Table 1.
Characteristics of randomized controlled trials of probiotics versus placebo in irritable bowel syndrome.
| Study | Year | Country | Type of IBS(%) | diagnostic criteria for IBS | recruitment | Sample size | Sex (Male/Female) | Age[years],mean ± SD | Probiotic | Probiotic dosage(CFU/D) | Duration of therapy | Criteria used to define symptom improvement following therapy or response | Outcome | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Probiotic | Placebo | |||||||||||||
| Gade and Thorn (1989) | 1989 | Denmark | all types | Manning | Primary care | 54 | 5/27 | 7/15 | 34 | Streptococcus faecium | Not stated | 4 weeks | IBS symptoms “improved” | Improvement in IBS symptoms Adverse events |
| Nobaek et al. (2006) | 2000 | Sweden | all types | Rome I | Advertisement | 52 | 9/16 | 7/20 | 51 | Lactobacillus plantarum | 5×107 | 4 weeks | > 1.5 improvement in VAS scale for abdominal pain, and continuous scale for IBS symptoms |
Abdominal pain(VAS) |
| Niedzielin et al. (2001) | 2001 | Poland | all types | clinical diagnosis | Primary care | 40 | 5/15 | 3/17 | 45 | Lactobacillus plantarum | 2×1010 | 4 weeks | improvement in IBS symptoms | Improvement in IBS symptoms Adverse events |
| Kim et al. (2003) | 2003 | USA | D:100 | Rome II | Secondary care | 25 | 2/10 | 5/8 | 42.8 ± 16.7 | Combination | 9×1011 | 8 weeks | Satisfactory relief of IBS symptoms for 50% of weeks, and continuous scale for IBS symptoms | Response(Satisfactory relief of IBS symptoms for 50% of weeks) Overall symptoms score Bloating(100-mm VAS) Abdominal pain(100-mm VAS) Adverse events |
| Kajander et al. (2005) | 2005 | Finland | D:48 C:23 A:29 |
Rome I and II | Advertising | 103 | 13/39 | 11/40 | 46 | Combination | 8–9×109 | 6 months | Relief of IBS symptoms, and continuous scale for IBS symptoms | Global symptoms score Abdominal pain(a 4-point numerical scale) Adverse events |
| Kim et al. (2005) | 2005 | USA | D:42 C:33 A:25 |
Rome II | Secondary care and advertising | 48 | 3/21 | 0/24 | 43 | Combination | 9×1011 | 4-8 weeks | Satisfactory relief of IBS symptom for 50% of weeks | Response(Satisfactory relief of IBS symptoms for 50% of weeks) Bloating(100-mmVAS) Abdominal pain(100-mmVAS) Adverse events |
| Niv et al. (2005) | 2005 | Israel | D:37 C:18.5 M:44.4 |
Rome II | Secondary care | 54 | 7/20 | 11/16 | 45.6 | L. reuteri ATCC 55730 | 4×108 for 1wk, then 2×108 | 6 months | continuous scale for IBS symptoms | Global symptoms score Adverse events |
| O'Mahony et al. (2005) | 2005 | Ireland | D:28 C:26 A:45 |
Rome II | Secondary care | 75 | not stated | 44.3 | L. salivarius UCC4331 or B. infantis 35624 | 1×1010 | 8 weeks | Continuous scale for IBS symptoms | Global symptoms score Abdominal pain(7-point Likert score) Bloating(7-pointLikert score) Adverse events |
|
| Kim et al. (2006) | 2006 | Korea | D:70 A:30 |
clinical diagnosis | Secondary care | 34 | 14/3 | 11/6 | 39.35 ± 11.9 | Combination | 3×109(Bacillus subtilis) 2.7×1010(Streptococcus faecium) |
4 weeks | Continuous scale for IBS symptoms | Bloating(10-pointVAS) Abdominal pain(10-pointVAS) Adverse events |
| Simren and Lindh (2006) | 2006 | Sweden | all types | Rome II | Advertising | 76 | not stated | 40 | L.plantarum DSM 9843 | 2×1010 | 6 weeks | Continuous scale for IBS symptoms | Global symptoms score(IBS-SSS) | |
