Probiotics in Helicobacter pylori eradication therapy: A systematic review and meta-analysis

Table 1 Baseline characteristic of studies included in the systematic review and meta-analysis

Study	Patients (n)	Age (yr)	Methods of diagnosis	Methods of assessment	Probiotic regimens	Eradication therapy regimens and dosage (mg/d)1
Navarro-Rodriguez et al[39], 2013	107	Adults	UBT + HA + Giemsa + RUT	UBT + HA + Giemsa + RUT	Lacto + Bifido + Strep	400F + 60La/60M + 1000Te
Ahmad et al[40], 2013	66	Children	RUT/HA	HpSA	Lacto + Bifido + Strep	3000A + 360F + 60M
Shavakhi et al[41],2013	180	Adults	RUT/HA	UBT	Lacto + Bifido + Strep	2000A + 480B + 1000C + 40M
Kyriakos et al[42], 2013	70	Adults	RUT + HA	UBT	Saccha	2000A + 1000C + 40M
Jiang et al[43], 20132	80	Adults	RUT + Giemsa	UBT	Bacillus	2000A + 60La + 3000Le
Dajani et al[44], 20132	301	Both	UBT/RUT/HA/HpSA	UBT	Bifido	2000A + 1000C/800Me + PPI
Deguchi et al[45], 2012	229	Adults	Culture/(HA + RUT)	(UBT + HpSA) + Culture	Lacto	1500A + 400C + 20R
Tolone et al[46], 2012	68	Children	UBT + HA	UBT	Lacto + Bifido + Strep	6000A + 1800C + 60M
Mirzaee et al[47], 20122	102	Adults	UBT	UBT	NM	2000A + 1000C + 40P
Manfredi et al[48], 20122	227	Adults	RUT/HpSA	HpSA	Lacto + Bifido + Strep	2000A + 1000C + 40E + 1000Ti
Du et al[49], 20122	234	Adults	UBT/RUT/Giemsa	UBT	Lacto + Bacillus + Strep	2000A + 1000C + 40M
Bekar et al[50], 2011	82	Adults	UBT	UBT	Lacto + Bifido	2000A + 1000C + 60La
Yoon et al[51], 2011	337	NM	UBT/RUT/HA	UBT	Lacto + Bifido + Strep	2000A + 1000C + 80E
He et al[52], 2011	84	Adults	UBT + RUT	UBT + RUT	Lacto + Bifido + Entero	2000A + 1000C + (40-60)R + 1000Ti
Xu et al[53], 2010	120	NM	(UBT/RUT) + HA	UBT	Lacto + Bifido + Entero	2000A + (20-40)E + 200F
Yaşar et al[54], 2010	76	Adults	HA	UBT	Bifido	2000A + 1000C + 80P
Wen et al[55], 2010	200	NM	UBT + RUT	UBT	Lacto + Bifido + Entero	2000A + 40P + 800Ti
Song et al[56], 20102	991	Adults	RUT/HA	UBT	Saccha	2000A + 1000C + 40M
Szajewska et al[57], 2009	83	Children	2 of (UBT, RUT, HA)	UBT	Lacto	3000A + 1200C + 60M
Hurduc et al[58], 2009	90	Children	RUT + HA	RUT + HA	Saccha	3000A + 1800C + 60E/60M
