Probiotic mixture VSL#3: An overview of basic and clinical studies in chronic diseases

Table 1 Trials assessing the effect of VSL#3 in patients with diarrhea-predominant enteritis

Ref.	Design	n	VSL#3 intake
Delia et al[40], 2002	Not mentioned	190 patients receiving radiotherapy on the pelvic area (including 95 who received radiotherapy alone and 95 treated with VSL#3)	6 to 7 wk with one bag three times/d
Delia et al[39], 2007	RCT	490 with postoperative radiation therapy	1 sachet (4.5 × 1011 viable lyophilized bacteria/g) three times a day starting from the first day of radiation therapy until the end of radiation therapy
Dubey et al[44], 2008	RCT	230 rotavirus-positive acute diarrhea children; 224 children completed the study (113 in the VSL#3 group and 111 in the placebo group)	4 d, < 5 kg children, 2 sachets a day; 5 to 10 kg children, 4 sachets a day; each sachet of VSL#3 contained 9 × 1010 bacteria
Frohmader et al[46], 2010	RCT	45 who needed enteral nutrition for more than 3 d (including 20 intervention and 25 control)	Not clear
Selinger et al[37], 2013	RCT	229 exposed to systemic antibiotics (including 117 with VSL#3 and 112 with placebo)	1 sachet (4.5 × 1011 live bacteria per sachet) twice a day during the antibiotic course and for a further 7 d
Lacouture et al[47], 2016	Randomized, multicenter, triple cohort, phase II trial	Patients with advanced NSCLC treated with dacomitinib were enrolled in two cohorts (cohort I: 114 patients, including 56 in the doxycycline group, 58 in the placebo group; cohort II: 59 patients with VSL#3 plus topical alclometasone)	5 wk with 4 capsules once daily (patients in the United States) or 1 sachet daily (patients in South Korea) in cohort II

RCT: Randomized controlled trial; NSCLC: Non-small-cell lung cancer.

Table 2 Trials assessing the effect of VSL#3 in patients with irritable bowel syndrome

Ref.	Design	n	VSL#3 intake
Bazzocchi et al[49], 2002	Open non-controlled trial	42 with diarrhea-predominant IBS	3 g (3 × 1011 cells/g), administered to each patient in the morning, in fasting conditions, for 20 d
Kim et al[50], 2003	RCT	25 with diarrhea-predominant IBS (including 13 with placebo and 12 with VSL#3)	8 wk with 4.5 × 1011 lyophilized bacteria a day
Kim et al[51], 2005	RCT	48 with IBS and significant bloating (including 24 with placebo and 24 with VSL# 3)	Twice a day (31 patients received 4 wk and 17 patients received 8 wk), the daily dose was not clear
Guandalini et al[53], 2010	RCT	59 children completed the study	6 wk with 1 sachet of VSL#3 (once a day for children 4 to 11 yr old; twice a day for those 12 to 18 yr old)
Vicari et al[60], 2014	Not clear	106 infertile male patients with CBP and IBS; 95 completed	6 to 12 mo with 4.5 × 1011 CFU a day following rifaximin
Wong et al[52], 2015	RCT	42 with IBS (including 20 with VSL#3 and 22 with placebo)	6 wk with 4 capsules (each capsule contained 1.125 × 1011 viable lyophilized bacteria) twice a day
Vicari et al[59], 2017	Not mentioned	85 patients with CP/CPPS (45 with subtype IIIa and 40 with subtype IIIb) plus diarrhea-predominant IBS and 75 patients with diarrhea-predominant IBS alone	4.5 × 1011 CFU a day following rifaximin, the number of days was not clear

IBS: Irritable bowel syndrome; CFU: Colony-forming unit; RCT: Randomized controlled trial; CBP: Chronic bacterial prostatitis; CP: Chronic prostatitis; CPPS: Chronic pelvic pain syndrome.

Table 3 Trials assessing the effect of VSL#3 in patients with ulcerative colitis

Ref.	Design	n	VSL#3 intake
Venturi et al[66], 1999	Not mentioned	20 with UC who were intolerant or allergic to 5-ASA	12 mo with 3 g, 5 × 1011 cells/g, twice a day
Tursi et al[70], 2004	Multicenter, randomized trial	90 with newly diagnosed or recently relapsed mild-to-moderate UC	8 wk with 3 g a day, 1 g bags contained 3 × 1011 viable lyophilized bacteria
Bibiloni et al[71], 2005	Open-label trial	34 ambulatory patients with active UC; 32 patients completed	6 wk with 3.6 × 1012 bacteria a day in two divided doses
Soo et al[72], 2008	Not mentioned	15 patients with UC	5 wk with 1 sachet (containing 9 × 1011 lyophilized bacteria) twice a day
Sood et al[68], 2009	RCT	147 with active mild-to-moderate UC (including 77 with VSL#3 and 70 with placebo)	12 wk with 3.6 × 1012 CFU twice a day
Huynh et al[74], 2009	Open-label study	18 patients between ages of 3 and 17 with mild-to-moderate acute UC	One dose of VSL#3 sachet containing 4.5 × 1011 viable lyophilized bacteria; patients were treated twice daily for 8 wk with a dose of VSL#3 based on their age, range: one-half sachet to two and one-half sachets
Miele et al[73], 2009	RCT	29 consecutive patients (mean age: 9.8 yr; range: 1.7 to 16.1 yr) with newly diagnosed UC (VSL#3 group: n = 14; placebo group: n = 15)	Weight-based dose, range: 4.5 × 1011 to 1.8 × 1012 bacteria a day, the treatment time was not clear
Tursi et al[67], 2010	RCT	144 with relapsing UC (including 71 with VSL#3 and 73 with placebo); 65 patients with VSL#3 and 66 with placebo completed	8 wk with 3.6 × 1012 CFU a day

