Table 1.

Non-antibiotic preventative strategies – studies in Animals

Strategy	Author/Year	Model used	Number of animals	Endpoints	Results	Significance
Probiotics	Chiva 2002 [40]	Rats with CCl4-induced cirrhosis	N=29 rats (10 with probiotic + antioxidant, 11 with antioxidant, 8 control)	Intestinal flora, endotoxemia, and bacterial translocation	Rats treated with antioxidants + Lactobacillus or antioxidants only had reduced intestinal bacterial burden and bacterial translocation. Only the group treated with antioxidant + Lactobacillus had decreased endotoxemia.	Positive study
Probiotics	Adawi 2001 [41]	Rats with Acute liver injury induced through intraperitoneal injection of D-galactosamine	N=30 rats (6 rats in each of five groups)	Extent of liver injury, bacterial translocation, and intestinal microflora	All lactobacillus probiotics reduced the incidence of bacterial translocation, whereas Bifidobacterium increased the incidence of bacterial translocation.	Positive study
Probiotics	Sanchez 2015 [42]	Rats with CCl4-induced cirrhosis	N=46 rats (24 water only, 22 VSL#3+water)	Bacterial translocation, intestinal microbiota, gut barrier / inflammatory response	The probiotic combination VSL#3 decreases bacterial translocation, the pro-inflammatory state and ileal oxidative damage; it increases ileal occludin expression in rats with experimental cirrhosis	Positive study
Probiotics	Bauer 2002 [46]	Rats with CCl4-induced cirrhosis	N=34 rats with lactobacillus v. control, N=20 in norfloxacin + lactobacillus v. control	Bacterial translocation, ascitic fluid infection	Rats treated with Lactobacilli showed no difference in bacterial translocation or ascitic fluid infection compared to those with control (with or without norfloxacin pretreatment)	Negative study
Cisapride	Pardo 2000 [62]	Rats with CCl4-induced cirrhosis	Cirrhotic rats randomized to cisapride (N=15) or saline (N=15)	Intestinal bacterial overgrowth, bacterial translocation	Cisapride significantly reduced intestinal bacterial overgrowth and bacterial translocation in cirrhotic rats	Positive study
Cisapride	Zhang 2003 [63]	Rats with CCl4-induced cirrhosis	Cirrhotic rats divided into no treatment (N=25), cisapride treatment (N=20), and saline treatment (N=20)	Intestinal bacterial overgrowth, bacterial translocation, intestinal transit and permeability	Compared with the placebo group, cisapride-treated rats had lower rates of bacterial/endotoxin translocation and intestinal bacterial overgrowth, which was closely associated with increased intestinal transit and improved intestinal permeability by cisapride.	Positive study
Beta-blockers	Perez-Paramo 2000 [61]	Rats with CCl4-induced cirrhosis	Cirrhotic rats randomized to propranolol (N=13) or placebo (N=12)	Intestinal bacterial load, transit and permeability of the bowel, and rate of bacterial translocation	Compared with the placebo group, propranolol-treated animals had significanctly faster intestinal transit, and lower rates of bacterial overgrowth and translocation.	Positive study
Bile acids	Ding 1993 [85]	Rats with bile-duct ligation (BDL)	BDL rats received saline (n=15) vs. cholic acid (n=9), deoxycholic acid (n=12), or whole bile (n=12)	Bacterial translocation; serum endotoxin	Rate of bacterial translocation was signficantly lower in bile-treated animals compared with saline-treated animals. Assays for endotoxin were negative in bile-treated animals and positive in saline-treated animals	Positive study
Conjugated bile acids	Lorenzo-Zuniga 2003 [79]	Rats with CCl4-induced cirrhosis	N=60 cirrhotic rats, randomized to cholylsarcosine (n=20), cholylglycine (n=20) or placebo (n=20). N=20 healthy non-cirrhotic controls	Bacterial overgrowth, bacterial translocation, and endotoxemia	Administration of conjugated bile acids reduced ileal bacterial content to normal levels in cirrhotic rats. Bacterial translocation was lower in cirrhotic rats who received conjugated bile acids (33% with cholylsarcosine, and 26% with cholylglycine) than in animals who received placebo (66%).	Positive study
FXR agonist: Obeticholic acid (OCA)	Verbeke 2015 [86]	Rats with bile-duct ligation (BDL)	N=28 untreated healthy controls; N=51 BDL (then randomized to vehicle, ursodeoxycholic acid, or obeticholic acid)	Gut permeability, inflammation, and bacterial translocation	After treatment with obeticholic acid, BDL-rats showed decreased markers of inflammation in the gut, normalized gut permeability, and a significant reduction in translocated bacterial strains.	Positive study
FXR agonist: Obeticholic acid	Ubeda 2014 [89]	Rats with CCl4-induced cirrhosis	N=22 rats with cirrhosis randomized to OCA or vehicle; N=14 controls	Gut bacterial translocation; ileal inflammation; hepatic fibrogenesis	In cirrhotic rats and compared with vehicle, OCA reduces bacterial translocation (83% vs. 20%, p<0.01), reduces markers of ileal inflammation (IL-17, IFNɣ, TLR4) and ameliorates hepatic expression of fibrosis markers	Positve study
FXR agonist: GW4064	Inagaki 2006 [87]	Mice with bile-duct ligation (BDL)	BDL mice randomized to vehicle or FXR agonist GW4064	Gut bacterial overgrowth; bacterial translocation; gut barrier integrity	Administration of GW4064 (FXR agonist) in BDL mice: reduced bacterial overgrowth in the ileum and cecum; reduced bacterial translocation; and restored the intestinal barrier (shown via occludin immunostaining and mucosal damage).	Positive study