This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Masami Minemura, the Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan
Yukihiro Shimizu, Gastroenterology Center, Nanto Municipal Hospital, Toyama 932-0211, Japan
ORCID number: $[AuthorORCIDs]
Author contributions: Minemura M wrote the second half of the manuscript; Shimizu Y organized the whole manuscript and wrote the first half of the manuscript.
Conflict-of-interest: The authors have no conflict-of-interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Yukihiro Shimizu, MD, PhD, Gastroenterology Center, Nanto Municipal Hospital, 936 Inami, Nanto, Toyama 932-0211, Japan. email@example.com
Received: November 25, 2014 Peer-review started: November 26, 2014 First decision: December 26, 2014 Revised: January 8, 2015 Accepted: January 21, 2015 Article in press: January 21, 2015 Published online: February 14, 2015
Several studies revealed that gut microbiota are associated with various human diseases, e.g., metabolic diseases, allergies, gastroenterological diseases, and liver diseases. The liver can be greatly affected by changes in gut microbiota due to the entry of gut bacteria or their metabolites into the liver through the portal vein, and the liver-gut axis is important to understand the pathophysiology of several liver diseases, especially non-alcoholic fatty liver disease and hepatic encephalopathy. Moreover, gut microbiota play a significant role in the development of alcoholic liver disease and hepatocarcinogenesis. Based on these previous findings, trials using probiotics have been performed for the prevention or treatment of liver diseases. In this review, we summarize the current understanding of the changes in gut microbiota associated with various liver diseases, and we describe the therapeutic trials of probiotics for those diseases.
Core tip: Gut microbiota are associated with various human diseases (e.g., metabolic, gastroenterological and liver diseases, and allergies). Genomic analyses of gut microbiota have enabled the comprehensive identification of the population of gut bacteria and revealed that changes in these populations are involved in various diseases’ pathophysiology. The liver is affected by changes in the intestinal milieu due to the entry of gut bacteria or their metabolites into the liver through the portal vein. Here we summarize the current understanding of changes in gut microbiota associated with various liver diseases. We also summarize the recent therapeutic trials of probiotics in liver diseases.
Citation: Minemura M, Shimizu Y. Gut microbiota and liver diseases. World J Gastroenterol 2015; 21(6): 1691-1702
More than 1014 microorganisms live in the human gastroenterological tract, including > 104 bacterial species. Most of the bacteria are anaerobic, and the numbers and composition of the bacteria differ according to the site of the gut (Table 1). The numbers of bacteria increase from the stomach, to the jejunum, ileum and colon. The composition of the bacterial flora also changes according to age and diet[2,3]. It has been clarified that gut microbiota play a critical role in the formation of the gut immune system[4,5] and that they also affect the systemic immune system[6,7]. Moreover, interactions between gut microbiota and the liver[8-12] or brain[13-15] have been analyzed. The composition of the microbiota is also associated with various diseases. In this review, we summarize the current understanding of the role of gut microbiota, especially in relation to liver diseases, and we describe relevant clinical trials of the treatment of liver diseases by probiotics.
Since most of the gut bacteria cannot be cultured, comprehensive analyses of them have been difficult. Advances in molecular biological techniques have enabled the analyses of the whole genomes of gut microbiota, and real-time PCR, microarray, and pyrosequencing have been applied to improve the resolution of the microbial biodiversity and quantification of microbial species. Among those gene-based methods, DNA pyrosequencing based on 16S rRNA genes is currently the most useful method for comprehensive analysis of gut microbiota with high resolution and accurate quantification.
Composition of gut microbiota and its change according to age
Claesson et al analyzed the composition of intestinal microbiota by pyrosequencing of over 40000 16S rRNA gene V4 region amplicons. They found that the phylum Bacteroides was the most predominant species of bacteria in 68% of the individuals studied, with an average proportion of 57%, followed by the phylum Firmicutes with an average proportion of 40%. Other detected species were Proteobacteria, Actinobacteria, and Faecalibacteria. The composition differed dramatically among individuals, and was also different according to the individuals’ ages. Elderly individuals were reported to show increased Bacteroides species diversity whereas bifidobacteria were reduced, although contrasting results have been obtained[21,22].
FUNCTIONS OF GUT MICROBIOTA
Digestion and metabolism
Human enzymes are known to be unable to digest complex carbohydrates and plant polysaccharides. Instead, gut microbiota ferment the non-digestible carbohydrates, including cellulose, resistant starch and inulin in the colon to yield energy for microbial growth and end products such as short-chain fatty acids (SCFAs). The SCFAs formed are organic fatty acids, and the major SCFAs consist of acetate, propionate and butyrate. Butylate is an energy substrate for the colonic epithelium, and acetate and propionate are energy substrates for peripheral tissues. Propionic and butyric acids were shown to regulate cell proliferation and differentiation, and to induce hormone release, the hepatic control of lipids, and carbohydrate metabolism. Moreover, several SCFAs have been shown to exert anti-inflammatory and immunomodulatory effects[26,27].
Immune response to gut microbiota
Although we harbor more than 104 bacterial species in the gut and the composition is relatively stable in each person without causing inflammation, the mechanisms responsible for maintaining the flora over the long term are not yet clearly understood. The maintenance of the gut flora may be based on immune tolerance to microbiota because of the formation of the repertoire of microbiota during early life after birth, when the immune system is too immature to eradicate intestinal micro-organisms.
Round et al showed that Bacteroides fragilis could induce immune tolerance to gut microbiota by developing and promoting functions of Foxp3+ regulatory T cells (Tregs) through polysaccharide A produced by the bacteria. In another study, certain Clostridium species, especially phylogenetic clusters IV and XIV (but not Lactobacillus or Bacteroides species) were the most effective in inducing the differentiation of Tregs. Natural killer T (NKT) cells, a subgroup of T cells that recognize self-antigens and microbial lipid antigens presented by CD1d, have an important role in the development and the composition of gut microbiota through the CD1d molecule. Conversely, the development and maturation of mucosal and systemic NKT cells are controlled by commensal gut microbiota. Moreover, CD1d presents self-antigens and microbial lipid antigens to NKT cells, which are involved in the pathogenesis of human inflammatory bowel disease. Thus, cross-talk between the microbiota and CD1d-restricted NKT cells plays an important role in microbial homeostasis and intestinal inflammation.