| Whorwell et al. (2006) | 2006 | UK | D:55.5 C:20.7 A:23.8 |
Rome II | Primary care | 362 | 0/270 | 0/92 | 41.9 ± 10.46 | B. infantis 35624 | 1×106,1×108,1×1010 | 4 weeks | Subjects' Global Assessment (SGA) of IBS symptoms,and continuous scale symptoms for IBS | Response(SGA) Global symptoms score Bloating(a 6-point numerical scale) Abdominal pain(a 6-point numerical scale) Adverse events |
| Guyonnet et al. (2007) | 2007 | France | C:100 | Rome II | Primary care | 267 | 29/106 | 39/93 | 49.3 ± 11.4 | Combination | B. animalis DN173010 (1.25×1010 c.f.u./125 g) S. thermophilus (1.2×109 c.f.u./125 g) and L. bulgaricus (1.2×109 c.f.u./125 g) b.i.d. | 6 weeks | improvement at least 10% vs. baseline | Response(improvement at least 10% vs. baseline) Global symptoms score(a 7-pointLikert score) Bloating(a 7-Likert score) Abdominal pain(a 7-Likert score) Adverse events |
| Drouault-Holowacz et al. (2007) | 2007 | France | D:29 C:29 A:41 non-classified:1% |
Rome II | Not stated | 100 | 8/40 | 16/36 | 45.4 ± 14 | Combination | 1 × 1010 | 4 weeks | Satisfactory relief of global IBS symptoms | Satisfactory relief of IBS symptoms Abdominal pain(a 4-pointLikert score) |
| Enck et al. (2008) | 2008 | Germany | all types | Primary care physicians | Primary care | 297 | 77/72 | 73/75 | 49.6 ± 13.6 | Enterococcus faecalis DSM16440 and Escherichia coli DSM17252 | (3.0-9.0×107c.f.u./1.5 ml)×0.75 ml t.i.d. for 1 week, then 1.5 ml t.i.d. for weeks 2 and 3, then 2.25 ml t.i.d. for weeks 3–8 | 8 weeks | 50% improvement in IBS global symptoms,and continuous scale symptoms for IBS | Response(50% improvement in IBS global symptoms) Global symptoms score(GSS) Adverse events |
| Kajander et al. (2008) | 2008 | Finland | D:45 C:30 A:25 |
Rome II | Primary care | 86 | 2/41 | 4/39 | 48 ± 13 | Combination | 1 × 107 | 20 weeks | Continuous scale for IBS symptoms | Global symptoms score Flatulence(a 5-point numerical scale) Distension(a 5-point numerical scale) abdominal pain(a 5-point numerical scale) Adverse events |
| Sinn et al. (2008) | 2008 | Korea | D:20 C:27.5 M:62.5 |
Rome III | Secondary care | 40 | 6/14 | 8/12 | 44.7 ± 13 | L. acidophilus SDC 2012 and 2013 | 4×109 | 4 weeks | Any reduction in abdominal pain score | Response(Any reduction in abdominal pain score) Abdominal pain(a 6-point numerical scale) Adverse events |
| Zeng et al. (2008) | 2008 | China | D:100 | Rome II | Tertiary care | 29 | 10/4 | 9/6 | 45.2 ± 10.7 | Streptococcus thermophilus, Lactobacillus bulgaricus, Lactobacillus acidophilus and Bifidobacterium Longum | S.thermophilus (4×1010 c.f.u.), L. bulgaricus (4×109 c.f.u.), L. acidophilus (4×109 c.f.u.), and B. longum (4×109 c.f.u.) |
4 weeks | Continuous scale for IBS symptoms | Global symptoms score Bloating(100-mm VAS) Abdominal pain(100-mm VAS) Adverse events |
| Agrawal et al. (2009) | 2009 | UK | C:100 | Rome III | Tertiary care | 34 | 0/17 | 0/17 | 39.4 ± 10.6 | Bifidobacterium lactis DN-173 010 Streptococcus thermophilus and Lactobacillus bulgaricus |
B. lactis DN-173 010(2.5×1010 c.f.u.), S.thermophilus (2.4×109 c.f.u.), L. bulgaricus (2.4×109 c.f.u.), |
4 weeks | Continuous scale for IBS symptoms | Global symptoms score Bloating(a 6-point numerical scale) Flatulence(a 6-point numerical scale) Abdominal pain(a 6-point numerical scale) |