Francavilla et al[59], 2008	40	NM	3 of (UBT, RUT, HA, HpSA)	UBT + HpSA	Lacto	2000A + 1000C + 40R + 1000Ti (sequential)
Kim et al[60], 2008	347	Adults	UBT/RUT/HA	UBT	Lacto + Bifido + Strep	2000A + 1000C + PPI
Huang et al[61], 2008	120	NM	UBT + RUT	UBT	Lacto + Bifido + Entero	1000C + (20-40)E/(20-40)R + 1000Rn
Imase et al[62], 20082	19	NM	NM	NM	Clost	1500A + 800C + 60La
Cindoruk et al[63], 2007	124	Adults	HA + Giemsa	UBT	Saccha	2000A + 1000C + 60La
Park et al[64], 2007	352	Adults	HA	UBT	Bacillus + Strep	2000A + 1000C + 40M
de Bortoli et al[65], 2007	206	NM	HA/(UBT + HpSA)	UBT	Lacto + Bifido + Strep	2000A + 1000C + 40E
Sahagún-Flores et al[66], 2007	71	Adults	HA	UBT	Lacto	2000A + 1000C + 40M
Lionetti et al[67], 2006	40	Children	2 of (UBT, RUT, HA)	UBT	Lacto	3000A + 900C + 60M + 1200Ti (sequential)
Goldman et al[68], 2006	65	Children	UBT	UBT	Lacto + Bifido	3000A + 900C + 60M
Sheu et al[69], 2006	138	NM	UBT + HA	UBT	Lacto + Bifido + Strep	2000A + 360B + 40M + 1000Me
Ziemniak et al[70], 20062	245	Adults	UBT	UBT	Lacto	2000A + 1000C + 80P
Sýkora et al[71], 2005	86	Children	2 of (RUT, HA, culture) + HpSA	UBT + HpSA	Lacto	3000A + 900C + (1200-2400)M
Myllyluoma et al[72], 2005	47	Adults	UBT + EIA	UBT	Lacto + Bifido + Propionibacterium	2000A + 1000C + 60La
Duman et al[73], 2005	389	NM	UBT + HA	NM	Saccha	2000A + 1000C + 40M
Shimbo et al[74], 2005	35	NM	RUT + Culture	UBT	Clost	3000A + 800C + 120La
Cao et al[75], 2005	128	NM	UBT + RUT	UBT + RUT	Lacto + Bifido + Entero	2000A + 300B + 40M + 800Me
Nista et al[76], 2004	106	Adults	UBT	UBT	Bacillus	2000A + 1000C + 40R
Tursi et al[77], 2004	70	NM	RUT + HA	UBT	Lacto	3000A + 800B + 40E/40P + 1000Ti
Guo et al[78], 2004	97	Adults	RUT + HA	UBT	Clost	1000A + 200F + 40M
Sheu et al[79], 2002	160	NM	(RUT/HA) + UBT	UBT/RUT/HA	Lacto + Bifido	2000A + 1000C + 60La
Cremonini et al[80], 20022	85	Adults	UBT	UBT	Lacto	1000C + 40R + 1000Ti
Armuzzi et al[81], 2001a	60	Adults	UBT + EIA	UBT	Lacto	1000C + 40R + 1000Ti
Armuzzi et al[82], 2001b	120	Adults	UBT + EIA	UBT	Lacto	1000C + 80P + 1000Ti
Canducci et al[83], 2000	120	NM	UBT + HA	UBT + HA	Lacto	1500A + 750C + 40R

