Hepatic encephalopathy (HE) involves impairment of cognitive function and is common in patients with liver cirrhosis or porto-systemic shunts. Spectrum of HE varies widely from minor cognitive dysfunction to lethargy, depressed consciousness and coma. Minimal hepatic encephalopathy (MHE) is characterized by impairment of cognitive functions and affects 60 % to 80 % of patients with cirrhosis and adversely affects daily functioning and health-related quality of life (HRQOL) (Dhiman 2013).

Literature search and study selection

We searched and collected relevant literature between 1985 and 2014 from databases of Pub Med, EMBASE and the Cochrane Central Register of Controlled Trials. The key words used in search were probiotics, prebiotics and synbiotics combined with lactulose, gut microflora, hepatic encephalopathy, minimal hepatic encephalopathy and liver cirrhosis. Studies involving patients with MHE or overt HE were included which compared efficacy of probiotics, prebiotics or synbiotics with no therapy, placebo or other modes of treatment like lactulose, rifaximin and L-ornithine L-aspartate with assessment of clinical outcomes like serum ammonia, reversal of MHE, development of overt HE and mortality.

Gut microbiota in cirrhosis

Pathogenesis of HE has been studied in detail and one of the factor held responsible is increase in production of ammonia, endotoxins and other neurotoxins by gut microflora. Changes in fecal microbiota in patients of cirrhosis is an indirect evidence that there is increase in potential pathogenic bacteria which perpetuate inflammatory pathways and leads to increase in various cytokines which impairs cognitive function in patients of cirrhosis (Chen et al. 2011 and Liu et al. 2004). In patients of liver cirrhosis and HE Bajaj et al. (2012) have demonstrated close relation between gut microbiota, cognitive functions and inflammatory pathways. Although dysbiosis has been proved in patients of cirrhosis (Zhang et al. 2013), patients with MHE were found to have higher number of streptococci which was postulated to be linked to cognitive impairment and higher ammonia levels. Similarly in another study by Bajaj (2014) in patients with overt HE found higher number of Alcaligenaceae and Porphyromonadaceae families in patients with poor cognition. Colonic microbiota composition is different in patients of cirrhosis with poor cognitive functions and may be related to the development of overt HE (Bajaj 2014).

SIBO was found to be significantly higher in patients of cirrhosis with MHE as compared to patients without MHE (38.6 vs. 8.9 %) (Gupta et al. 2010). In another study from India, SIBO was reported in 48 % patients with MHE and 46 % with grade I-II HE compared to 16 % in those without MHE. Orocecal transit time (OCTT) was also reported to be prolonged in patients with MHE and grade I-II HE compared to patients without HE (Lunia et al. 2013).

Probiotics in patients with cirrhosis – rationale for use

Prebiotics, probiotics and synbiotics produce beneficial alterations in gastrointestinal microflora and play important role in maintaining normal healthy state (Amodio et al. 2013). Prebiotics are selectively fermented substances that cause specific alterations in both the composition and/or activity of gut microbiota. Probiotics are live microorganisms that, when ingested in adequate amounts, modify gut flora. Synbiotics are supplements that combine prebiotics and probiotics. Prebiotics, probiotics and synbiotics may be helpful in the management of HE by modulating the gut microbiota. They improve gut dysbiosis by decreasing the number of pathogenic bacteria and thereby help in improving endotoxemia, HE and liver functions (Liu et al. 2004). The proposed mechanisms of action include (a) Gut microbiota modulation may lower blood ammonia levels in portal blood by suppressing bacterial urease activity, decreasing ammonia absorption by lowering pH, decreasing intestinal permeability and by boosting nutritional status of gut epithelium (b) decrease endotoxemia and proinflammatory milieu resulting in improvement in inflammation, oxidative stress and liver disease severity (c) decrease in uptake of other toxins such as indoles, oxindoles, phenols and mercaptans (Solga 2003; Dhiman 2013). Probiotics also reduce bacterial translocation from the gut and may be a useful weapon for preventing bacterial infections (Bauer et al. 2001; Bauer et al. 2002; Chiva et al. 2002; Wiest et al. 2003). This positively affects patients with HE and MHE, where active inflammatory cascade plays a pivotal role. This concept is supported by an experimental model of MHE induced by intraperitoneal injection of thioacetamide in rats, wherein probiotics were more effective than placebo in lowering serum ammonia and endotoxin levels by normalizing the latency of brainstem auditory evoked potentials and decreasing the occurrence of MHE without differences between the patients receiving probiotics or lactulose (Jia and Zhang 2005).

Probiotics are live microorganisms that, when ingested in adequate amounts, modify gut flora. Prebiotics are selectively fermented substances that cause specific alterations in both the composition and/or activity of gut microbiota. Synbiotics are supplements that combine prebiotics and probiotics. Prebiotics, probiotics and synbiotics may be helpful in the management of HE by modulating the gut microbiota. They improve gut dysbiosis by decreasing the number of pathogenic bacteria and thereby help in improving endotoxemia, HE and liver functions (Liu et al. 2004). Prebiotics, probiotics and synbiotics maintain normal healthy state by altering gastrointestinal microflora (Amodio et al. 2013). The proposed mechanisms of action include (a) Gut microbiota modulation may lower blood ammonia levels in portal blood by suppressing bacterial urease activity, decreasing ammonia absorption by lowering pH, decreasing intestinal permeability and by boosting nutritional status of gut epithelium (b) decrease in uptake of other toxins such as indoles, oxindoles, phenols and mercaptans (c) decrease endotoxemia and proinflammatory milieu resulting in improvement in inflammation, oxidative stress and liver disease severity (Solga 2003; Dhiman 2013). Probiotics also prevent bacterial infections by reducing bacterial translocation from the gut (Bauer et al. 2001; Bauer et al. 2002; Chiva et al. 2002; Wiest et al. 2003). This positively affects patients with HE and MHE, where active inflammatory cascade plays a pivotal role. This concept has been proved by an experimental model of MHE induced by intraperitoneal injection of thioacetamide in rats, wherein probiotics were more effective than placebo in lowering serum ammonia and endotoxin levels and decreasing the occurrence of MHE (Jia and Zhang 2005).