| Enck et al. (2009) | 2009 | Germany | All types | Kruis score | Primary care | 298 | 76/72 | 75/75 | 49.6 ± 13.6 | E. coli DSM17252 | (1.5–4.5×107 c.f.u./ml) 0.75 ml drops t.i.d. for 1 week, then 1.5 ml t.i.d. for weeks 2–8 | 8 weeks | No longer having IBS symptoms | Response(no longer having IBS symptoms) General symptom score Adverse events |
| Hong et al. (2009) | 2009 | Korea | D:45.7 C:20 M:8.6 non-classified:25.7 |
Rome III | tertiary care | 70 | 25/11 | 22/12 | 37 ± 14.85 | Combination | 4×1010 | 8 weeks | Reduction of symptom score by at least 50% | Response(Reduction of symptom score by at least 50%) Adverse events |
| Williams et al. (2009) | 2009 | UK | D:11.5C:27 A:61.5 |
Rome II | Advertising | 52 | 3/25 | 4/20 | 39 ± 11.5 | Combination | 2.5×1010 | 8 weeks | Continuous scale for IBS symptoms | Global symptom score |
| Simrén et al. (2010) | 2010 | Sweden | D:35 C:15 M:50 |
Rome II | Tertiary care | 74 | 11/26 | 11/26 | 43 ± 15.43 | Combination | 2×1010 | 8 weeks | Adequate relief of their IBS symptoms at least 50% of the weeks | Response(Adequate relief of their IBS symptoms) Global symptom score Abdominal pain(100-mm VAS) Bloating(100-mm VAS) Adverse events |
| Choi et al. (2011) | 2011 | Korea | D:71.6 M:28.4 |
Rome II | Tertiary care | 90 | 18/17 | 19/20 | 40.4 ± 12.9 | Saccharomyces boulardii | 4×1011 | 4 weeks | Continuous scale for IBS symptoms | Global symptoms score(7-point Likert scale) Bloating(7-point Likert scale) Abdominal pain(7-point Likert scale) Adverse events |
| Guglielmetti et al. (2011) | 2011 | Germany | D:21.3 C:19.7 M:58.2 non-classified:0.8 |
Rome III | Secondary care and advertising | 122 | 19/41 | 21/41 | 38.9 ± 12.75 | B. bifidum MIMBb75 | 1×109 | 4 weeks | Improvement in average weekly global IBS symptom score of 1 or more for 50% of weeks, and continuous scale for IBS symptoms | Response(Improvement in average weekly global IBS symptom score of 1 or more for 50% of weeks) Global symptoms score(7-point Likert score) Bloating(7-point Likert scale) Abdominal pain(7-point Likert scale) Adverse events |
| Michail and Kenche (2011) | 2011 | USA | D:100 | Rome III | Tertiary care | 24 | 5/10 | 3/6 | 21.8 ± 17 | Combination | 9×1011 | 8 weeks | Continuous scale for IBS symptoms | Global symptoms score(a clinical rating scale GSRS) Bloating(GSRS) Abdominal pain(GSRS) Adverse events |
| Sondergaard et al. (2011) | 2011 | Denmark and Sweden | all types | Rome II | Primary and secondary care | 52 | 7/20 | 6/19 | 51.3± 9.5 | Combination | 2.5×1010 | 8 weeks | Adequate relief of IBS symptoms and continuous scale for IBS symptoms | Adequate relief of IBS symptoms Global symptoms score(IBS SSI Francis et al) Abdominal pain(100-mm VAS) |
| Cha et al. (2012) | 2012 | Korea | D:100 | Rome III | Tertiary care | 50 | 12/13 | 14/11 | 39.1 ± 11.76 | Combination | 1×1010 | 8 weeks | Adequate relief of their IBS symptoms at least 50% of the weeks and continuous scale for IBS symptoms |
Response(Adequate relief of their IBS symptoms at least 50% of the weeks) Global symptoms score(10-point VAS) Abdominal pain(10-point VAS) Bloating(10-point VAS) Adverse events |
| Cui et al. (2012) | 2012 | China | D:48.3 C:20 M:11.7 non-classified:10 |