¹“400F + 60L + 1000Te” means “Furazolidon 400 mg/d, lansoprazole 60 mg/d, and tetracycline 1000 mg/d”. Patient’s weight were assumed as 60 kg to calculate the exact dosage if only the dosage per kg were available in the article;

²These articles were designed with multiple arms, but only relevant groups were combined and included in this meta-analysis. UBT: Urea breath test; RUT: Rapid urease test; HA: Histological assessment; Giemsa: Giemsa staining; HpSA: H. pylori stool antigen test; EIA: Enzyme-linked immunosorbent Assay; Culture: Culture test; Lacto: Lactobacillus; Bifido: Bifidobacterium; Strep: Streptococcus; Saccha: Saccharomyces; Entero: Enterococcus; Clost: Clostridium; A: Amoxicillin; B: Bismuth subcitrate; C: Clarithromycin; E: Esomeprazole; F: Furazolidon; La: Lansoprazole; Le: Levofloxacin; M: omeprazole; Me: Metronidazole; P: Pantoprazole; PPI: Proton pump inhibitor; R: Rabeprazole; Rn: Ornidazole; Ti: Tinidazole; Te: Tetracyline; NM: Not mentioned.

Table 2 Effect of probiotics plus standard therapy vs standard therapy on adverse events

Adverse Event	Trials (n)	Participants (n)	Probiotics group, %	Control group	RR and 95%CI	P value	Heterogeneity (P value)
Diarrhea	26	4935	5.71%	13.72%	0.41 (0.30-0.57)	< 0.001	58% (P < 0.001)
Nausea/vomiting	23	4067	6.95%	12.83%	0.60 (0.48-0.76)	< 0.001	23% (P = 0.16)
Epigastric discomfort	8	1806	6.09%	14.13%	0.57 (0.44-0.74)	< 0.001	0% (P = 0.60)
Abdominal bloating	13	1516	10.82%	14.51%	0.70 (0.55-0.90)	0.005	0% (P = 0.53)
Abdominal pain	10	1373	8.40%	13.05%	0.54 (0.35-0.83)	0.005	31% (P = 0.16)
Constipation	13	2021	3.96%	6.73%	0.55 (0.37-0.81)	0.002	0% (P = 0.77)
Taste disturbance	19	3611	11.79%	18.76%	0.63 (0.48-0.83)	< 0.001	73% (P < 0.001)

RR: Risk ratio.

Table 3 Subgroup analyses comparing the effect of probiotics plus standard therapy vs standard therapy on eradication rate based on intention-to-treat

Subgroups	Studies (n)	Patients (n)	Probiotics group	Control group	RR and 95%CI	P value	P value for Q statistics
Age
Adults	23	4116	81.86%	73.23%	1.12 (1.09-1.16)	< 0.001	0.224
Children	7	498	76.89%	64.78%	1.19 (1.07-1.32)	0.002	0.535
Probiotic strains
Multiple	22	3598	83.29%	73.73%	1.12 (1.08-1.17)	< 0.001	0.046
Single	21	2908	81.60%	70.60%	1.16 (1.11-1.21)	< 0.001	0.724
Dosage of probiotics (CFU/d)
≥ 5 × 109	15	2470	82.84%	73.06%	1.13 (1.08-1.18)	< 0.001	0.571
< 5 × 109	21	3283	81.49%	70.69%	1.14 (1.09-1.20)	< 0.001	0.046
Duration of probiotic intake
≥ 15 d	17	3411	81.15%	71.35%	1.14 (1.10-1.18)	< 0.001	0.976
< 15 d	24	2585	82.30%	71.28%	1.12 (1.06-1.18)	< 0.001	0.022
Duration of standard therapy
> 7 d	17	2050	81.79%	74.32%	1.11 (1.06-1.17)	< 0.001	0.167
= 7 d	27	4558	82.39%	70.97%	1.16 (1.12-1.20)	< 0.001	0.502
Duration between therapy ending and assessment
> 4 wk	20	2520	83.86%	73.36%	1.16 (1.11-1.21)	< 0.001	0.282
= 4 wk	22	3984	80.78%	70.91%	1.14 (1.10-1.18)	< 0.001	0.358
Probiotic (containing the following strains)
Lactobacillus	31	4165	82.67%	73.05%	1.14 (1.10-1.18)	< 0.001	0.088
Bifidobacterium	20	3059	82.66%	71.69%	1.14 (1.10-1.19)	< 0.001	0.058
Streptococcus	11	2262	81.47%	72.65%	1.11 (1.06-1.17)	< 0.001	0.085
Saccharomyces	4	1275	81.14%	69.94%	1.15 (1.08-1.24)	< 0.001	0.594
Bacillus	4	772	80.71%	69.74%	1.17 (1.08-1.28)	< 0.001	0.408
Enterococcus	5	652	87.30%	73.29%	1.17 (1.06-1.30)	0.003	0.046
Clostridium	3	151	93.06%	86.08%	1.08 (0.97-1.21)	0.164	0.456
Therapy regimens
First-line	16	3474	81.02%	71.00%	1.13 (1.08-1.17)	< 0.001	0.260
Second-line	3	435	88.63%	81.11%	1.08 (1.00-1.17)	0.058	0.185
Not specified	25	2699	82.67%	72.25%	1.18 (1.13-1.23)	< 0.001	0.268