It is believed that gut-produced ammonia plays a key role in the pathogenesis of hepatic encephalopathy because of the failure of the diseased liver to clear toxic products. Small intestinal overgrowth and delayed gastrointestinal transit time in cirrhotic patients plays an important role[22].

Lactulose and non-absorbable antibiotics currently hold a dominant position in the treatment of liver encephalopathy. One of the effects of lactulose may be a probiotic effect on lactobacilli that reduce the activity of bacterial ureases, resulting in a decrease in hyperammonemia. Probiotics can also have a similar effect and are already included in some recommendations for the treatment of minimal liver encephalopathy[23].

As early as the 1960s, the beneficial effect of Lactobacillus acidophilus was described on the course of liver encephalopathy in patients with liver cirrhosis[24]. In a more recent study on 97 patients, the beneficial effect of a synbiotic (mixture of a probiotic and prebiotic) on minimal liver encephalopathy was observed, with a decrease in ammonium levels as well as the improvement of symptoms of encephalopathy[25]. Minimal liver encephalopathy is described as an otherwise inexplicable impairment of cognitive functions such as prolonged psychomotor tempo, lack of attention, impairment of fine motor functions and the perception of visual sensations that can only be detected using special neurophysiological tests, and is present in 30%-70% of patients with liver cirrhosis without liver encephalopathy. In the treatment of advanced liver encephalopathy, a beneficial effect of Enterococcus faecium was observed, the administration of which led to an improvement in clinical status, electroencephalogram findings and a reduction of ammonium levels[26]; the treatment of the Enterococcus strain SF69[27] also had a similar effect. A mixture of probiotics[28] may have an even better effect. A combination of Bifidobacterium + fructo-oligosaccharides also demonstrated a significant reduction in the Trail Making Test B, a significant increase in the Symbol Digit Modalities Test and Block Design Test and improvement in some laboratory findings[29].

A study confirming improvement of liver encephalopathy during long-term administration of probiotic yogurts with the advantage of excellent adherence with potential for long-term adherence[30] is also of interest.

So far, there are only very few experimental studies, however, the studies comparing the efficacy of probiotic preparation Golden Bifid and lactulose on an experimental rat model of minimal hepatic encephalopathy induced by thioactamide showed excellent effects in lowering the level of ammonemia and endotoxemia, improving hepatic histopathology of rats, and decreasing the incidence of minimal hepatic encephalopathy[31].

The use of probiotics in common clinical practice as well as evaluation of the economic effect of the treatment will, however, require further studies. At the moment, a study titled “Probiotic Lactobacillus GG (LGG) in Patients with Minimal Hepatic Encephalopathy” is being conducted at Virginia Commonwealth University and we can only hope it will bring novel, positive results.

Infectious complications are very frequently caused by bacterial strains that originate from the digestive tract. Bacterial overgrowth, as well as the associated translocation of microbes across the dysfunctional mucous membrane barrier, occurs for the above-mentioned reasons, especially in liver cirrhosis. The small gut of cirrhotic rats is contaminated by colonic microflora, which translocate to mesenteric lymph nodes, and is the most important cause of infection of ascites and spontaneous bacterial peritonitis. The identity of microbial strains in the gut, mesenteric lymph nodes and ascites was demonstrated by analysis of macrorestricted fragments DNA[32].

In 50%-70% of patients with liver cirrhosis, bacterial overgrowth occurs in the small intestine as a result of gram-negative colon microflora contamination. As a result, an impairment of the intestinal barrier with increased bacterial translocation occurs. Apparently, it is the most important point of entry of infection in cirrhotic patients; generally, infections are very common in liver cirrhosis and can be involved in many complications associated with the disease. In the first animal studies with short term application of Lactobacillus GG, the treatment did not prevent translocation of colonic microflora, although it was able to colonize the cecum in 90% of cirrhotic rats[33]. In later studies, preventive treatment with Lactobacillus plantarum inhibited an increase in permeability after subsequent application of E. coli[34], and Lactobacillus johnsonii La1 with antioxidants were able to decrease endotoxemia and prevent bacterial translocation in cirrhotic rats[35].

In clinical studies, administration of a symbiotic reduced the endotoxemia, which is an indicator of the degree of translocation[11]. In our study, a reduction in endotoxemia was achieved through administration of E. coli Nissle for 42 d[36]. The clinical significance of this has yet to be verified, but the beneficial influence on the prophylaxis of severe infectious complications, such as spontaneous bacterial peritonitis, can be expected.

In both the above-mentioned papers, an improvement in functional liver capabilities was observed, evaluated according to the Child-Pugh classification. It can be presumed that the recovery of physiological microflora in the digestive tract will reduce the liver load of toxic metabolites, above all endotoxin, which might potentially be absorbed. It stimulates secretion of cytokines. The cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1 and interleukin-6 can influence the formation and degradation of the extracellular matrix, which is important for the development of liver fibrosis as well as during cirrhotic rearrangement[37]. Apart from the above-mentioned decrease in endotoxin levels, a direct decrease in cytokine levels after administration of VSL#3 probiotic has also been reported[38]. There are some data showing, that Se-enriched Lactobacillus can intervene in carbon tetrachloride-induced liver injury in mice by enhancing macrophage function to maintain normal and beneficial effects, elevating antioxidant-enzyme activities, reducing lipid peroxidation reaction and inhibiting excessive release of TNF-α[39]. However, this extremely important finding will have to be confirmed. Another study with VSL#3, presenting a trend of a reduction in plasma endotoxin, on the other hand showed no change in the hepatic venous pressure gradient or intestinal permeability[40].