Rome III | Tertiary care | 60 | 11/26 | 7/16 | 44.66 ± 15.23 | Combination | 1.5×107 | 4 weeks | reduction of symptom score by at least 30% | Improvement in IBS symptoms |
| Dapoigny et al. (2012) | 2012 | France | D:30 C:22 M:34 U:14 |
Rome III | Tertiary care | 50 | 5/20 | 10/15 | 47.05± 10.98 | Lactobacillus casei rhamnosus LCR35 | 6×108 | 4 weeks | IBS severity score reduced by at least 50% | Response (IBS severity score reduced by at least 50%) Adverse events |
| Ducrotte et al. (2012) | 2012 | India | all types | Rome III | Primary care | 214 | 70/38 | 81/25 | 37.28± 12.6 | L. plantarum LP299V DSM 9843 | 1×1011 | 4 weeks | Patients rated treatment efficacy as excellent or good | Global assessment of treatment efficacy Adverse events |
| Farup et al. (2012) | 2012 | Norway | D:37.5 C:6.25 A:56.25 |
Rome II | Secondary care | 28 | Not stated | Not stated | 50± 11 | L. plantarum MF 1298 | 1×1010 | 3 weeks | Continuous scale for IBS symptoms | Global symptoms score |
| Kruis et al. (2012) | 2012 | Germany | all types | Rome II | Tertiary care | 120 | 12/48 | 16/44 | 45.7± 12.4 | E. coli Nissle 1917 | 2.5–25×109 for 4 days then 5–50×109 for 12 weeks | 12 weeks | Patients reported contented with treatment | Response (Patients reported contented with treatment) Adverse events |
| Amirimani et al. (2013) | 2013 | Iran | all types | Rome III | Secondary care | 102 | 21/32 | 15/24 | 41.8± 12.5 | Lactobacillus reuteri | 1×1011 | 4 weeks | Continuous scale for IBS symptoms | Abdominal pain(questionare) Bloating(questionare) Adverse events |
| Begtrup et al. (2013) | 2013 | Denmark | D:40 C:19 M:38 U:2 |
Rome III | Primary care | 131 | 51/16 | 46/18 | 30.52± 9.42 | Combination | 5.2×1010 | 6 months | Adequate relief of global IBS symptoms for at least 50% of the time, and continuous scale for IBS symptoms | Response (Adequate relief of global IBS symptoms) Global symptoms score Abdominal pain(GSRS-IBS) Bloating(GSRS-IBS) Adverse events |
| Charbonneau et al. (2013) | 2013 | Ireland | all types | Rome II | Population based | 76 | 8/31 | 6/31 | 45.5± 11 | B. infantis 35624 | 1×109 | 8 weeks | Continuous scale for IBS symptoms | Global symptom severity(a six-point scale) Abdominal pain((a six-point numerical scale) Bloating(a six-point numerical scale) Adverse events |
| Roberts et al. (2013) | 2013 | UK | C and M | ROME III | Primary care | 179 | 13/75 | 14/77 | 44.18± 12.36 | Bifidobacterium lactis CNCM I-2494 S. thermophilus and L. bulgaricus |
2.5×1010
2.4×109 2.4×109 |
12 weeks | Subjective global assessment (SGA) of symptom relief | Subjective global assessment (SGA) of symptom relief IBS-SSS Abdominal pain(6 point Likert scale) Bloating(6 point Likert scale) |
| Abbas et al. (2014) | 2014 | Pakistan | D:100 | Rome III | Tertiary care | 72 | 27/10 | 26/9 | 35.4± 11.9 | Saccharomyces boulardii | 3×109 | 6 weeks | Continuous scale for IBS symptoms | Abdominal pain(a 4-point scale) Bloating(a 4-point scale) Adverse events |
| Jafari et al. (2014) | 2014 | India | all types | Rome III | Secondary care | 108 | 21/33 | 22/32 | 36.7± 11.5 | Combination | 8×109 | 4 weeks | Satisfactory relief of global IBS symptoms for at least 50% of the time | Relief of IBS symptoms Abdominal pain(100-mm VAS) Bloating(100-mm VAS) |
| Lorenzo-Zuniga et al. (2014) | 2014 | Spain | D:100 | Rome III | Tertiary care | 84 | 16/39 | 15/14 | 46.8± 12.5 | Combination | high dose (1-3×1010) low dose (3-6×109) |