These overall data suggest that the immune tolerance is important not only for the maintenance of gut microbiota, but also for suppressing harmful immune responses to microbiota in the gut. Inflammatory bowel diseases are now thought to be caused by an uncontrolled immune response to gut microbiota.
Role of gut microbiota in the maturation of the immune system
The role of gut microbiota in gut immune maturation, including the numbers of intestinal CD4+and CD8+ T cells and dendritic cells, has been demonstrated in mice. The effect of early gut colonization on systemic immune responses was also shown by Hansen et al, who reported that a single oral inoculation of a bacteria suspension made from caecal content of specific pathogen-free mice to germ-free mice at 3 wk of age, but not at 1 wk of age, permanently changed the gut microbiota composition, and the delayed colonization caused permanent changes in the immune systems of the mice. The mechanisms responsible for the influence of commensal bacteria on host immunity are thought to be nutrient- and metabolite-dependent.
Collectively, these data indicate an interplay between gut microbiota and the host’s immune system.
GUT MICROBIOTA AND HUMAN DISEASES
Several specific changes in the composition of gut microbiota in a number of human diseases have been reported (Table 2). It would be reasonable to speculate that not a single disease-causing microbe but rather microbial dysbiosis causes those diseases.
Table 2 Changes in gut microbiota in human diseases.
Change in microbiota
Lactobacillus spp. ↓
Firmicutes/Bacteroidetes ratio ↓
Type 2 Diabetes
Bacteroidetes/Firmicutes ratio ↑
GUT MICROBIOTA AND THE LIVER
Since 70% of the liver’s blood is supplied from the portal vein, gut-derived toxins and microbial products constantly enter the liver. The liver could thus be greatly influenced by the composition and function of gut microbes, mainly by receiving metabolites derived from the microbes.
In normal conditions, small amounts of bacteria or bacterial metabolites enter the liver, and most of them are eliminated by Kupffer cells with little activation. However, when the gut-mucosal barrier is damaged by intestinal inflammation or portal hypertension, large amounts of bacteria enter the liver and activate Kupffer cells and hepatic stellate cells. One of the pathogenic bacteria-derived factors is lipopolysaccharide (LPS), and LPS activates those cells via its binding to Toll-like receptor 4 on their surface. Upon the activation of those cells, pro-inflammatory cytokines are produced and are involved in liver damage. It is of note that alcohol was shown to disrupt the intestinal epithelial cell tight junctions and impair the functioning of the gut barrier, leading to bacterial translocation and enhanced entry of bacteria metabolites into the portal vein.
Moreover, the impaired motility of the intestines, increased epithelial permeability, and increased release of pro-inflammatory cytokines in the intestines found in cases of liver cirrhosis with portal hypertension may affect the liver.
GUT MICROBIOTA AND LIVER DISEASES
There are several reports on the changes in gut microbiota in liver diseases, and the representative data are summarized in Table 3.
Table 3 Changes in gut microbiota in liver diseases.
Change in microbiota
Streptococcus spp. ↑
Veillonella spp. ↑
Alcoholic liver cirrhosis
Cirrhosis with encephalopathy
NAFLD: Nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease
Nonalcoholic fatty liver disease (NAFLD) is a common disease all over the world, following the increasing prevalence of obesity and metabolic syndrome. About 10% of patients with NAFLD are now thought to progress to non-alcoholic steatohepatitis (NASH) with the potential to develop liver cirrhosis and even hepatocellular carcinoma (HCC). Since it is now evident that the gut microbiota play an important role in energy storage and the subsequent development of obesity, the role of gut microbiota in the development and progression of NAFLD has become a focus of research.
Indeed, the compositions of microbiota have been shown to differ in obese and lean individuals, with increased Firmicutes and decreased Bacteroidetes levels in the obese under the intake of the same amount of food. Extensive analyses of gut microbiota in patients with NAFLD have been performed recently, and individuals with NAFLD were found to show a lower percentage of Bacteroidetes and higher levels of Prevotella and Porphyromonas species compared to healthy controls. Moreover, the predisposition to develop to NAFLD was dependent on the expression of Toll-like receptors (TLR) 4 or 9, or tumor necrosis factor-alpha (TNF-α) receptor.
The mechanisms underlying the progression from simple fatty liver to NASH are not fully understood, but a study suggested that NASH harbors modified microbiota that produce endogenous ethanol, leading to the development of NASH.
A bacteria-mediated mechanism for the progression of NASH was recently proposed by Imajo et al. They found that obesity-induced leptin upregulates CD14 via STAT3 signaling, resulting in hyper-responsibility to low-dose LPSs, leading to the liver inflammation and fibrosis of NASH.
In liver cirrhosis, the decreased secretions of bile acid[42,43] and portal hypertension could affect the composition and the growth of gut microbiota. Previous studies[45,46] revealed that the gut microbiota in patients with liver cirrhosis showed a higher prevalence of pathogenic bacteria such as Enterobacteriaceae and Streptococcaceae and a lower prevalence of beneficial bacteria such as Bifidobacteria and Lachnospiraceae compared to healthy controls. The gut microbial communities were the same irrespective of their etiologies, indicating that the composition characteristics in the liver cirrhosis patients were due mostly to the liver cirrhosis. Interestingly, a positive correlation was observed between the patients’ Child-Turcotte-Pugh (CTP) scores and Streptococcaceae, whereas Lachnospiraceae was significantly decreased in the cirrhosis patients and negatively correlated with the CTP scores, suggesting a contribution of gut microbiota to the prognosis of patients with liver cirrhosis[45,46].
Qin et al analyzed the gut microbiomes in liver cirrhosis patients by quantitative metagenomics, and they found that the gut microbiota in the patients contained less Bacteroidetes and Firmicutes and more Streptococcus spp. and Veillonella spp. compared to healthy controls. Both Streptococcus spp. and Veillonella spp. are bacteria of oral origin and might be associated with the pathophysiology of liver cirrhosis. Although the functions and the contribution of these bacteria in the pathogenesis and complications of liver cirrhosis remain to be clarified, these findings could help develop a new therapeutic strategy against liver cirrhosis by focusing on the gut microbiota.
