariate analysis of factors associated with responder on 4 wk.
| Responder (n = 28) |
Non-responder (n = 16) |
P | |
|---|---|---|---|
| Age | 56.8 (17.9) | 57.3 (16.9) | .919 |
| Sex, male, n (%) | 10 (35.7) | 7 (43.8) | .598 |
| BMI class, n (%) | .400 | ||
| Underweight | 2 (7.1) | 0 | |
| Normal | 19 (67.9) | 9 (56.3) | |
| Overweight | 3 (10.7) | 5 (31.3) | |
| Obesity | 4 (14.3) | 2 (12.5) | |
| IBS type, n (%) | .364 | ||
| IBS-D | 21 (75.0) | 10 (62.5) | |
| IBS-M | 7 (25.0) | 5 (31.3) | |
| IBS-C | 0 (0) | 1 (6.3) | |
| IBS-SSS class, n (%) | .354 | ||
| Moderate | 10 (35.7) | 8 (50.0) | |
| Severe | 18 (64.3) | 8 (50.0) |
BMI = body mass index, IBS = irritable bowel syndrome, QOL = quality of life, SD = standard deviation, SSS = severity scoring system.
No severe adverse effects were observed in our study. Human gut-derived multi-strain probiotics were well tolerated by the patients. At the beginning of the study, 2 participants reported diarrhea and bloating within 2 weeks. The reported symptoms resolved within 4 weeks (Table 4).
Table 4.
Incidence of adverse event during study periods.
| 2 wk (n = 44) |
4 wk (n = 44) |
|
|---|---|---|
| Abdominal pain, n (%) | 0 | 0 |
| Constipation, n (%) | 0 | 0 |
| Diarrhea, n (%) | 1 (2.3) | 0 |
| Nausea, n (%) | 0 | 0 |
| Bloating, n (%) | 1 (2.3) | 0 |
| Vomiting, n (%) | 0 | 0 |
5. Discussion
This study showed that the human gut derived multi-strain probiotics would be effective and safe in patients with IBS. This was due to the observed improvements in IBS-related symptoms and QOL. These results are consistent with the finding that microbiome modulation therapy has a significant effect on IBS symptoms.
We found that human gut-derived multi-strain probiotic treatment significantly improved the IBS-SSS score in approximately 60% of the patients. This is consistent with previous studies on microbiome modulation therapy.[33,34,36,37,41,47] One of the secondary outcomes, which is the change in the IBS-SSS1 subscore, shows that human gut-derived multi-strain probiotics significantly improved the severity of abdominal pain. Previous studies also observed a significant decrease in the IBS-SSS score in the probiotic group, mainly due to a significant decrease in abdominal pain and improved QOL.[32–34]
To date, few studies of microbiome modulation therapies have been conducted in IBS patients according to the ROME IV criteria,[40,41] which tends to increase the number of patients classified as severe IBS. Our study included a large number of patients with severe IBS; nevertheless, our human gut-derived multi-strain probiotics showed good outcomes in patients with IBS, resulting in a significant increase in the proportion of patients with mild symptoms in the study group.
IBS often affects QOL, especially in patients with moderate-to-severe disease. IBS-related symptoms (i.e., abdominal pain and discomfort) have been demonstrated to lower the QOL of patients with IBS in several studies. In addition, even if the IBS-related symptoms improve, dietary restrictions (i.e., low fodmap diet, gluten-free diet, and traditional dietary advice) for treatment can affect the QOL. In our study, we found that human gut-derived multi-strain probiotic treatment significantly improved the total IBS-QOL score. Improvement in the IBS-QOL score was found mainly in patients with moderate-to-severe IBS. Previous studies have also shown that microbiome modulation treatment improves IBS-QOL in patients with IBS.[33,41] It is thought that human gut-derived multi-strain probiotic treatment can possibly improve the QOL of patients since there were no dietary restrictions, in addition to an improvement of abdominal pain and discomfort and few adverse effects.
Similar to our study, previous studies reported that multi-strain probiotics had a significant improvement in IBS patients.[34,48–51] Skrzydło-Radomańska et al reported that use of multi-strain probiotic yielded a significant improvement of IBS-SSS score and IBS-GIS score in IBS patients.[34] Sisson et al reported that multi-strain probiotics has a significant improvement of IBS-SSS score.[51] Also, other network meta-analysis reported multi-strain probiotics have potent effects compared with single strain probiotics.[49,50] However, there is still debate on what is the cause of difference in clinical outcomes between single-strain and multi-strain probiotics, and further ongoing research is deemed necessary to address this issue.