6 weeks | “Considerably relieved” or “completely relieved” of global IBS symptoms for at least 50% of the time | Health-related quality of life(a specifc questionnaire ranging from 1-100) Respond(relief of symptoms) Adverse events |
| Ludidi et al. (2014) | 2014 | Netherlands | all types | Rome III | Secondary care and advertising | 40 | 6/15 | 7/12 | 40.5± 14.4 | Combination | 5×109 | 6 weeks | A 30% or greater improvement in mean symptom composite score(MSS) | Respond(mean symptom composite score MSS) |
| Pedersen et al. (2014) | 2014 | Denmark | D:38 C:17.3 A:40.7 non-classified:4 |
Rome III | Tertiary care | 81 | 14/27 | 11/29 | Not stated | Lactobacillus rhamnosus GG | 1.2×1010 | 6 weeks | Continuous scale for IBS symptoms | IBS-SSS |
| Shavakhi et al. (2014) | 2014 | Iran | D:32.6 C:45.7 A:21.7 |
Rome II | Tertiary care | 129 | 20/46 | 24/39 | 36.2± 9.2 | Combination | 2×108 | 2 weeks | Continuous scale for IBS symptoms | Abdominal pain(a 4-point scale) Distension(a 4-point scale) |
| Sisson et al. (2014) | 2014 | UK | D:37.6 C:21.5 M:35.5 U:5.4 |
Rome III | Primary care and secondary care | 186 | 40/84 | 17/45 | 38.3± 10.6 | Combination | 2×108/kg | 12 weeks | Patients reported mild or no symptoms | Respond(IBS-SSS) IBS symptom severity scores (IBS-SSS) Abdominal pain(IBS-SSS) Bloating(IBS-SSS) Adverse events |
| Stevenson et al. (2014) | 2014 | South Africa | D:37.6 C:21.5 |
Rome II | Secondary care | 81 | 2/52 | 0/27 | 47.9± 13 | Lactobacillus plantarum 299 v | 1×1010 | 8 weeks | Continuous scale for IBS symptoms | IBS symptom severity scores (IBS-SSS) Adverse events |
| Yoon et al. (2014) | 2014 | Korea | D:53.1 C40.8 M:6.1 |
Rome III | Tertiary care | 49 | 11/14 | 6/18 | 44.5± 14.3 | Combination | 1×1010 | 4 weeks | Global relief of IBS symptoms | Global relief of IBS symptoms Abdominal pain(a 10-point numerical scale) Bloating(a 10-point numerical scale) Adverse events |
| Faghihi et al. (2015) | 2015 | Iran | D:35.3 C39.6 M:25.1 |
Rome II | Secondary care | 139 | Not stated | Not stated | 38± 13.3 | Escherichia coli Nissle 1917 | Not stated | 6 weeks | Continuous scale for IBS symptoms | Global symptoms score(Birmingham IBS Symptom Questionnaire) |
| Pineton de Chambrun et al. (2015) | 2015 | France | D:28.5 C46.9 M:24.6 |
Rome III | Not stated | 179 | 14/72 | 11/82 | 44± 13.3 | Saccharomyces cerevisiae CNCM I-3856 | 4×109 | 8 weeks | A reduction in the abdominal pain score of 1 arbitrary unit (au) for at least 50% of the time | Improvement in IBS symptoms Abdominal pain(7-point Likert scale) Adverse events |
| Yoon et al. (2015) | 2015 | Korea | D:48.1 C:18.5 M:21 U:12.4 |
Rome III | Tertiary care | 80 | 24/17 | 19/20 | 59.3± 12.2 | Combination | 1×1010 | 4 weeks | Adequate relief of global IBS symptoms | Adequate relief of global IBS symptoms Global symptoms score(10-point VAS) Abdominal pain(10-point VAS) Bloating(10-point VAS) |
| Lyra et al. (2016) | 2016 | Finland | D:38.9 C:16.6 M:44 U:0.5 |
Rome III | Primary care | 391 | 62/198 | 37/94 | 47.9± 12.9 | L.acidophilus NCFM (ATCC 700396) | low-dose: 1×109
high-dose: 1×1010 |
12 weeks | Continuous scale for IBS symptoms | IBS symptom severity scores (IBS-SSS) Abdominal pain(IBS-SSS) Bloating(IBS-SSS) Adverse events |