Alcoholic liver disease
Chronic alcohol consumption is related to fatty liver, liver fibrosis and liver cirrhosis, and both alcohol and acetaldehyde have been suspected to be pathogenic for liver injury. However, the importance of gut microbiota in the pathogenesis of alcoholic liver injury has been revealed. In alcohol-fed mice, Akkermansia and Bacteroides were increased, and Lactobacillus was decreased. In human alcoholics, a decrease in Bacteroidaceae and an increase in Prevotellaceae were found. Besides gut dysbiosis, increased gut permeability-due to the disruption of tight junctions caused by ethanol and acetaldehyde-leads to the increased entry of LPS, endotoxin and bacterial DNA into the liver[50,51]. These activate Kupffer cells via TLR4 or TLR 9 on the cell surface, and induce pro-inflammatory cytokines from Kupffer cells.
Tuomisto et al analyzed bacterial DNA in the feces of patients with alcoholic liver cirrhosis, and they found that the feces contained more bacterial DNA of Enterobactericaea compared to those of healthy volunteers. They also analyzed ascites, and found that 50% of the ascites from the alcoholic liver cirrhosis patients contained Enterobactericaea, a Clostridium leptum group or Lactobacillus spp..
Hepatic encephalopathy (HE) is a complication often found in patients with advanced liver cirrhosis. It greatly affects the quality of life in those patients. HE is characterized by reversible cognitive impairment which is caused not by organic organ damage but by toxic substances produced by microbiota in the intestine. Although ammonia is thought to be the main factor causing HE, other factors such as mercaptans, phenols, short- and medium-chain fatty acids and benzodiazepine-like compounds could contribute to the development of HE. Since most of these factors are derived from gut microbiota, analyses of the composition of the microbes will be important for both the understanding and management of HE.
A report from Bajaj et al found that fecal microbiota in cirrhotic patients contained significantly higher levels of Enterobacteriaceae, Alcaligeneceae, and Fusobacteriaceae and lower levels of Ruminococcaceae and Lachnospiraceae compared to those in controls. Moreover, in cirrhotic patients with HE, the correlation between Porphyromonadacae and Alcaligenacae with poor performance on cognitive tests was observed. However, Bajaj et al later reported that sigmoid colon mucosal microbiomes are different from stool microbiomes in patients with liver cirrhosis and HE, and they found that in patients with HE the mucosal microbiome, but not the stool microbiome, showed less Roseburia and more Enterococcus, Veillonella, Megasphaera, and Burkholderia compared to non-HE subjects. These data suggest that a stool microbiota analysis might not be enough to understand the pathogenesis of HE, and that changes in the colonic mucosal microbiota could contribute to the development of HE.
Eighty percent of HCCs develop in fibrotic or cirrhotic livers, and the main etiologies include hepatitis B, hepatitis C, and alcohol intake. However, as obesity has become more prevalent in most developed countries, the development of HCC in patients with NAFLD has been increasing. In viral hepatitis, chronic inflammation of the liver is thought to be associated with hepatocarcinogenesis, but the mechanism underlying the development of HCC in NAFLD patients has not been clarified.
Yoshimoto et al reported that obese mice show alterations of gut microbiota, leading to an increased production of a gut bacterial metabolite, deoxycholic acid (DCA), which is known to cause DNA damage. Increased levels of DCA in the enterohepatic circulation induce a senescence-associated secretory phenotype in the hepatic stellate cells, which secrete inflammatory and tumor-promoting factors in the liver. The obese mice showed HCC development after exposure to a chemical carcinogen. These data indicate that gut bacterial metabolites promote obesity-induced HCC development in mice. Yoshimoto et al also found that a similar pathway may contribute to NASH-associated HCC development in humans.
Dapito et al demonstrated in a mouse model that TLR4 activation by LPS from the intestinal microbiota was closely associated with injury- and inflammation-driven tumor promotion but not with the tumor initiation of hepatocarcinogenesis induced by a combination of diethylnitrosamine and the hepatotoxin carbon tetrachloride. The contribution of intestinal microbiota was confirmed by a decrease in hepatocarcinogenesis in germ-free mice compared to specific pathogen-free mice. On the other hand, a metabolite from gut microbiota, propionate, was shown to inhibit the cancer cell proliferation of liver cancer cells in the liver in a mouse model.
Intratumoral interleukin-17-producing T helper cells (Th17) were found to be associated with poor prognoses of patients with HCC, possibly due to the promotion of angiogenesis and tumor growth, and most of these Th17 cells are generated in the gut by an interaction with gut microbiota. Therefore, there could be close associations among HCC progression, the generation of Th17 cells, and gut microbiota. Taken together, the above-described findings indicate that the development of liver cancer can be modulated by gut microbiota, suggesting the possibility of therapeutic intervention.
UTILIZATION OF PROBIOTICS IN LIVER DISEASES
Bacterial translocation and endotoxemia, which can be caused by increased permeability of the intestinal mucosa, are thought to contribute to the pathogenesis of various complications in liver cirrhosis such as hepatic encephalopathy[63,64] and spontaneous bacterial peritonitis[65,66]. The changes of intestinal microflora might also be associated with the pathogenesis of NASH. Beneficial effects of probiotics have been reported in not only gastrointestinal but also liver diseases. Here we describe therapeutic trials using probiotics and their indications in liver diseases.
HE is a common complication of liver cirrhosis. Gut flora are associated with the pathogenesis of HE, because urease-producing gut bacteria such as Klebsiella and Proteus species can increase the production of ammonia and endotoxins. It was reported in several studies that the alteration of gut flora using probiotics and/or prebiotics could improve HE. The probiotics include strains of lactic acid bacilli (e.g., Lactobacillus and Bifidobacterium), a nonpathogenic strain of Escherichia coli (e.g., E. coli Nissle 1917), Clostridium butyricum, Streptococcus salivarius, and Saccharomyces boulardii (a nonpathogenic strain of yeast), and VSL#3. The most-studied probiotic, VSL#3, consists of a mixture of eight probiotic strains (Streptococcus thermophilus, Bifidobacterium breve, B. longum, B. infantis, Lactobacillus acidophilus, L. plantarum, L. paracasei, and L. bulgaricus).