The gut microbiota is a complex and abundant ecosystem that influences various physiological systems in the human body. Nonetheless, due to its considerable complexity and variability across individuals, the precise role of the gut microbiota in human physiology is not fully understood. According to previous studies, patients with IBS showed a notable increase in the Firmicutes to Bacteroidetes ratio at the phylum level, as well as significant alterations in the composition and activities of Lactobacillus and Bifidobacterium.[52,53] Microbiome modulation therapy, such as probiotics, prebiotics, and FMT, has been carried out in several studies and has shown various results.[38,47] Previous studies have shown improvement in 60 to 80% of patients with IBS. Several studies reported that 2-thirds of patients with IBS had dysbiosis. Therefore, it is likely that IBS improves through microbiome modulation therapy in patients with dysbiosis. We speculated that human gut-derived multi-strain probiotics also likely improved IBS-SSS and IBS-QOL through this mechanism. Future studies on the relationship between dysbiosis in patients and improvement of IBS after human gut-derived multi-strain probiotic treatment are needed. Furthermore, a recent study reported 2 microbiome subtypes in a group that showed the effect of low fodmap treatment in IBS.[54] We speculate that these subtypes will also exist in groups that benefit from human gut-derived multi-strain probiotic treatment.
Treatment duration is thought to play an important role. Previous studies have reported improvement in symptoms after 4 to 8 weeks of treatment.[32–34] In our study, there was no improvement at 2 weeks, but improvement was observed at 4 weeks. Other studies also reported that no significant improvement was not achieved at 2 weeks.[55,56] It is necessary to determine the effective duration of treatment by determining the changes in the microbiome according to the duration of treatment.
Our patients received 1 × 1010 CFU per day and tolerated this dose well. No serious adverse events were observed. Adverse events, including diarrhea and bloating, have been reported; however, their incidence was not different from those reported in previous studies. Given that diarrhea and bloating are common symptoms in IBS patients, it cannot be ruled out that the reported adverse effects may not be a result of the probiotic preparation.
This study had several limitations. First, this was a prospective, observational study. Second, this study was only conducted for 4 weeks, and the long-term outcomes are relatively unknown. Third, this study included all of the IBS-type patients; however, only a small proportion of patients with IBS-C was included. Further large-scale RCT are needed to ensure the efficacy and safety of the human gut-derived multi-strain probiotics in IBS-C patients. Nevertheless, our study showed a response rate that exceeded the expected 55% for both primary and secondary outcome variables. Taking into consideration that the placebo effect usually does not exceed 25%, the superiority of our human gut-derived multi-strain probiotics could be demonstrated.
6. Conclusions
In conclusion, human gut-derived multi-strain probiotics showed excellent effects in reducing IBS disease severity and improving patient QOL. Furthermore, the human gut-derived multi-strain probiotics has substantial advantages in terms of its efficacy and safety. Therefore, human gut-derived multi-strain probiotics could be considered as one of the standard treatments for IBS patients.
Author contributions
Conceptualization: Chang Kyo Oh, Jae Gun Park, You Jin Kim.
Data curation: Chang Kyo Oh, Jae Gun Park, You Jin Kim.
Formal analysis: Chang Kyo Oh.
Funding acquisition: Chang Kyo Oh.
Investigation: Chang Kyo Oh.
Methodology: Chang Kyo Oh, Jae Gun Park.
Project administration: Chang Kyo Oh.
Resources: Chang Kyo Oh, Jin Bae Kim.
Software: Chang Kyo Oh.
Supervision: Chang Kyo Oh.
Validation: Chang Kyo Oh.
Visualization: Chang Kyo Oh.
Writing – original draft: Chang Kyo Oh.
Writing – review & editing: Chang Kyo Oh.
Abbreviations:
- CFU
- colony-forming unit
- FMT
- fecal microbiota transplantation
- IBS
- irritable bowel syndrome
- QOL
- quality of life
- RCT
- randomized controlled trial
- SSS
- severity scoring system
This research was supported by Hallym University Research Fund, 2022 (HURF-2022-04).
Informed consent was obtained from all subjects involved in the study.
The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of Kangnam Sacred Heart Hospital (Approval number: HKS202207017002).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
How to cite this article: Oh CK, Park JK, Kim YJ, Kim JB. Efficacy and safety of human gut-derived multi-strain probiotics in patients with irritable bowel syndrome: A prospective open-label observation study. Medicine 2023;102:34(e34899).
Contributor Information
Jae Keun Park, Email: jaekpark@hallym.or.kr.