| Majeed et al. (2016) | 2016 | India | D:100 | Rome III | Tertiary care | 36 | 7/11 | 10/8 | 35.8± 10.8 | Bacillus coagulans MTCC 5856 | 2×109 | 90 days | Continuous scale for IBS symptoms | Abdominal pain(Questionnaire) Bloating(Questionnaire) Adverse events |
| Mezzasalma et al. (2016) | 2016 | Italy | C:100 | Rome III | Not stated | 150 | Not stated | Not stated | 37.4± 12.5 | 1: L.acidophilus, L. reuteri 2: L.plantarum, L. rhamnosus, B. animalis subsp. Lactis |
1: 1×1010
2: 1.5×1010 |
60 days | A decrease of abdominal pain of at least 30% compared to the basal condition for at least 50% of the intervention time | Response(the subject reporting a decrease of symptoms of at least 30% compared to the basal condition for at least 50% of the intervention time) |
| Spiller et al. (2016) | 2016 | France | D:20.8 C47.5 M:31.7 |
Rome III | Primary care and secondary care | 379 | 31/161 | 31/156 | 45.3± 14.9 | Saccharomyces cerevisiae I-3856 | 8×109 | 12 weeks | An improvement of 50% of the weekly average''intestinal pain/discomfort score'' compared with baseline average score for at least 4 out of the last 8 weeks of the study | Response Global symptoms score Abdominal pain(8-point Likert scale) Bloating(8-point Likert scale) Adverse events |
| Thijssen et al. (2016) | 2016 | Netherlands | D:30 C:25 A:28.75 U:16.25 |
Rome II | Secondary care,tertiary care, and advertising | 80 | 13/26 | 12/29 | 41.8± 14.1 | Lactobacillus casei Shirota | 1.3×1010 | 8 weeks | An mean symptom score(MSS) decrease of at least 30% | Response (An mean symptom score(MSS) decrease of at least 30%) |
| Hod et al. (2017) | 2017 | Israel | D:100 | Rome III | Community and secondary and tertiary care | 107 | 0/54 | 0/53 | Not extractable | Combination | 5×1010 | 8 weeks | improvement in symptoms for at least 50% of the tme |
Response Adverse events |
| Ishaque et al. (2018) | 2018 | Bangladesh | D:100 | Rome III | Tertiary care | 360 | 136/45 | 145/34 | 31.9 ± 9.9 | Combination | 8×109 | 16weeks | Continuous scale for IBS symptoms | IBS symptom severity scores (IBS-SSS) Abdominal pain(IBS-SSS) Adverse events |
| Khodadoostan et al. (2018) | 2018 | Iran | D:100 | Rome III | Secondary care and tertiary care | 67 | 21/12 | 22/12 | 34.1 ± 11.0 | Combination | 2×109 | 6 months | Continuous scale for IBS symptoms | Abdominal pain(10-point VAS) |
| Kim et al. (2018) | 2018 | Korea | not stated | not stated | Advertising | 42 | 19/11 | 6/6 | 32.7 ± 6.6 | Lactobacillus gasseri BNR17 | low-dose: 1×109
high-dose: 1×1010 |
4 weeks | Continuous scale for IBS symptoms | Abdominal pain(5-point Likert scale) Bloating(5-point Likert scale) |
| Preston et al. (2018) | 2018 | USA | D:46.4 C:35.7 M:18.6 |
Rome III | Tertiary care | 113 | 47/29 | 21/16 | 40.4 ± 13.5 | Combination | 1×1011 | 6 weeks | Continuous scale for IBS symptoms | IBS symptom severity scores (IBS-SSS) Abdominal pain(IBS-SSS) Adverse events |
| Sun et al. (2018) | 2018 | China | D:100 | Rome III | Tertiary care | 200 | 63/42 | 53/42 | 43.9 ± 12.7 | Clostridium butyricum | 5.67×107 | 4 weeks | A reduction of ≥50 points of total IBS-SSS score | Response (A reduction of ≥50 points of total IBS-SSS score) IBS symptom severity scores (IBS-SSS) Abdominal pain(IBS-SSS) Bloating(IBS-SSS) Adverse events |