As of 2011, nine randomized controlled trials (RCTs) had been reported comparing probiotics and synbiotics with no intervention or placebo in patients with HE (Table 4)[69-77]. Some of these studies included cases using lactulose for prebiotics or as control arms; lactulose acts by altering the colonic pH and improving gastrointestinal transit. McGee et al and Holte et al independently reported a systematic review and a meta-analysis of these randomized trials on probiotics for HE, respectively. Both groups found that patients treated with probiotics appeared to have reduced plasma ammonia concentrations compared to patients treated with placebo or no intervention, but treatment with neither probiotics nor synbiotics did not significantly alter the clinically relevant outcomes (i.e., mortality and quality of life). The trials had high risks of systematic and random errors, because each sample size was small and the dosing periods and quantities of the probiotics were different among the trials.
Table 4 Randomized controlled trials for hepatic encephalopathy.
1RCTs included in meta-analysis by McGee et al;
2RCTs included in meta-analysis by Holte et al.
After those meta-analyses, Agrawal et al reported a randomized trial examining the use of probiotics for the secondary prophylaxis of HE. The study assigned 235 patients who had suffered from HE previously, and the results showed that recurrent HE occurred in fewer patients who received probiotics or lactulose compared with no treatment (34% and 27%, respectively, vs 57%). There was no significant difference in recurrence rates between the patients who received probiotics and those who received lactulose. Lunia et al reported preventive effects of probiotics on the development of HE in patients with liver cirrhosis who had not experienced overt HE. Patients who received the probiotics were less likely to develop overt HE compared to controls (1.2% vs 19%; HR = 2.1). These prospective trials indicate that probiotics could be effective in preventing overt HE.
On the other hand, Lactobacillus GG AT strain 53103 (LGG), which is a well-studied probiotic with a published history of safety and efficacy in humans, was examined to evaluate its safety and tolerability in patients with minimal HE. The trial showed that LGG was safe and well-tolerated in patients with cirrhosis and could cause reductions of the endotoxemia and TNF-α production seen in these patients.
Among the various probiotics, the most efficacious species for HE appeared to be Lactobacilli and Bifidobacteria. However, additional prospective and randomized controlled trials are needed before these probiotics can be routinely recommended.
NAFLD is characterized by the accumulation of triglyceride in hepatocytes in non-alcohol users. NAFLD can progress to more severe liver diseases, such as NASH[83,84]. It has been reported the NAFLD/NASH was associated with increased intestinal permeability and small bowel bacterial overgrowth, which could increase the production of proinflammatory cytokines and contribute to the pathogenesis of NASH. Several pharmacologic treatments for NAFLD/NASH have been reported, including insulin-sensitizers (e.g., pioglitazone), antioxidants (e.g., N-acetylcysteine, vitamin E), ursodeoxycholic acid, and anti-TNF-α agents, but a standard treatment has not been established.
In animal models of NASH, treatments with probiotics such as VSL#3 improved the histological findings including reduced fat deposits and damage to the liver parenchyma, with decreasing serum alanine aminotransferase (ALT) levels[87,88]. VSL#3 also reduced oxidative and inflammatory liver damage in mouse NASH models.
Several clinical trials of probiotics administered to patients with NAFLD have been reported. Loguercio et al found that the administration of VSL#3 might reduce liver injury and improve liver function in NAFLD patients. Four relatively high-quality RCTs that evaluated the effects of probiotics in NAFLD patients were reported (Table 5)[90-93]. All four trials showed that probiotic therapy significantly decreased the serum levels of ALT, but only two of the trials revealed an improvement of liver steatosis, which was evaluated by repeated liver biopsies or proton-magnetic resonance. Ma et al performed a meta-analysis of these four RCTs to assess the efficacy of probiotic therapies, and they found that the probiotic therapy significantly decreased the levels of aminotransferases, total-cholesterol, high-density lipoprotein (HDL) and TNF-α in the serum, and the homeostasis model assessment of insulin resistance. The lower levels of HDL in the probiotic-treated groups compared to the placebo groups was unexpected, and the mechanism is unclear. In two of the RCTs, probiotics were used with prebiotics in NAFLD patients, and the combination significantly reduced the patients’ serum aminotransferase levels and liver steatosis.
Table 5 Randomized controlled trials for non-alcoholic steatohepatitis.
Lactobacillus plantarum, Lactobacillus deslbrueckii, Lactobacillus acidophilus, Lactobacillus rhamnosus and Bifidobacterium bifidum (The Lepicol probiotic formula) vs usual care
Liver fat (IHTG) ↓
1RCTs included in meta-analysis by Ma et al. PG-PS: Peptidoglycan-polysaccharide; IHTG: Intrahepatic triglyceride content; NASH: Non-alcoholic steatohepatitis; NS: Not significant.
Lactobacillus, bifidobacterium, and streptococcus are used as probiotics for patients with NASH, and prebiotics such as fructo-oligosaccharides (FOS) are frequently used with these probiotics because they can be fermented by bifidobacteria and lactobacilli. FOS could contribute to bifidobacteria growth as the dominant species in the large bowel and reduce the growth of harmful bacteria.
Although the above-described studies have several limitations including small sample sizes and a lack of data about the patients’ diets and exercise, the treatments with probiotics and prebiotics for patients with NAFLD are promising.
Alcoholic liver disease
The chronic consumption of alcohol induces various biological abnormalities including liver injury (ranging from fatty liver, liver fibrosis, and alcoholic hepatitis to liver cirrhosis), pancreatitis, impaired neutrophil functions, endotoxemia, and increased oxidative stress in the gut. Most of these abnormalities could be associated with altered gut microbiota, raising the possibility that probiotics would be effective for the improvement of these conditions.
In an open-label study with Lactobacillus casei Shirota, patients with alcoholic cirrhosis who received the probiotic for 4 wk showed a restoration of neutrophil phagocytic capacity, possibly due to the decreased expression of TLR4 on the surface of these cells. In a mouse model fed an ethanol-containing diet, heat-killed Lactobacillus brevis (L. brevis) SBC8803 significantly decreased the serum levels of ALT and AST and the hepatic content of triglyceride and total cholesterol in the liver caused by ethanol, which may be associated with the up-regulation of TNF-α and sterol regulatory element-binding proteins in the liver.
