Meta-analysis of probiotics for the treatment of irritable bowel syndrome

Table 1 Description of 20 randomized, controlled trials of probiotics for IBS included in systematic review

Reference	Probiotic	Type of control	Number of subjects randomized	Number analyzed	Dose (cfu/d)	Duration of treatment (wk)	% attrition
Maupas[45]	Saccharomyces cerevisiae boulardii lyo	Placebo capsules	34	34	9 × 109	4	0
Gade[46]	Streptococcus faecium 40371	Placebo tablets	58	54	1 × 1012	4	7
Halpern[47]	L. acidophilus (heat killed)“Lacteol Fort”	Placebo capsules	29	18	2 × 1010	6	38
Nobaek[48]	Lactobacillus plantarum DSM9843, in rose hip drink	Placebo plain rose hip drink	60	52	5 × 107	4	13
O'Sullivan[49]	Lactobacillus rhamnosus GG	Placebo tablets	24	19	1 × 1010	8	21
Niedzielin[50]	Lactobacillus plantarum 299v, “ProViva” drink	Placebo drink	40	40	2 × 1010	4	0
Kim[51]	VSL#3 (mix of 8 strains) powder packet1	Placebo powder	25	25	9 × 1011	8	4
Bausserman[52]	Lactobacillus rhamnosus GG	Placebo capsules	58	50	2 × 1010	6	22
Bittner[53]	Prescript-assist® 29 soil strains and prebiotic “leonardite”	Placebo capsules	27	25	2.6 × 108	2	7
Kajander[54]	L. rhamnosus GG + L. rham. LC705 + Bifido. breve Bb99 +Prop. freudenreichii	Placebo capsules	103	81	8-9 × 109	24	21
Kim[55]	VSL#3 yogurt1	Placebo yogurt	48	48	8 × 109	4	0
Niv[56]	Lactobacillus reuteri 55730	Placebo capsules	54	39	2 × 108	24	28
O’Mahony[17]	L. salivaricus UCC4331	Placebo drink	54	51	1 × 1010	8	16
O’Mahony[17]	Bifido. infantis 35624	Placebo drink	53	49	1 × 1010	8	16
Kim[57]	B. subtilus + Strept. faecalis	Placebo capsules	40	34	3 × 1010	4	15
Simren[58]	L. plantarum 299v in rose hip drink	plain rose hip drink	66	58	2 × 109	6	12
Whorwell[35]	Bifido. infantis 35624 in 3 doses	Placebo capsules	362	292	1 × 106	4	19
					1 × 108
					1 × 1010
Enck[59]	E. coli + Strept faecalis drink	Placebo drink	297	264	4.5 × 102	8	11
Gawronska[60]	L. rhamnosus GG	Placebo capsules	37	37	6 × 109	4	0
Marteau[61]	Bifido. longum, Lact acidophilus, Lactococcus lactis, Strept. thermophilus	Placebo capsules	106	100	1 × 1010	4	6
Simren[62]	Lact. paracasei, Lact acidophilus, Bifido. lactis in yoghurt	Control milk	74	67	2 × 1010	8	9

IBS: Irritable bowel syndrome; cfu/d: Colony forming units per day; Bifido.: Bifidobacterium; B.: Bacillus; E.: Escherichia; L.: Lactobacillus; Prop.: Propionibacterium.

¹VSL#3 is a mixture of 8 probiotic strains (Lactobacillus casei, L. plantarum, L. acidophilus, L. bulgaricus, Bifido. longum, Bifido. breve, Bifido. infantis and Streptococcus thermophilus).

Table 2 Examples of excluded randomized, controlled trials of probiotics for IBS

Reference	Probiotic	Number of subjects randomized	Number of subjects analyzed	Dose (cfu/mL)	Duration	Exclusion reason
DiBaise[63]	L. plantarum 299v vs placebo	29	20	6 × 109	4 wk	Withdrawn by author
Saggioro[64]	L. plantarum + L. acidophilus	46	39	1 × 1011	4 wk	Quality score = 2.0
Saggioro[64]	L. plantarum + Bifido. breve	44	37	1 × 1010	4 wk	Quality score = 2.0
Long[65]	Bifido. (species not given)	60	60	6 × 109	2 wk	Quality score = 2.5
Kajander[66]	L. rhamnosus GG + L. rham. LC705 + Bifid. breve Bb99 +Prop. freudenreichii	103	83	8-9 × 109	6 mo	Duplicate study of Kajander K 2005
Bittner[67]	Prescript-assist®, 29 soil strains and prebiotic	24	24	2.6 × 108	Varied	Controls from Bittner 2005 study, phase 4 study
Moon[68]	Bacillus subtilis + St. faecium	34	34	750 mL/d, cfu/d not given	4 wk	Outcome data not provided for each group in abstract

cfu/mL: Colony forming units per milliliter; IBS: Irritable bowel syndrome; L.: Lactobacillus; Bifido.: Bifidobacterium.