UC: Ulcerative colitis; CFU: Colony-forming unit; RCT: Randomized controlled trial; 5-ASA: 5-aminosalicylic acid.

Table 4 Trials assessing the effect of VSL#3 in patients with pouchitis

Ref.	Design	n	VSL#3 intake
Gionchetti et al[91], 2000	RCT	40 patients in clinical and endoscopic remission of pouchitis	9 mo with 6 g, 5 × 1011 viable lyophilized bacteria/g, a day
Gionchetti et al[14], 2003	RCT	40 patients undergoing IPAA for UC (including 20 with VSL#3 and 20 with placebo)	12 mo with 9 × 1011 bacteria a day
Mimura et al[90], 2004	Not clear	36 with pouchitis: 20 with VSL#3 and 16 with placebo	12 mo with 6 g a day, 3 × 1011 bacteria/g
Shen et al[93], 2005	Not mentioned	31 patients with antibiotic-dependent pouchitis	8 mo with 6 g/d
Kühbacher et al[12], 2006	RCT	15 patients with pouchitis: 10 with VSL#3 and 5 with placebo	12 mo with 6 g, 3 × 1011 viable lyophilized bacteria/g, once a day
Gionchetti et al[92], 2007	Not mentioned	23 consecutive patients with active mild pouchitis	4 wk with 3.6 × 1012 bacteria a day

RCT: Randomized controlled trial; IPAA: Ileal pouch anal anastomosis; UC: Ulcerative colitis.

Table 5 Trials assessing the effect of VSL#3 in patients with non-alcoholic fatty liver disease

Ref.	Design	n	VSL#3 intake
Loguercio et al[109], 2005	Not mentioned	78 patients: 22 with NAFLD, 20 with alcoholic cirrhosis, 20 with HCV-related chronic hepatitis, and 16 with HCV-related cirrhosis	3 mo, the daily dose was not clear
Alisi et al[110], 2014	RCT	48 randomized children; 44 (22 with VSL#3 and 22 with placebo) completed the study	4 mo with 1 sachet a day (less than 10 yr old) or 2 sachets a day (older than 10 yr old)
Miccheli et al[111], 2015	RCT	31 pediatric NAFLD patients	4 mo with 1 sachet a day (less than 10 yr old) or 2 sachets a day (older than 10 yr old)

NAFLD: Non-alcoholic fatty liver disease; HCV: Hepatitis C virus; RCT: Randomized controlled trial.

Table 6 Trials assessing the effect of VSL#3 in patients with cirrhosis

Ref.	Design	n	VSL#3 intake
Gupta et al[127], 2013	RCT	94 with cirrhosis	2 mo with 9 × 1011 CFU a day
Jayakumar et al[129], 2013	RCT	17 with decompensated cirrhosis; 15 completed	2 mo with 3.6 × 1012 bacteria a day
Rincón et al[128], 2014	Not mentioned	17 with cirrhosis and ascites; 12 completed	6 wk, the dose was not clear
Marlicz et al[130], 2016	Not mentioned	20 with cirrhosis (13 with compensated liver cirrhosis, 7 with decompensated liver cirrhosis), and 10 healthy controls	Daily for 28 d, the daily dose was not clear

RCT: Randomized controlled trial; CFU: Colony-forming unit.

Table 7 Trials assessing the effect of VSL#3 in patients with hepatic encephalopathy

Ref.	Design	n	VSL#3 intake
Mittal et al[136], 2011	RCT	322 patients were screened for MHE; 160 patients were found to have MHE and included in the trial	3 mo with 1.1 × 1011 CFU twice a day
Lunia et al[137], 2014	RCT	160 with cirrhosis without OHE (including 86 in treatment group, 42 with MHE; 74 in control group, 33 with MHE)	3 mo with 1 capsule 3 times a day, the dose was not clear
Dhiman et al[138], 2014	RCT	130 with cirrhosis who had recovered from HE (including 66 with VSL#3, 64 with placebo)	6 mo with 9 × 1011 CFU a day
Pratap Mouli et al[135], 2015	RCT	227 with CLD were screened for MHE; 120 were diagnosed with MHE; 40 in the lactulose group and 33 in the VSL#3 group completed	2 mo with 4.5 × 1011 CFU a day

HE: Hepatic encephalopathy; RCT: Randomized controlled trial; MHE: Minimal hepatic encephalopathy; CFU: Colony-forming unit; OHE: Overt hepatic encephalopathy; CLD: Chronic liver diseases.