In a pilot study reported by Kirpich et al, alcoholic patients who received bifidobacteria and lactobacilli for 5 d showed increased numbers of those bacteria in the gut, and they showed significantly lower AST and ALT activity in the serum, indicating that a short-term administration of probiotics can change the gut microbiota, leading to the amelioration of liver injury induced by chronic alcohol consumption. The therapeutic effect of probiotics could be due to a reduction in oxidative stress and inflammation in the intestine and liver and the preservation of gut barrier function. L. plantarum was recently microencapsulated and administered to rats chronically fed alcohol. The rats showed reductions in the levels of endotoxemia, serum aminotransferase, NF-κB, cytokines such as TNF-α, and IL12/p40, and they also showed improvements in the histology of the intestine and liver. Considering the greater survival of probiotics under gastric acidic conditions, this approach might be efficacious. However, the bacteria-free culture supernatant of Lactobacillus rhamnosus GG was proven to suppress the alcohol-induced intestinal permeability, endotoxemia and subsequent liver injury. It thus remains uncertain whether the survival of probiotics is necessary for obtaining the optimal effect of treatment with probiotics.
Most HCCs develop in the liver chronically infected by Hepatitis B or C virus. However, with the increasing prevalence of metabolic syndrome, the incidence of HCC from NASH has been increasing. Although the mechanism of HCC development from NASH in association with dysbiosis of gut microbiota has been proposed as mentioned above, no therapeutic trials for the prevention of HCC in patients with NASH have been reported, to our knowledge. Reports of the therapeutic prevention of HCC using probiotics are limited to aflatoxin-induced HCC. In a clinical study, healthy but aflatoxin-exposed subjects were randomly assigned to two groups; one group received a mixture of Lactobacillus rhamnosus LC705 and Propionibacterium freudenreichii subsp. shermanii strains and the other received a placebo, and the groups’ urinary excretions of aflatoxin-DNA adduct (aflatoxin B(1)-N(7)-guanine) were compared. The results showed that the elevated urinary excretion of aflatoxin B(1)-N(7)-guanine was significantly decreased in the probiotics group but not in the controls, suggesting the inhibition of the intestinal absorption of aflatoxin B(1) by probiotics. These data may also indicate that probiotics therapy could contribute to the inhibition of aflatoxin B-induced hepatocarcinogenesis. In a rat study examining the effects of probiotic fermented milk and chlorophyllin on the prevention of aflatoxin-induced hepatocarcinogenesis, the probiotics treatment reduced the expressions of c-myc, bcl-2, cyclin D1 and rasp-21, suggesting the protective potential of the probiotics in aflatoxin-induced hepatocarcinogenesis.
Probiotic and symbiotic therapies have been attempted to maintain liver function or prevent post-surgical infections in patients undergoing liver resection or liver transplantation.
Rayes reported a randomized double-blind study with a composition of four lactic acid bacteria (Pediacoccus pentosaceus 5-33:3, Leuconostoc mesenteroides 77:1, Lactobacillus paracasei ssp. paracasei F19, and L. plantarum 2362) and four fibers. The treated group received probiotics for 15 d, and the control group received fibers only. The treated group showed less post-operative infections (3% in the treated group vs 48% in the control group) and needed shorter antibiotic therapy compared to the control group. Similar results were obtained in a study conducted in Japan in which probiotics treatment reduced the perioperative infections in liver transplantation recipients from 24% to 4%. In another study, treatment with probiotics 3 d preoperatively and 7 d postoperatively was found to be efficacious for the better and faster recovery of liver functions. These data suggest that perioperative probiotics or synbiotics may have significant benefits by reducing infections and by maintaining liver functions in patients undergoing liver resection or liver transplantation.
P- Reviewer: Jiang YF, Shen T S- Editor: Qi Y L- Editor: A E- Editor: Ma S
Orrhage K, Nord CE. Bifidobacteria and lactobacilli in human health.Drugs Exp Clin Res. 2000;26:95-111.
Patrignani P, Tacconelli S, Bruno A. Gut microbiota, host gene expression, and aging.J Clin Gastroenterol. 2014;48 Suppl 1:S28-S31.
Voreades N, Kozil A, Weir TL. Diet and the development of the human intestinal microbiome.Front Microbiol. 2014;5:494.
Neish AS. Mucosal immunity and the microbiome.Ann Am Thorac Soc. 2014;11 Suppl 1:S28-S32.
Chung H, Pamp SJ, Hill JA, Surana NK, Edelman SM, Troy EB, Reading NC, Villablanca EJ, Wang S, Mora JR. Gut immune maturation depends on colonization with a host-specific microbiota.Cell. 2012;149:1578-1593.
Kamada N, Seo SU, Chen GY, Núñez G. Role of the gut microbiota in immunity and inflammatory disease.Nat Rev Immunol. 2013;13:321-335.
Spasova DS, Surh CD. Blowing on embers: commensal microbiota and our immune system.Front Immunol. 2014;5:318.
Quigley EM, Monsour HP. The gut microbiota and the liver: implications for clinical practice.Expert Rev Gastroenterol Hepatol. 2013;7:723-732.
Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases.Gastroenterology. 2014;146:1513-1524.
Bruce-Keller AJ, Salbaum JM, Luo M, Blanchard E 4th, Taylor CM, Welsh DA, Berthoud HR. Obese-type Gut Microbiota Induce Neurobehavioral Changes in the Absence of Obesity.Biol Psychiatry. 2014;Epub ahead of print.
Hyland NP, Quigley EM, Brint E. Microbiota-host interactions in irritable bowel syndrome: epithelial barrier, immune regulation and brain-gut interactions.World J Gastroenterol. 2014;20:8859-8866.
O'Mahony SM, Clarke G, Borre YE, Dinan TG, Cryan JF. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis.Behav Brain Res. 2015;277:32-48.
Lagier JC, Million M, Hugon P, Armougom F, Raoult D. Human gut microbiota: repertoire and variations.Front Cell Infect Microbiol. 2012;2:136.
Biagi E, Candela M, Fairweather-Tait S, Franceschi C, Brigidi P. Aging of the human metaorganism: the microbial counterpart.Age (Dordr). 2012;34:247-267.
Petrosino JF, Highlander S, Luna RA, Gibbs RA, Versalovic J. Metagenomic pyrosequencing and microbial identification.Clin Chem. 2009;55:856-866.
