Probiotics are “live micro-organisms” that provide health benefits for the host when consumed in adequate amounts

Probiotics are “live micro-organisms” that provide health benefits for the host when consumed in adequate amounts.97 Beyond beneficial effects on gastrointestinal diseases, probiotics also exert a beneficial role in liver diseases.98-103
Kumar et al. demonstrated that probiotic fermented milk and chlorophyllin significantly lower tumor incidence, DNA damage and the mRNA level of c-myc, bcl-2, cyclin D1, and rasp-21 in aflatoxin B1 (AFB1)-induced HCC rats compared to control group.104
Li et al. reported that probiotic feeding could effectively reduce the liver tumor size in xenograft mice. The probiotic Prohep comprises Lactobacillus rhamnosus GG (LGG), Escherichia coli Nissle 1917, and heat-inactivated VSL#3. Prohep feeding increased relative abundance of certain beneficial bacteria, including Prevotella and Oscillibacter in the gut microbial composition. Interestingly, Prevotella and Oscillibacter produced anti-inflammatory metabolites, which resulted in reduced Th17 polarization and increased differentiation of anti-inflammatory Treg/Tr1 cells in the gut. In addition, SCFAs were implicated in anti-tumor effect of probiotics.83 Probiotics of LGG protected mice against high-fructose-induced NAFLD by improving liver function, restoring the duodenal tight junction protein, and reducing duodenal I?B protein, as well as reducing hepatic TNF-?, IL-8R and IL-1? mRNA in mice.105 Another study of Kim et al. also reported that orally administrated with LGG restored microbial composition and reduced hepatic fat content accompanied by down-regulated expressions of lipogenic and pro-inflammatory genes in the liver of high-fat-diet fed mice. Furthermore, LGG decreased the cholesterol content via inhibition of FXR and FGF15 signaling, resulting in the upregulation of hepatic CYP7A1.106
Lactobacillus casei shirota (LcS) supplementation improved NASH and restored lactic acid bacteria including Bifidobacterium and Lactobacillusin in methionine choline-deficiency-induced NASH mouse models.107 LcS supplementation exerted similar beneficial effects in high-fat diet-induced and db/db obese mice via improved insulin sensitivity and reduced plasma lipopolysaccharide-binding protein (LBP).108 In a fructose-induced NAFLD mouse models, LcS protected against NAFLD via suppression on LPS/TLR4 signaling in the liver.109 LcS exerted the beneficial role in metabolic diseases in part by reducing endotoxemia.
Probiotics have protective role in improving dyslipidemia and NAFLD. L. plantarum MA2 significantly lowered serum lipid in high-fat diet induced NAFLD in rats.110 Moreover, L. plantarum NCU116 also improved liver function and decreased hepatic fat along with the reduction of endotoxin and proinflammatory cytokines in rats with high-fat diet induced NAFLD.111 In addition, L. johnsonii BS15, L. reuteri GMNL-263 and L. gasseri BNR17 also possess the potential in preventing NAFLD in obese mice.112,113
Bifidobacterium (Bif) isolated from the mammalian gastrointestinal tract, is a frequently used probiotic.114-116 Administration of Bif prevented fat accumulation and increased insulin sensitivity in HFD-fed rats.117 Administration of B. pseudocatenulatum CECT 7765 could ameliorate metabolic including improvement of serum cholesterol, triglycerides, glucose tolerance, insulin resistance and immunological dysfunctions related to obesity in HFD-fed mice.118 Probiotic of Bif was superior to Lactobacillus acidophilus in decreasing hepatic fat accumulation.119
The probiotic mixture including LGG, Lactobacillus plantarum WCFS1 and anthraquinone from Cassia obtusifolia L. reduced blood lipid levels and improved insulin resistance in NAFLD rats.120 Another study also showed that supplementation of combined probiotic including Bifidobacterium infantis, Lactobacillus acidopilus, and Bacillus cereu could improve liver function and gut dysbiosis via inhibition of the LPS/TLR4 signaling pathway.101
Kefir is a probiotic fermented milk drink which originated in the Caucasus Mountains and contains over 50 species of lactic acid bacteria and yeast. Kefir could inhibit obesity and NAFLD progress via improvement of fatty acid oxidation and gut dysbiosis in HFD-fed mice.121 In many animal studies, administering probiotics with mixed bacteria exerted beneficial effects on NAFLD prevention.122,123
Probiotics of clostridium butyricum MIYAIRI 588?a butyrate-producing bacteria, could reduce lipid droplets and improve insulin resistance in rats with HFD-induced NAFLD.124 This stain also decreased hepatic lipids and LPS in rats with choline-deficient/L-amino acid-defined diet-induced NAFLD.125
Although the health effects of probiotics were mainly obtained from experimental studies, some consistent results were observed in clinical studies. VSL#3 supplementation greatly improved liver function and increased glucagon-like peptide (GLP-1) levels in obese children who had NASH. Thus, the effects of VSL#3 could be GLP-1-dependent.126 Administering probiotics such as Lactobacillus rhamnosus strain GG and bacteria mixture of Lactobacillus bulgaricus and Streptococcus thermophiles exert similar beneficial effects on obese children with NAFLD.127,128 However, in a study conducted by Solga et al., 4-months of VSL#3 supplementation increased lipid content in the liver of 4 patients with hepatic steatosis. The limitation of this study was small number of study subjects129. In 2010, a randomized-double-blinded research conducted by Andreasen et al. revealed that 4-weeks -intake of L. acidophilus NCFM improved insulin sensitivity compared with placebo but did not affect the systemic inflammatory response measure by baseline plasma concentrations of TNF, IL-6, IL-1ra and C-reactive protein.130 Additionally, in another double-blind placebo-controlled study, 6-weeks Lactobacillus acidophilus supplementation did not change serum lipids in volunteers with elevated cholesterols.131 The above gut microbiota-targeted therapies with probiotics on liver diseases in animal models and human subjects had been summarized in Table 9 and Table 10, respectively.