Table 3 Quality scoring for 20 randomized, controlled trials of probiotics for IBS (Linde Internal Validity Scale)

Reference	Total quality score1	Treatment allocation	Randomization method	Baseline comparison	Patients blinded	Evaluators blinded	Handling and reporting of withdrawals/use of ITT	Data source2
Maupas[45]	6	1	1	1	1	1	1	Paper
Gade[46]	4.5	1	1	0	1	1	0.5	Paper
Halpern[47]	4	1	1	0.5	1	0.5	0	Paper
Nobaek[48]	3	1	0	0	1	0.5	0.5	Paper
O'Sullivan[49]	3	1	0	1	0.5	0.5	0	Author
Niedzielin[50]	4	1	0	1	1	0	1	Paper
Kim[51]	4.5	1	0	0.5	1	1	1	Paper
Bausserman[52]	5.5	1	1	1	1	1	0.5	Paper
Bittner[53]	3	1	0	0	0.5	0.5	1	Author
Kajander[54]	4.5	1	1	1	0.5	0.5	0	Paper
Kim[55]	4	1	0	1	1	0.5	0.5	Paper
Niv[56]	3.5	1	0	0.5	1	0.5	0.5	Paper
O’Mahony[17]	4.5	1	1	0	1	1	0.5	Paper
Kim[57]	4	1	0	1	0.5	0.5	1	Paper
Simren[58]3	3	1	0.5	0	1	0.5	0	Author
Whorwell[35]	3.5	1	0	0.5	1	0.5	0.5	Paper
Enck[59]3	4	1	0.5	0	1	0.5	1	Author
Gawronska[60]	4.5	1	1	0	1	0.5	1	Paper
Marteau[61]3	4.5	1	0.5	1	1	0.5	0.5	Author
Simren[62]3	3.5	1	0.5	0	1	0	1	Author

¹Linde Internal Validity Scale score is based on columns 3-8; range, 0 (poor) to 6 (excellent). (Linde 1996)[29];

²Indicates whether additional contact with authors was required to obtain information needed for quality scoring;

³Data from published meeting abstract only.

Table 4 Outcome assessment and reporting for 20 included clinical trials of probiotics for IBS

	Outcome
Reference	Global response	Abdominal pain	Bloating/distension	Flatulence	Stool frequency	Mucous	Stool consistency	Dyspepsia
Maupas[45]	R	R	R		R		R	R
Gade[46]	R	R	R	R			R
Halpern[47]	R	A	A		A	A	A
Nobaek[48]	R	R		R	A		R
O’Sullivan[49]		R	R	A	R		A
Niedzielin[50]	R	R		R	A		A
Kim[51]	R	R	R	R	R		R
Bausserman[52]	A	R	R	A			A
Bittner[53]		A		A				A
Kajander[54]	R	R	R	R	R	A	A
Kim[55]		R	R	R	R		R
Niv[56]		R	R	R	A
O’Mahony[17]	R	R	R		A		R
Kim[57]		R	A	A	A		A
Simren[58]	R	A	A	A	A	A	A
Whorwell[35]	R	R	R	R	A
Enck[59]	R	R	A		A		A
Gawronska[60]		R
Marteau[61]	R	R			A		A
Simren[62]	R	A	A
Percent reporting	65%	80%	50%	40%	25%	0	30%	5%

A: Assessed; R: Reported in sufficient detail to allow extraction of data. Bold font indicates that this was the primary outcome identified by the authors for analysis. If author reported no difference between active and placebo groups for a given symptom, but did provide further details, the outcome was classified as assessed only.