Claesson MJ, Cusack S, O’Sullivan O, Greene-Diniz R, de Weerd H, Flannery E, Marchesi JR, Falush D, Dinan T, Fitzgerald G. Composition, variability, and temporal stability of the intestinal microbiota of the elderly.Proc Natl Acad Sci USA. 2011;108 Suppl 1:4586-4591.
Hopkins MJ, Macfarlane GT. Changes in predominant bacterial populations in human faeces with age and with Clostridium difficile infection.J Med Microbiol. 2002;51:448-454.
Woodmansey EJ, McMurdo ME, Macfarlane GT, Macfarlane S. Comparison of compositions and metabolic activities of fecal microbiotas in young adults and in antibiotic-treated and non-antibiotic-treated elderly subjects.Appl Environ Microbiol. 2004;70:6113-6122.
Bergman EN. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species.Physiol Rev. 1990;70:567-590.
Puddu A, Sanguineti R, Montecucco F, Viviani GL. Evidence for the gut microbiota short-chain fatty acids as key pathophysiological molecules improving diabetes.Mediators Inflamm. 2014;2014:162021.
Topping DL, Clifton PM. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides.Physiol Rev. 2001;81:1031-1064.
Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43.Nature. 2009;461:1282-1286.
Sina C, Gavrilova O, Förster M, Till A, Derer S, Hildebrand F, Raabe B, Chalaris A, Scheller J, Rehmann A. G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation.J Immunol. 2009;183:7514-7522.
Clemente JC, Ursell LK, Parfrey LW, Knight R. The impact of the gut microbiota on human health: an integrative view.Cell. 2012;148:1258-1270.
Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota.Proc Natl Acad Sci USA. 2010;107:12204-12209.
Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, Cheng G, Yamasaki S, Saito T, Ohba Y. Induction of colonic regulatory T cells by indigenous Clostridium species.Science. 2011;331:337-341.
Zeissig S, Blumberg RS. Commensal microbial regulation of natural killer T cells at the frontiers of the mucosal immune system.FEBS Lett. 2014;588:4188-4194.
Olszak T, Neves JF, Dowds CM, Baker K, Glickman J, Davidson NO, Lin CS, Jobin C, Brand S, Sotlar K. Protective mucosal immunity mediated by epithelial CD1d and IL-10.Nature. 2014;509:497-502.
Ferreira CM, Vieira AT, Vinolo MA, Oliveira FA, Curi R, Martins Fdos S. The central role of the gut microbiota in chronic inflammatory diseases.J Immunol Res. 2014;2014:689492.
Hansen CH, Nielsen DS, Kverka M, Zakostelska Z, Klimesova K, Hudcovic T, Tlaskalova-Hogenova H, Hansen AK. Patterns of early gut colonization shape future immune responses of the host.PLoS One. 2012;7:e34043.
Ivanov II, Honda K. Intestinal commensal microbes as immune modulators.Cell Host Microbe. 2012;12:496-508.
Seo YS, Shah VH. The role of gut-liver axis in the pathogenesis of liver cirrhosis and portal hypertension.Clin Mol Hepatol. 2012;18:337-346.
Quigley EM, Stanton C, Murphy EF. The gut microbiota and the liver. Pathophysiological and clinical implications.J Hepatol. 2013;58:1020-1027.
Clarke SF, Murphy EF, Nilaweera K, Ross PR, Shanahan F, O’Toole PW, Cotter PD. The gut microbiota and its relationship to diet and obesity: new insights.Gut Microbes. 2012;3:186-202.
Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity.Nature. 2012;482:179-185.
Zhu L, Baker SS, Gill C, Liu W, Alkhouri R, Baker RD, Gill SR. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH.Hepatology. 2013;57:601-609.
Imajo K, Fujita K, Yoneda M, Nozaki Y, Ogawa Y, Shinohara Y, Kato S, Mawatari H, Shibata W, Kitani H. Hyperresponsivity to low-dose endotoxin during progression to nonalcoholic steatohepatitis is regulated by leptin-mediated signaling.Cell Metab. 2012;16:44-54.
Miettinen TA. Lipid absorption, bile acids, and cholesterol metabolism in patients with chronic liver disease.Gut. 1972;13:682-689.
Sung JY, Shaffer EA, Costerton JW. Antibacterial activity of bile salts against common biliary pathogens. Effects of hydrophobicity of the molecule and in the presence of phospholipids.Dig Dis Sci. 1993;38:2104-2112.
Gunnarsdottir SA, Sadik R, Shev S, Simrén M, Sjövall H, Stotzer PO, Abrahamsson H, Olsson R, Björnsson ES. Small intestinal motility disturbances and bacterial overgrowth in patients with liver cirrhosis and portal hypertension.Am J Gastroenterol. 2003;98:1362-1370.
Chen Y, Yang F, Lu H, Wang B, Chen Y, Lei D, Wang Y, Zhu B, Li L. Characterization of fecal microbial communities in patients with liver cirrhosis.Hepatology. 2011;54:562-572.
Lu H, Wu Z, Xu W, Yang J, Chen Y, Li L. Intestinal microbiota was assessed in cirrhotic patients with hepatitis B virus infection. Intestinal microbiota of HBV cirrhotic patients.Microb Ecol. 2011;61:693-703.
Qin N, Yang F, Li A, Prifti E, Chen Y, Shao L, Guo J, Le Chatelier E, Yao J, Wu L. Alterations of the human gut microbiome in liver cirrhosis.Nature. 2014;513:59-64.
Yan AW, Fouts DE, Brandl J, Stärkel P, Torralba M, Schott E, Tsukamoto H, Nelson KE, Brenner DA, Schnabl B. Enteric dysbiosis associated with a mouse model of alcoholic liver disease.Hepatology. 2011;53:96-105.
Mutlu EA, Gillevet PM, Rangwala H, Sikaroodi M, Naqvi A, Engen PA, Kwasny M, Lau CK, Keshavarzian A. Colonic microbiome is altered in alcoholism.Am J Physiol Gastrointest Liver Physiol. 2012;302:G966-G978.
Fukui H, Brauner B, Bode JC, Bode C. Plasma endotoxin concentrations in patients with alcoholic and non-alcoholic liver disease: reevaluation with an improved chromogenic assay.J Hepatol. 1991;12:162-169.