Yu Jin Kim, Email: jbkim87@hallym.or.kr.
Jin Bae Kim, Email: jbkim87@hallym.or.kr.
References
- [1].Palsson OS, Whitehead W, Törnblom H, et al. Prevalence of Rome IV functional bowel disorders among adults in the United States, Canada, and the United Kingdom. Gastroenterology. 2020;158:1262–1273.e3. [DOI] [PubMed] [Google Scholar]
- [2].Lacy BE, Mearin F, Chang L, et al. Bowel disorders. Gastroenterology. 2016;150:1393–1407.e5. [DOI] [PubMed] [Google Scholar]
- [3].Black CJ, Ford AC. Global burden of irritable bowel syndrome: trends, predictions and risk factors. Nat Rev Gastroenterol Hepatol. 2020;17:473–86. [DOI] [PubMed] [Google Scholar]
- [4].Oka P, Parr H, Barberio B, et al. Global prevalence of irritable bowel syndrome according to Rome III or IV criteria: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2020;5:908–17. [DOI] [PubMed] [Google Scholar]
- [5].Chang L. Epidemiology and quality of life in functional gastrointestinal disorders. Aliment Pharmacol Ther. 2004;20:31–9. [DOI] [PubMed] [Google Scholar]
- [6].Raskov H, Burcharth J, Pommergaard H-C, et al. Irritable bowel syndrome, the microbiota and the gut-brain axis. Gut Microbes. 2016;7:365–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [7].Simrén M, Barbara G, Flint HJ, et al. Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut. 2013;62:159–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [8].Piche T, Barbara G, Aubert P, et al. Impaired intestinal barrier integrity in the colon of patients with irritable bowel syndrome: involvement of soluble mediators. Gut. 2009;58:196–201. [DOI] [PubMed] [Google Scholar]
- [9].Marshall J, Thabane M, Garg A, et al. Intestinal permeability in patients with irritable bowel syndrome after a waterborne outbreak of acute gastroenteritis in Walkerton, Ontario. Aliment Pharmacol Ther. 2004;20:1317–22. [DOI] [PubMed] [Google Scholar]
- [10].Mujagic Z, Kasapi M, Jonkers DM, et al. Integrated fecal microbiome–metabolome signatures reflect stress and serotonin metabolism in irritable bowel syndrome. Gut Microbes. 2022;14:2063016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [11].Kassinen A, Krogius-Kurikka L, Mäkivuokko H, et al. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology. 2007;133:24–33. [DOI] [PubMed] [Google Scholar]
- [12].Salonen A, de Vos WM, Palva A. Gastrointestinal microbiota in irritable bowel syndrome: present state and perspectives. Microbiology. 2010;156:3205–15. [DOI] [PubMed] [Google Scholar]
- [13].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. [DOI] [PubMed] [Google Scholar]
- [14].McIntosh K, Reed DE, Schneider T, et al. FODMAPs alter symptoms and the metabolome of patients with IBS: a randomised controlled trial. Gut. 2017;66:1241–51. [DOI] [PubMed] [Google Scholar]
- [15].Mari A, Abu Baker F, Mahamid M, et al. The evolving role of gut microbiota in the management of irritable bowel syndrome: an overview of the current knowledge. J Clin Med. 2020;9:685. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [16].Bhattarai Y, Muniz Pedrogo DA, Kashyap PC. Irritable bowel syndrome: a gut microbiota-related disorder. Am J Physiol Gastrointest Liver Physiol. 2017;312:G52–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [17].Collins SM. A role for the gut microbiota in IBS. Nat Rev Gastroenterol Hepatol. 2014;11:497–505. [DOI] [PubMed] [Google Scholar]
- [18].Tana C, Umesaki Y, Imaoka A, et al. Altered profiles of intestinal microbiota and organic acids may be the origin of symptoms in irritable bowel syndrome. Neurogastroenterol Motil. 2010;22:512–9, e114. [DOI] [PubMed] [Google Scholar]
- [19].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;141:1792–801. [DOI] [PubMed] [Google Scholar]
- [20].Parkes GC, Brostoff J, Whelan K, et al. Gastrointestinal microbiota in irritable bowel syndrome: their role in its pathogenesis and treatment. Am J Gastroenterol. 2008;103:1557–67. [DOI] [PubMed] [Google Scholar]
- [21].Johnsen PH, Hilpüsch F, Cavanagh JP, et al. Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome: a double-blind, randomised, placebo-controlled, parallel-group, single-centre trial. Lancet Gastroenterol Hepatol. 2018;3:17–24. [DOI] [PubMed] [Google Scholar]