Table 5 Global Improvement in IBS Symptoms in 14 probiotic/placebo treatment arms

Reference	Probiotic	Global improvement in IBS symptoms		Definition of primary outcome1
		Probiotic n/n (%)	Placebo n/n (%)
Maupas[45]	Saccharomyces cerevisiae boulardii lyo	13/16 (81)	13/18 (72)	Improvement of symptoms
Gade[46]	Strept faecalis	26/32 (81)	9/22 (41)	Improvement of symptoms based on physician assessment
Halpern[47]	L. acidophilus	17/18 (94)	13/18 (72)	Absence of symptoms
Nobaek[48]	L. plantarum	11/25 (44)	7/27 (26)	Decrease ≥ 1.5 on VAS symptom scale
Niedzielin[50]	L. plantarum	9/20 (45)	3/20 (15)	Absence of symptoms
Kim[51]	VSL#32	4/12 (34)	5/13 (38)	Satisfactory relief of IBS symptoms
Kajander[54]	L. rhamnosus GG + L. rham. LC705 + Bifid. breve Bb99 + Prop. freudenreichii	31/41 (76)	17/40 (43)	Symptoms alleviated based on significant reduction of symptom scores
Simren[58]	L. plantarum	10/29 (35)	11/29 (38)	Reduction ≥ 50% of total symptom score
Whorwell[35]	Bifido. infantis (dose, 106 cfu/mL)	33/74 (44)	32/76 (42)	Adequate relief of symptoms
Whorwell[35]	Bifido. infantis (dose, 108 cfu/mL)	45/72 (62)	32/76 (42)	Adequate relief of symptoms
Whorwell[35]	Bifido. infantis (dose, 1010 cfu/mL)	26/71 (37)	32/76 (42)	Adequate relief of symptoms
Enck[59]	E. coli + Strept faecalis	102/149 (68)	56/148 (38)	Reduction of ≥ 50% in total symptom score
Marteau[61]	Bifido. longum, L. acidophilus, Lactococcus lactis, Strept thermophilus	20/47 (42.6)	22/52 (42.3)	Relief of discomfort
Simren[62]	L. paracasei, L. acidophilus, Bifido. lactis in yoghurt	14/33 (42)	17/34 (50)	Reduction of ≥ 50% in total symptom score

¹Unless otherwise stated, all primary outcomes are defined based on patient report.

²VSL#3 is a mixture of 8 probiotic strains (Lactobacillus casei, L. plantarum, L. acidophilus, L. bulgaricus, Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium infantis and Streptococcus thermophilus).

Table 6 Relief of abdominal pain in 11 probiotic/placebo treatment arms

Reference	Probiotic	Improvement in abdominal pain		Definition of secondary outcome1
		Probiotic n/n (%)	Placebo n/n (%)
Gade[46]	Strept faecalis	25/32 (78)	10/22 (45)	Absence or presence of symptom
Nobaek[48]	L. plantarum	9/25 (36)	5/27 (18)	Decrease ≥ 1.5 on VAS symptom scale
O'Sullivan[49]	L. rhamnosus GG	9/19 (47)	12/19 (63)	Symptom improved
Niedzielin[50]	Lacto plantarum	20/20 (100)	11/20 (55)	Absence of symptoms
Bausserman[52]	Lacto rhamnosus GG	11/25 (44)	10/25 (40)	Decrease of ≥ 1 point symptom score
Kajander[54]	L. rhamnosus GG + L. rham. LC705 + Bifid. breve Bb99 +Prop. freudenreichii	27/41 (66)	17/40 (43)	Symptoms alleviated
Whorwell[35]	Bifido. infantis (106 dose)	32/74 (43)	39/76 (52)	Adequate relief of symptoms
Whorwell[35]	Bifido. infantis (108 dose)	42/72 (59)	39/76 (52)	Adequate relief of symptoms
Whorwell[35]	Bifido. infantis (1010 dose)	28/71 (39)	39/76 (52)	Adequate relief of symptoms
Enck[59]	E. coli + Strept faecalis	108/149 (72)	66/148 (45)	≥ 50% decrease in symptom score
Gawronska[60]	Lacto rhamnosus GG	6/18 (33)	1/19 (5)	Absence of pain

¹All secondary outcomes are defined based on patient report.

Table 7 Recommendations for future research studies examining probiotics as a treatment for irritable bowel syndrome

Recommendations
More trials testing the same probiotic strain
Larger sample size
Longer duration of treatment and follow-up
Intention to treat analysis:
All participants analyzed with the group to which they were originally assigned, regardless of compliance with treatment, response to treatment, or use of prohibited (non-study) medications.
Greater efforts to minimize loss to follow-up
Standardized assessment of IBS outcomes
Provide some assessment of global relief of IBS symptoms
Detailed collection and reporting of data on potential adverse reactions