In liver cirrhosis of alcoholic etiology, the alcohol itself may play a role, such as increased gut permeability, endotoxemia, and TNF-α production[41]. In rats, Lactobacillus GG has been shown to reduce alcohol induced gut leakiness and steatohepatitis[42]. The same group also found that the mucosa-associated microflora was altered in rats on a high alcohol diet, and this dysbiosis could be counteracted by Lactobacillus GG or oat supplementation[43]. In a rat model of acute pancreatitis, synbiotic (Lactobacillus acidophilus, Lactobacillus helveticus and Bifidobacterium in an enriched medium) and metronidazole were able to effectively protect against endotoxin/bacterial translocation, as well as liver damage in the course of acute pancreatitis and concomitant heavy alcohol consumption. The beneficial effect of synbiotics on liver histology seems to be correlated with endotoxemia. Metronidazole did not produce such a beneficial effect; in fact, it further worsened liver damage when alcohol was added to the background of ongoing acute pancreatic inflammation[44].

However, no large randomization study has been carried out as yet which would be relevant for clinical practice, although a recent study again confirmed the theoretic presumptions for beneficial action in this field[45]. The “Probiotics for the Prevention of Major Complications of Cirrhosis” study, carried out in the Meir Medical Center in Israel, was finished last year but its results have not yet been published.

Fatty liver disease that develops in the absence of alcohol abuse is increasingly recognized as a major health burden. Non-alcoholic steatohepatitis (NASH) was first described by Ludwig in 1980 as a disease that histologically mimicked alcoholic hepatitis and that also may progress to cirrhosis[46]. The diagnostic criteria for NASH continue to evolve and rely on the histologic findings of steatosis, hepatocellular injury (ballooning, Mallory bodies), and the pattern of fibrosis in patients with minimal intake of ethanol (< 20 g ethanol/d)[47]. Recently, NASH has been studied extensively as it is relatively frequent, and may lead to the development of liver cirrhosis. So far, treatment has not been established and probiotics may play an important role, as the bacterial overgrowth and associated increase of proinflammatory cytokines are important etiopathogenic mechanisms of NASH[48]. Clinical studies so far have been missing in this field, but the positive effect of probiotics has already been described in some laboratory studies. In mice with non-alcoholic liver steatosis, treatment with probiotics or anti-TNF antibodies improved the histological picture of the degree of damage to the liver parenchyma, led to a decrease in the alkaline phosphatase level, improved insulin resistance, and the content of total fatty acids in the liver also dropped. In another study on a model of non-alcoholic liver steatosis, treatment with the probiotic VSL#3 or TNF-α antibodies had a positive influence on histological findings, the fatty acids in hepatocytes were reduced, the ALT level decreased and the expression of TNF-α[49,50] was reduced. Similar data suggesting that VSL#3 administration could limit oxidative and inflammatory liver damage were published in a more recent study[51]. Some previous studies showed that a high fat diet caused obesity, hepatic steatosis and natural killer T-cell (NKT cell) depletion[52]. The VSL#3 was also shown to increase hepatic NKT cell number and reduce inflammatory signaling[53]. Another study indicated that VSL#3 modulates liver fibrosis but does not protect from inflammation and steatosis in NASH. It means, that VSL#3 effects on fibrosis may occur even in the absence of significant changes in markers of inflammation and fat in the liver[54].

In the Cochrane Library Review, there is currently no unambiguous recommendation for administration of probiotics in NASH, even if the results from pilot studies seem promising. Randomized clinical trials are necessary to assess the clinical implication of probiotic therapy in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis[55]. Two clinical studies on the effects of probiotics on NASH are currently being conducted in Hong Kong and in Israel. Hopefully their conclusions will be encouraging.

In the past, several papers were published that confirmed the positive influence of probiotic administration on postoperative course after large abdominal surgery. The studies are mostly of small sample size and exhibit design flaws, but they showed statistically significant differences in infectious complications in favor of synbiotics[56-58], and the synbiotic group did require significantly less days of antibiotic therapy[59].

Patients in the postoperative period after a liver transplant are mainly at risk of infection by organisms, coming in most cases from the digestive tract. As already discussed in the theoretical part of our paper, the translocation of bacteria or their parts across the intestinal wall into the circulation occurs as a result of disturbances in barrier function of the intestine and disturbance of the immune system. Bacteria that translocated from the intestinal tract can be carried through the circulation into more distant systems and cause colonization or infection in extraintestinal locations. A prospective, randomized, double-blind study was published on 66 patients after liver transplantation, whereas half of the patients received a combination of 4 Lactobacillus spp. together with the standard enteral nutrition. In the probiotic group, a significant reduction in postoperative bacterial infection (3% against 48%) was observed and the length of the antibiotic therapy was substantially reduced[60]. In our study on patients after liver transplantation, we demonstrated a correlation between an increase in endotoxin and the subsequent presence of phenotypically as well as genotypically identical strains (originally cultivated from the gastrointestinal tract) in an extraintestinal location[61]. Monitoring serum endotoxin levels can probably confirm bacterial translocation with an increased risk of infectious complications and this result further confirms the positive effect of probiotics in patients after liver transplantation. However, the conclusion is similar from the perspective of evidence-based medicine-use of prebiotics and probiotics in prevention of bacterial sepsis after liver transplantation is promising. Further randomized clinical trials are necessary.