Rivera CA, Bradford BU, Seabra V, Thurman RG. Role of endotoxin in the hypermetabolic state after acute ethanol exposure.Am J Physiol. 1998;275:G1252-G1258.
Roh YS, Seki E. Toll-like receptors in alcoholic liver disease, non-alcoholic steatohepatitis and carcinogenesis.J Gastroenterol Hepatol. 2013;28 Suppl 1:38-42.
Tuomisto S, Pessi T, Collin P, Vuento R, Aittoniemi J, Karhunen PJ. Changes in gut bacterial populations and their translocation into liver and ascites in alcoholic liver cirrhotics.BMC Gastroenterol. 2014;14:40.
Bajaj JS, Ridlon JM, Hylemon PB, Thacker LR, Heuman DM, Smith S, Sikaroodi M, Gillevet PM. Linkage of gut microbiome with cognition in hepatic encephalopathy.Am J Physiol Gastrointest Liver Physiol. 2012;302:G168-G175.
Bajaj JS, Hylemon PB, Ridlon JM, Heuman DM, Daita K, White MB, Monteith P, Noble NA, Sikaroodi M, Gillevet PM. Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation.Am J Physiol Gastrointest Liver Physiol. 2012;303:G675-G685.
Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, Iwakura Y, Oshima K, Morita H, Hattori M. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome.Nature. 2013;499:97-101.
Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, Caviglia JM, Khiabanian H, Adeyemi A, Bataller R. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4.Cancer Cell. 2012;21:504-516.
Bindels LB, Porporato P, Dewulf EM, Verrax J, Neyrinck AM, Martin JC, Scott KP, Buc Calderon P, Feron O, Muccioli GG. Gut microbiota-derived propionate reduces cancer cell proliferation in the liver.Br J Cancer. 2012;107:1337-1344.
Zhang JP, Yan J, Xu J, Pang XH, Chen MS, Li L, Wu C, Li SP, Zheng L. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients.J Hepatol. 2009;50:980-989.
Numasaki M, Fukushi J, Ono M, Narula SK, Zavodny PJ, Kudo T, Robbins PD, Tahara H, Lotze MT. Interleukin-17 promotes angiogenesis and tumor growth.Blood. 2003;101:2620-2627.
Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV. Induction of intestinal Th17 cells by segmented filamentous bacteria.Cell. 2009;139:485-498.
Ersöz G, Aydin A, Erdem S, Yüksel D, Akarca U, Kumanlioglu K. Intestinal permeability in liver cirrhosis.Eur J Gastroenterol Hepatol. 1999;11:409-412.
Lata J, Stiburek O, Kopacova M. Spontaneous bacterial peritonitis: a severe complication of liver cirrhosis.World J Gastroenterol. 2009;15:5505-5510.
Medina J, Fernández-Salazar LI, García-Buey L, Moreno-Otero R. Approach to the pathogenesis and treatment of nonalcoholic steatohepatitis.Diabetes Care. 2004;27:2057-2066.
Loguercio C, Federico A, Tuccillo C, Terracciano F, D’Auria MV, De Simone C, Del Vecchio Blanco C. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases.J Clin Gastroenterol. 2005;39:540-543.
Loguercio C, Del Vecchio Blanco C, Coltorti M. Enterococcus lactic acid bacteria strain SF68 and lactulose in hepatic encephalopathy: a controlled study.J Int Med Res. 1987;15:335-343.
Loguercio C, Abbiati R, Rinaldi M, Romano A, Del Vecchio Blanco C, Coltorti M. Long-term effects of Enterococcus faecium SF68 versus lactulose in the treatment of patients with cirrhosis and grade 1-2 hepatic encephalopathy.J Hepatol. 1995;23:39-46.
Liu Q, Duan ZP, Ha DK, Bengmark S, Kurtovic J, Riordan SM. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis.Hepatology. 2004;39:1441-1449.
Malaguarnera M, Greco F, Barone G, Gargante MP, Malaguarnera M, Toscano MA. Bifidobacterium longum with fructo-oligosaccharide (FOS) treatment in minimal hepatic encephalopathy: a randomized, double-blind, placebo-controlled study.Dig Dis Sci. 2007;52:3259-3265.
Bajaj JS, Saeian K, Christensen KM, Hafeezullah M, Varma RR, Franco J, Pleuss JA, Krakower G, Hoffmann RG, Binion DG. Probiotic yogurt for the treatment of minimal hepatic encephalopathy.Am J Gastroenterol. 2008;103:1707-1715.
Sharma P, Sharma BC, Puri V, Sarin SK. An open-label randomized controlled trial of lactulose and probiotics in the treatment of minimal hepatic encephalopathy.Eur J Gastroenterol Hepatol. 2008;20:506-511.
Mittal VV, Sharma BC, Sharma P, Sarin SK. A randomized controlled trial comparing lactulose, probiotics, and L-ornithine L-aspartate in treatment of minimal hepatic encephalopathy.Eur J Gastroenterol Hepatol. 2011;23:725-732.
Malaguarnera M, Gargante MP, Malaguarnera G, Salmeri M, Mastrojeni S, Rampello L, Pennisi G, Li Volti G, Galvano F. Bifidobacterium combined with fructo-oligosaccharide versus lactulose in the treatment of patients with hepatic encephalopathy.Eur J Gastroenterol Hepatol. 2010;22:199-206.
Pereg D, Kotliroff A, Gadoth N, Hadary R, Lishner M, Kitay-Cohen Y. Probiotics for patients with compensated liver cirrhosis: a double-blind placebo-controlled study.Nutrition. 2011;27:177-181.
McGee RG, Bakens A, Wiley K, Riordan SM, Webster AC. Probiotics for patients with hepatic encephalopathy.Cochrane Database Syst Rev. 2011;CD008716.
Holte K, Krag A, Gluud LL. Systematic review and meta-analysis of randomized trials on probiotics for hepatic encephalopathy.Hepatol Res. 2012;42:1008-1015.
Agrawal A, Sharma BC, Sharma P, Sarin SK. Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no therapy.Am J Gastroenterol. 2012;107:1043-1050.
Lunia MK, Sharma BC, Sharma P, Sachdeva S, Srivastava S. Probiotics prevent hepatic encephalopathy in patients with cirrhosis: a randomized controlled trial.Clin Gastroenterol Hepatol. 2014;12:1003-8.e1.