- [22].El-Salhy M, Hatlebakk JG, Gilja OH, et al. Efficacy of faecal microbiota transplantation for patients with irritable bowel syndrome in a randomised, double-blind, placebo-controlled study. Gut. 2020;69:859–67. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [23].Wilson B, Rossi M, Dimidi E, et al. Prebiotics in irritable bowel syndrome and other functional bowel disorders in adults: a systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr. 2019;109:1098–111. [DOI] [PubMed] [Google Scholar]
- [24].Hill C, Guarner F, Reid G, et al. Expert consensus document: the International scientific association for probiotics and prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014;4:506–14. [DOI] [PubMed] [Google Scholar]
- [25].Cremon C, Barbaro MR, Ventura M, et al. Pre-and probiotic overview. Curr Opin Pharmacol. 2018;43:87–92. [DOI] [PubMed] [Google Scholar]
- [26].Barbara G, Stanghellini V. Biomarkers in IBS: when will they replace symptoms for diagnosis and management? Gut. 2009;58:1571–5. [DOI] [PubMed] [Google Scholar]
- [27].Barbara G, Feinle-Bisset C, Ghoshal UC, et al. The intestinal microenvironment and functional gastrointestinal disorders. Gastroenterology. 2016;150:1305–1318.e8. [DOI] [PubMed] [Google Scholar]
- [28].Barbara G, Stanghellini V, Brandi G, et al. Interactions between commensal bacteria and gut sensorimotor function in health and disease. American J Gastroenterol. 2005;100:2560–8. [DOI] [PubMed] [Google Scholar]
- [29].Agrawal A, Houghton LA, Morris J, et al. Clinical trial: the effects of a fermented milk product containing Bifidobacterium lactis DN-173 010 on abdominal distension and gastrointestinal transit in irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2009;29:104–14. [DOI] [PubMed] [Google Scholar]
- [30].Collins SM, Surette M, Bercik P. The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol. 2012;10:735–42. [DOI] [PubMed] [Google Scholar]
- [31].Kajander K, Myllyluoma E, Rajilić-Stojanović M, et al. Clinical trial: multispecies probiotic supplementation alleviates the symptoms of irritable bowel syndrome and stabilizes intestinal microbiota. Aliment Pharmacol Ther. 2008;27:48–57. [DOI] [PubMed] [Google Scholar]
- [32].Lewis ED, Antony JM, Crowley DC, et al. Efficacy of Lactobacillus paracasei HA-196 and Bifidobacterium longum R0175 in alleviating symptoms of irritable bowel syndrome (IBS): a randomized, placebo-controlled study. Nutrients. 2020;12:1159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [33].Martoni CJ, Srivastava S, Leyer GJ. Lactobacillus acidophilus DDS-1 and Bifidobacterium lactis UABla-12 improve abdominal pain severity and symptomology in irritable bowel syndrome: randomized controlled trial. Nutrients. 2020;12:363. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [34].Skrzydło-Radomańska B, Prozorow-Król B, Cichoż-Lach H, et al. The effectiveness and safety of multi-strain probiotic preparation in patients with diarrhea-predominant irritable bowel syndrome: a randomized controlled study. Nutrients. 2021;13:756. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [35].Mack I, Schwille-Kiuntke J, Mazurak N, et al. A nonviable probiotic in irritable bowel syndrome: a randomized, double-blind, placebo-controlled, multicenter study. Clin Gastroenterol Hepatol. 2022;20:1039–1047.e9. [DOI] [PubMed] [Google Scholar]
- [36].Andresen V, Gschossmann J, Layer P. Heat-inactivated Bifidobacterium bifidum MIMBb75 (SYN-HI-001) in the treatment of irritable bowel syndrome: a multicentre, randomised, double-blind, placebo-controlled clinical trial. Lancet Gastroenterol Hepatol. 2020;5:658–66. [DOI] [PubMed] [Google Scholar]
- [37].Madempudi RS, Ahire JJ, Neelamraju J, et al. Randomized clinical trial: the effect of probiotic Bacillus coagulans Unique IS2 vs. placebo on the symptoms management of irritable bowel syndrome in adults. Sci Rep. 2019;9:1–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [38].Ford AC, Harris LA, Lacy BE, et al. Systematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome. Aliment Pharmacol Ther. 2018;48:1044–60. [DOI] [PubMed] [Google Scholar]