3.2 Gut microbiota-targeted therapy with prebiotic
Prebiotics are food ingredients that selectively stimulate the growth or activity of beneficial microorganisms such as bacteria and fungi.132,133 Prebiotics can alter the composition and/or activity of gut microbiota. Increasing evidence showed that prebiotic prevented NAFLD development in both experimental and clinical studies.99,134-136
In 2009, Cani et al. revealed that prebiotics of fructooligosaccharide (FOS, a mixture of fermentable dietary fibers) altered gut micriobiota and increased endogenous glucagon-like peptide-2 (GLP-2) production, and consequently reduced serum LPS and hepatic inflammatory in obese mice.137 In a methionine-choline-deficient diet-induced steatohepatitis mouse models, a dietary fructooligosaccharide restored the gut microbiota composition and intestinal epithelial barrier function as well as decreased steatohepatitis.138 FOS treatment altered microbiota composition and increased glucagon-like peptide 1(GLP-1), resulting in reduced hepatic triglyceride in C57Bl/6J mice with n-3 PUFA (polyunsaturated fatty acid)-depleted diet-induced NAFLD.139 FOS also increased fatty acid oxidation through activating peroxisome proliferator-activated receptor-alpha (PPAR-?) and decreased cholesterol content via inhibiting sterol-regulatory-element-binding protein isoform 2 (SREBP-2) in liver without affecting SREBP-1 expression and activity.139,140 Supplement of FOS, an inulin-type fructan, reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels significantly in NASH patients in a randomized double-blind clinic study.134 Administration of mixed galacto-oligosaccharides and fructo-oligosaccharides (9:1) increased the abundance of Bifidobacteria infants.141 Prebiotic inulin and oligofructose (50:50 in mixture) supplement enhanced the abundance of Bifidobacterium and Faecalibacterium prausnitzii, which negatively associated with serum LPS levels.142
As a prebiotic, Lactulose increases the growth of lactic acid bacteria and Bifidobacteria.143 A study demonstrated that lactulose decreased the serum LPS and hepatic inflammation in rats with NASH.144 Chitin-glucan, a prebiotic from fungal source, inhibited hepatic triglyceride accumulation and body weight gain, improved glucose intolerance via restoring bacteria of clostridial cluster XIVa in HFD-induced obese mice.145
Treatment of isomalto-oligosaccharides plus lycopene increased adipose tissue fat mobilization, inhibited body weight gain, and improved insulin sensitivity. In addition, the production of SCFAs was increased in HFD-induced NAFLD mice.146 The above gut microbiota-targeted therapies with prebiotics on liver diseases in animal models and human subjects had been summarized in Table 11 and Table 12, respectively.
Taken together, prebiotics had an enormous potential in preventing liver disease development through improving intestinal barrier, decreasing metabolic endotoxemia, and inhibiting fat accumulation.

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3.3 Gut microbiota-targeted therapy with synbiotic
Synbiotics refer to the combination of probiotics and prebiotics in a form of synergism.147 A synbiotics treatment using a combination of Lactobacillus paracasei B21060 plus arabinogalactan and fructooligosaccharides decreased hepatic inflammation and increased the expression of PPARs and their targeted genes in rats with HFD-induced NAFLD.148 A synbiotic containing seven probiotics and FOS reduced ALT in patients with NAFLD in a randomized double-blind placebo-controlled pilot study.149 Compared to lifestyle intervention alone, combination of synbiotic including B. longum and FOS as well as lifestyle intervention improved NASH in patients. This intervention reduced serum TNF?, C-reactive protein, endotoxin, and AST contents. Moreover, HOMA-IR (homeostasis model assessment of insulin resistance) and NASH activity index were also improved.150 Synbiotic supplementation?Protexin, produced by Probiotics International Ltd?or Familact, produced by Zisttakhmir company?which contained seven species of probiotic bacteria and fructooligosaccharides, also improved fasting blood glucose, serum triglyceride, and inflammatory cytokines in both lean and obese NAFLD patients.151,152
Wan’s group recently demonstrated that Synbiotics Bifidobacterium infantis (B. infantis) and milk oligosaccharides (MO) prevented cancer-prone NASH in WD-fed FXR KO mice. B. infantis and/or MO treatments improved insulin sensitivity and reduced hepatic lymphocyte infiltration accompanied by reduced expression of pro-inflammatory genes and alternation BA profile in WD-fed FXR KO mice. B. infantis and MO increased TGR5-regulated signaling via increasing ileal BA membrane receptor TGR5 as well as Glp1r, PC1/3, and Nos3.153 B. infantis and/or MO treatment also could reverse the reduced ileal short chain fatty acid (SCFA) signaling in WD-fed FXR KO mice. MO and B. Infantis plus MO increased the contents of intestinal acetate, propionate, butyrate, and valerate. MO and B. Infantis plus MO inhibited the growth of genus Bilophila and the expression levels of bacterial genes including dissimilatory sulfite reductase (dsrA) and methyl coenzyme M reductase A (mcrA), which were all increased in cancer-prone FXR KO mice.154
The above gut microbiota-targeted therapies with prebiotics on liver diseases in animal models and human subjects had been summarized in Table 13 and Table 14, respectively.

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