The Role of Probiotic Lactic Acid Bacteria and Bifidobacteria in the Prevention and Treatment of Inflammatory Bowel Disease and Other Related Diseases: A Systematic Review of Randomized Human Clinical Trials

Table 1

Summary of randomized clinical intervention trials of probiotics in IBD.

	Reference	Type of study	Number of patients	Age of patients (years)	Characteristics of patients	Probiotic strain	Medication	Intervention time/dose	Form of administration	Main outcome
Crohn’s disease (CD)	Prantera et al., 2002 [50]	RDBPCT	45	22–71	Patients with a complete resection of all diseased intestine	Lactobacillus rhamnosus GG	No	365 d/6 10^10 CFU twice daily	Oral	No effects compared with placebo group
	Schultz et al., 2004 [51]	RDBPCT	11	—	Patients with moderate to active CD	Lactobacillus rhamnosus GG	Yes	183 d/2 10^9 CFU per day	Oral	No effects compared with placebo group
	Bousvaros et al., 2005 [52]	RDBPCT	75	5–21	Patients on CD remission	Lactobacillus rhamnosus GG	Yes	730 d/1 10^10 CFU twice daily	Oral	No effects compared with placebo group
	Marteau et al., 2006 [53]	RDBPCT	98	27–42	Patients that had undergone surgical resection	Lactobacillus. johnsonii LA1	Yes	183 d/2 10^9 CFU twice daily	Oral	No effects compared with placebo group
	van Gossum et al., 2007 [54]	RDBPCT	70	18–65	Patients with an elective ileocaecal resection	Lactobacillus johnsonii LA1	No	84 d/1 10^10 CFU per day	Oral	No effects compared with placebo group
	Chermesh et al., 2007 [56]	RDBPCT	30	25 (mean age)	Patients that had undergone surgery treatment	^*Synbiotic 2000	Yes	730 d/1 10^10 CFU per day	Oral	No effects compared with placebo group
	Fujimori et al., 2007 [55]	CS	10	27 (mean age)	Patients with active CD	^*Synbiotic therapy	Yes	395 d/7.5 10^10 CFU per day and 3.3 g of psyllium thrice daily	Oral	Synbiotic therapy was safely and effectively used to treat active CD
	Steed et al., 2010 [57]	RDBPCT	35	18–79	Patients with active CD	Bifidobacterium longum plus ^*Synergy 1	Yes	183 d/2 10^11 viable CFU and 6 g Synergy I twice daily	Oral	Synbiotic improved clinical symptoms in patients with active CD
Ulcerative colitis (UC)	Ishikawa et al., 2003 [60]	RCT	21	39–60	Patients on UC remission	^*BFM	Yes	365 d/1 10^10 CFU per day	Oral	BFM supplementation successfully maintained remission
	Kato et al., 2004 [62]	RPCT	20	32 (mean age)	Patients with active UC	^*BFM	Yes	84 d/1 10^10 CFU per day	Oral	BFM supplementation was more effective than conventional treatment alone
	Tursi et al., 2004 [75]	RCT	90	19–69	Newly diagnosed or recently relapsed mild to moderate UC	^*VSL#3	Yes	56 d/3 10^11 CFU per day	Oral	Balsalazide/VSL#3 was significantly superior to balsalazide alone and to mesalazine in obtaining remission
	Cui et al., 2004 [65]	RCT	30	—	Patients with active UC	^*BIFICO	Yes	56 d/1.26 g per day	Oral	BIFICO administration impeded the activation of NF-B and elevated the expression of IL-10
	Furrie et al., 2005 [71]	RCT	18	24–67	Patients with active UC	Bifidobacterium longum plus ^*Synergy 1	Yes	28 d/2 10^11 CFU and 6 g of Synergy 1 twice daily	Oral	Short-term treatment improved the full clinical appearance of chronic inflammation in patients with active UC
	Zocco et al., 2006 [67]	ROLT	187	33 (mean age)	Patients on UC clinical remission	Lactobacillus. GG	Yes	365 d/6 10^9 CFU twice daily	Oral	Lactobacillus  GG was not inferior to mesalazine and was significantly better at delaying relapses
	Fujimori et al., 2009 [72]	RCT	120		Patients on remission or with mildly active UC without a history of operation for UC	Bifidobacterium longum plus psyllium	Yes	28 d/2 10^9 CFU per day and 4 g of psyllium twice daily	Oral	Synbiotic treatment improved the quality of life better than probiotic or prebiotic treatment
	Miele et al., 2009 [23]	RDBPCT	29	1.7–16.1	Children newly diagnosed with UC	^*VSL#3	Yes	365 d/4.5 10^11–1.8 10^12 CFU per day	Oral	VSL#3 was safe and effective in children treated for active UC^**
	Hegazy and El-Bedewy, 2010 [68]	RCT	45	47 (mean age)	Mild to moderate UC patients with chronic diarrhea	^*Lacteol	Yes	56 d/1 10^10 CFU per day	Oral	Supplementation with probiotics could be advantageous in preventing relapse of UC and maintaining remission
	Tursi et al., 2010 [61]	RDBPCT	131	47 (mean age)	Patients with mild to moderate relapsing UC	^*VSL#3	Yes	56 d/1.8 10^12 CFU twice daily	Oral	VSL#3 administration reduced the UCDAI scores in patients affected by relapsing mild-to-moderate UC
	D’Incà et al., 2011 [70]	RCT	26	—	Patients with mild left-side UC	Lactobacillus casei DG	Yes	56 d/8 10^8 CFU twice daily	Oral and rectal	5-ASA plus rectally administered probiotic modified the colonic microbiota, reduced the expression of TLR-4,  IL-1β, and increased IL-10 mRNA
	Wildt et al., 2011 [64]	RDBPCT	32	≥18	Patients with UC in remission	^*Probio-Tec AB-25	No	364 d/2.5 10^10 CFU per day	Oral	Probio-Tec AB-25 was well tolerated
	Ishikawa et al., 2011 [73]	RCT	41	45.5 (mean age)	Patients with mild to moderate UC	Bifidobacterium breve strain Yakult plus GOS	Yes	365 d/1 10^9 CFU thrice a day and 5.5 g of GOS once a day	Oral	Synbiotic administration can improve the clinical condition
	Oliva et al., 2012 [69]	RCT	31	7–18	Patients with mild to moderate UC	Lactobacillus reuteris ATCC 55730	Yes	61 d/1 10^10 CFU per day	Rectal enema	Rectal infusion decreased the expression of proinflammatory cytokines and increased the expression of IL-10 in children