- [39].Skrzydło-Radomańska B, Prozorow-Król B, Cichoż-Lach H, et al. The effectiveness of synbiotic preparation containing Lactobacillus and Bifidobacterium probiotic strains and short chain fructooligosaccharides in patients with diarrhea predominant irritable bowel syndrome—a randomized double-blind, placebo-controlled study. Nutrients. 2020;12:1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [40].Quigley EM, Markinson L, Stevenson A, et al. Randomised clinical trial: efficacy and safety of the live biotherapeutic product MRx1234 in patients with irritable bowel syndrome. Aliment Pharmacol Ther. 2023;57:81–93. [DOI] [PubMed] [Google Scholar]
- [41].Sabaté J-M, Iglicki F. Effect of Bifidobacterium longum 35624 on disease severity and quality of life in patients with irritable bowel syndrome. World J Gastroenterol. 2022;28:732–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [42].Francis CY, Morris J, Whorwell PJ. The irritable bowel severity scoring system: a simple method of monitoring irritable bowel syndrome and its progress. Aliment Pharmacol Ther. 1997;11:395–402. [DOI] [PubMed] [Google Scholar]
- [43].Patrick DL, Drossman DA, Frederick IO, et al. Quality of life in persons with irritable bowel syndrome (development and validation of a new measure). Dig Dis Sci. 1998;43:400–11. [DOI] [PubMed] [Google Scholar]
- [44].Bosman M, Elsenbruch S, Corsetti M, et al. The placebo response rate in pharmacological trials in patients with irritable bowel syndrome: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2021;6:459–73. [DOI] [PubMed] [Google Scholar]
- [45].Barberio B, Savarino EV, Black CJ, et al. Placebo response rates in trials of licensed drugs for irritable bowel syndrome with constipation or diarrhea: meta-analysis. Clin Gastroenterol Hepatol. 2022;20:e923–44. [DOI] [PubMed] [Google Scholar]
- [46].Shah E, Pimentel M. Placebo effect in clinical trial design for irritable bowel syndrome. J Neurogastroenterol Motil. 2014;20:163–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [47].Moayyedi P, Ford AC, Talley NJ, et al. The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut. 2010;59:325–32. [DOI] [PubMed] [Google Scholar]
- [48].Ishaque SM, Khosruzzaman S, Ahmed DS, et al. A randomized placebo-controlled clinical trial of a multi-strain probiotic formulation (Bio-Kult®) in the management of diarrhea-predominant irritable bowel syndrome. BMC Gastroenterol. 2018;18:1–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [49].Liang D, Longgui N, Guoqiang X. Efficacy of different probiotic protocols in irritable bowel syndrome: a network meta-analysis. Medicine (Baltim). 2019;98:e16068. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [50].Niu H-L, Xiao J-Y. The efficacy and safety of probiotics in patients with irritable bowel syndrome: evidence based on 35 randomized controlled trials. Int J Surg. 2020;75:116–27. [DOI] [PubMed] [Google Scholar]
- [51].Sisson G, Ayis S, Sherwood R, et al. Randomised clinical trial: a liquid multi-strain probiotic vs. placebo in the irritable bowel syndrome–a 12 week double-blind study. AlimenT Pharmacol Ther. 2014;40:51–62. [DOI] [PubMed] [Google Scholar]
- [52].Carroll IM, Ringel-Kulka T, Siddle JP, et al. Alterations in composition and diversity of the intestinal microbiota in patients with diarrhea-predominant irritable bowel syndrome. Neurogastroenterol Motil. 2012;24:521–e248. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [53].Kerckhoffs AP, Samsom M, van der Rest ME, et al. Lower Bifidobacteria counts in both duodenal mucosa-associated and fecal microbiota in irritable bowel syndrome patients. World J Gastroenterol. 2009;15:2887–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [54].Vervier K, Moss S, Kumar N, et al. Two microbiota subtypes identified in irritable bowel syndrome with distinct responses to the low FODMAP diet. Gut. 2022;71:1821–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [55].Shavakhi A, Minakari M, Farzamnia S, et al. The effects of multi-strain probiotic compound on symptoms and quality-of-life in patients with irritable bowel syndrome: a randomized placebo-controlled trial. Adv Biomed Res. 2014;3:140. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [56].Sadrin S, Sennoune S, Gout B, et al. A 2-strain mixture of Lactobacillus acidophilus in the treatment of irritable bowel syndrome: a placebo-controlled randomized clinical trial. Dig Liver Dis. 2020;52:534–40. [DOI] [PubMed] [Google Scholar]