Bajaj JS, Heuman DM, Hylemon PB, Sanyal AJ, Puri P, Sterling RK, Luketic V, Stravitz RT, Siddiqui MS, Fuchs M. Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis.Aliment Pharmacol Ther. 2014;39:1113-1125.
Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease.Mayo Clin Proc. 1980;55:434-438.
Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference.Hepatology. 2003;37:1202-1219.
Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, Mascianà R, Forgione A, Gabrieli ML, Perotti G. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease.Hepatology. 2009;49:1877-1887.
Socha P, Horvath A, Vajro P, Dziechciarz P, Dhawan A, Szajewska H. Pharmacological interventions for nonalcoholic fatty liver disease in adults and in children: a systematic review.J Pediatr Gastroenterol Nutr. 2009;48:587-596.
Fedorak RN, Madsen KL. Probiotics and prebiotics in gastrointestinal disorders.Curr Opin Gastroenterol. 2004;20:146-155.
Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, Desimone C, Song XY, Diehl AM. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease.Hepatology. 2003;37:343-350.
Velayudham A, Dolganiuc A, Ellis M, Petrasek J, Kodys K, Mandrekar P, Szabo G. VSL#3 probiotic treatment attenuates fibrosis without changes in steatohepatitis in a diet-induced nonalcoholic steatohepatitis model in mice.Hepatology. 2009;49:989-997.
Aller R, De Luis DA, Izaola O, Conde R, Gonzalez Sagrado M, Primo D, De La Fuente B, Gonzalez J. Effect of a probiotic on liver aminotransferases in nonalcoholic fatty liver disease patients: a double blind randomized clinical trial.Eur Rev Med Pharmacol Sci. 2011;15:1090-1095.
Vajro P, Mandato C, Licenziati MR, Franzese A, Vitale DF, Lenta S, Caropreso M, Vallone G, Meli R. Effects of Lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease.J Pediatr Gastroenterol Nutr. 2011;52:740-743.
Malaguarnera M, Vacante M, Antic T, Giordano M, Chisari G, Acquaviva R, Mastrojeni S, Malaguarnera G, Mistretta A, Li Volti G. Bifidobacterium longum with fructo-oligosaccharides in patients with non alcoholic steatohepatitis.Dig Dis Sci. 2012;57:545-553.
Wong VW, Won GL, Chim AM, Chu WC, Yeung DK, Li KC, Chan HL. Treatment of nonalcoholic steatohepatitis with probiotics. A proof-of-concept study.Ann Hepatol. 2013;12:256-262.
Ma YY, Li L, Yu CH, Shen Z, Chen LH, Li YM. Effects of probiotics on nonalcoholic fatty liver disease: a meta-analysis.World J Gastroenterol. 2013;19:6911-6918.
Tannock GW, Wilson CM, Loach D, Cook GM, Eason J, O’Toole PW, Holtrop G, Lawley B. Resource partitioning in relation to cohabitation of Lactobacillus species in the mouse forestomach.ISME J. 2012;6:927-938.
Gibson GR, Beatty ER, Wang X, Cummings JH. Selective stimulation of bifidobacteria in the human colon by oligofructose and inulin.Gastroenterology. 1995;108:975-982.
Stadlbauer V, Mookerjee RP, Hodges S, Wright GA, Davies NA, Jalan R. Effect of probiotic treatment on deranged neutrophil function and cytokine responses in patients with compensated alcoholic cirrhosis.J Hepatol. 2008;48:945-951.
Segawa S, Wakita Y, Hirata H, Watari J. Oral administration of heat-killed Lactobacillus brevis SBC8803 ameliorates alcoholic liver disease in ethanol-containing diet-fed C57BL/6N mice.Int J Food Microbiol. 2008;128:371-377.
Kirpich IA, Solovieva NV, Leikhter SN, Shidakova NA, Lebedeva OV, Sidorov PI, Bazhukova TA, Soloviev AG, Barve SS, McClain CJ. Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: a pilot study.Alcohol. 2008;42:675-682.
Forsyth CB, Farhadi A, Jakate SM, Tang Y, Shaikh M, Keshavarzian A. Lactobacillus GG treatment ameliorates alcohol-induced intestinal oxidative stress, gut leakiness, and liver injury in a rat model of alcoholic steatohepatitis.Alcohol. 2009;43:163-172.
Arora S, Kaur IP, Chopra K, Rishi P. Efficiency of double layered microencapsulated probiotic to modulate proinflammatory molecular markers for the management of alcoholic liver disease.Mediators Inflamm. 2014;2014:715130.
Wang Y, Liu Y, Sidhu A, Ma Z, McClain C, Feng W. Lactobacillus rhamnosus GG culture supernatant ameliorates acute alcohol-induced intestinal permeability and liver injury.Am J Physiol Gastrointest Liver Physiol. 2012;303:G32-G41.
El-Nezami HS, Polychronaki NN, Ma J, Zhu H, Ling W, Salminen EK, Juvonen RO, Salminen SJ, Poussa T, Mykkänen HM. Probiotic supplementation reduces a biomarker for increased risk of liver cancer in young men from Southern China.Am J Clin Nutr. 2006;83:1199-1203.
Kumar M, Verma V, Nagpal R, Kumar A, Gautam SK, Behare PV, Grover CR, Aggarwal PK. Effect of probiotic fermented milk and chlorophyllin on gene expressions and genotoxicity during AFB1-induced hepatocellular carcinoma.Gene. 2011;490:54-59.
Rayes N, Seehofer D, Theruvath T, Schiller RA, Langrehr JM, Jonas S, Bengmark S, Neuhaus P. Supply of pre- and probiotics reduces bacterial infection rates after liver transplantation--a randomized, double-blind trial.Am J Transplant. 2005;5:125-130.
Eguchi S, Takatsuki M, Hidaka M, Soyama A, Ichikawa T, Kanematsu T. Perioperative synbiotic treatment to prevent infectious complications in patients after elective living donor liver transplantation: a prospective randomized study.Am J Surg. 2011;201:498-502.
Rifatbegovic Z, Mesic D, Ljuca F, Zildzic M, Avdagic M, Grbic K, Agic M, Hadziefendic B. Effect of probiotics on liver function after surgery resection for malignancy in the liver cirrhotic.Med Arh. 2010;64:208-211.