5-ASA: 5-aminosalicylic acid; BFM: bifidobacteria-fermented milk; CFU: colonic forming unit; CS: clinical study; d: days; GOS: galactooligosaccharide; IBS: irritable bowel syndrome; IL: interleukin; NF-κB: nuclear factor kappa B; OPUM: open-label prospective uncontrolled multicenter study; RCT: randomized clinical trial; RDBPCT: randomized double-blind placebo-controlled trial; ROLT: randomized open-label trial; RPCT: randomized placebo-controlled trial, TLR: toll-like receptor; UCDAI: ulcerative colitis disease activity index.
^*Description of the bacterial and prebiotic contents of each product Synbiotic 2000: Pediococcus pentosaceus, L. raffinolactis, L. paracasei subsp. paracasei 19, and L. plantarum 2362 (10¹⁰ CFU of each bacteria) and -glucans, inulin, pectin, and resistant starch (2.5 g of each fermentable fiber). Synbiotic therapy: Bifidobacterium breve and Lactobacillus casei (3 10¹⁰ CFU/daily of each bacteria) and 1.5 10¹⁰ CFU/daily of Bifidobacterium longum plus 3.3 g of psyllium twice daily. Synergy I: Orafti, Tienen, Belgium. BFM: live Yakult strains of Bifidobacterium breve, Bifidobacterium bifidum, and Lactobacillus acidophilus YIT 0168 in at least 10⁹ per 100 mL bottle. VSL#3: Lactobacillus casei, Lactobacillus plantarum, Lactobacillus acidophilus and Lactobacillus delbrueckii subsp. bulgaricus, Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium infantis, Streptococcus salivarius subsp. thermophilus, and cornstarch. BIFICO: bifid triple viable capsule (oral capsules of live enterococci, bifidobacteria, and lactobacilli). Lacteol: 1 10¹⁰ CFU of Lactobacillus delbrueckii and Lactobacillus fermentum. Probio-Tec AB 25: Lactobacillus acidophilus strain LA-5 and Bifidobacterium animalis subsp. lactis strain BB-12 (1.25 10¹⁰ of each bacteria). Synbiotic zir fos: Bifidobacterium longum W11 (5 10⁹ CFU) and Fos-Actilight (2.5 g). ^**Relative Risk of relapse within 1 year of follow-up (RR: 0.32 CI: 0.025–0.773).