Probiotics in the management of minimal hepatic encephalopathy and overt hepatic encephalopathy

Several studies have evaluated the role of probiotics in the management of MHE and overt HE (Table 1). Liu et al. (2004) randomized patients with MHE to receive synbiotic (probiotic and fermentable fiber), fermentable fiber alone or placebo for 30 days. Patients with MHE had significant fecal overgrowth of potential pathogenic Escherichia coli and Staphylococcus species. Treatment with synbiotic or fermentable fiber alone significantly increased the fecal content of non–urease producing Lactobacillus species, decline in blood ammonia levels and reversal of MHE in 50 % of subjects as compared to reversal rate of only 13 % in placebo group.

Table 1 Randomized controlled trials on probiotics in treatment of minimal and overt hepatic encephalopathy (HE)
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In another study patients with MHE were randomized to receive probiotic yogurt or no treatment for 60 days (Bajaj et al. 2008). Reversal rate of MHE was significantly higher in the probiotic group (70 % vs. 0 %). Frequency of overt HE on follow up was also significantly lower in the probiotic group than in no treatment group (0 % vs. 25 %). Ziada et al. (2013) assessed the effects of probiotics on MHE and neurometabolites using magnetic resonance spectroscopy of the brain. They randomized 90 patients to lactulose, probiotics and control groups for 4 weeks. Rate of reversal of MHE in the lactulose, probiotics and control group was 54.2 %, 53.8 % and 12 % respectively. The relative risk reduction of developing overt HE in lactulose and probiotics group was 60 % and 80 % respectively. In a study from India, 105 patients with MHE were randomized to receive lactulose, probiotics or combination of lactulose plus probiotics for 1 month (Sharma et al. 2008). Psychometric tests, P300 auditory event related potentials and venous ammonia levels improved significantly in patients treated with lactulose, probiotics and combination of lactulose plus probiotics groups after treatment. Patients treated with lactulose, probiotics and lactulose plus probiotics showed normalization of abnormal psychometry and p300 auditory event related potentials in 54.8 %, 51.6 % and 56.6 % respectively.

Another RCT from India compared lactulose, probiotics and L-ornithine L-asparatate in 160 patients with MHE for 3 months showed significant reversal of MHE in 47.5 %, 35 % and 35 % in lactulose, probiotics and L-ornithine L-asparatate groups, respectively compared to 10 % in no treatment group. In addition there was significant improvement in sickness impact profile questionnaire score and reduction in ammonia levels in all treatment groups versus no treatment group (Mittal et al. 2011).

Malaguarnera et al. (2010) reported that in patients with cirrhosis treatment with bifidobacterium combined with fructo-oligosaccharide for 60 days is as effective as lactulose for improvement in blood ammonia levels and psychometric tests.

However Saji et al. (2011) in a RCT of 43 patients found no significant changes in the parameters like arterial ammonia, evoked responses and number connection tests before and after treatment with probiotics when compared to placebo.

In a non-inferiority RCT comparing efficacy of probiotics with lactulose, Mouli et al. (2014) found MHE improvement rates and reduction in serum ammonia to be similar after 2 months of treatment in the two groups.

Probiotics in the management of minimal hepatic Encephalopathy and overt hepatic encephalopathy

Several studies have evaluated the role of probiotics in the management of MHE and overt HE (Table 1). In a randomized controlled trial Liu et al. (2004) have shown that synbiotic (probiotic and fermentable fiber), significantly increased the fecal content of non–urease producing Lactobacillus species, decline in blood ammonia levels and reversal of MHE in 50 % of subjects as compared to reversal rate of only 13 % in placebo group in 30 days. In another study by Bajaj et al. (2008) in patients with MHE, reversal rate of MHE was significantly higher in the probiotic group (70 % vs. 0 %) and frequency of overt HE on follow up was also significantly lower in the probiotic group than in no treatment group (0 % vs. 25 %). Ziada et al. (2013) assessed the effects of probiotics on MHE and neurometabolites using magnetic resonance spectroscopy of the brain. They randomized 90 patients to lactulose, probiotics and control groups for 4 weeks. Rate of reversal of MHE in the lactulose, probiotics and control group was 54.2 %, 53.8 % and 12 % respectively. In a study from India, 105 patients with MHE were randomized to receive lactulose, probiotics or combination of lactulose plus probiotics for 1 month (Sharma et al. 2008). Psychometric tests, P300 auditory event related potentials and venous ammonia levels improved significantly in patients treated with lactulose, probiotics and combination of lactulose plus probiotics groups after treatment. Another RCT from India compared lactulose, probiotics and L-ornithine L-asparatate in 160 patients with MHE for 3 months showed significant reversal of MHE in 47.5 %, 35 % and 35 % in lactulose, probiotics and L-ornithine L-asparatate groups, respectively compared to 10 % in no treatment group (Mittal et al. 2011). Malaguarnera et al. (2010) reported that in patients with cirrhosis treatment with bifidobacterium combined with fructo-oligosaccharide for 60 days is as effective as lactulose for improvement in blood ammonia levels and psychometric tests. However Saji et al. (2011) in a RCT of 43 patients found no significant changes in the parameters like arterial ammonia, evoked responses and number connection tests before and after treatment with probiotics when compared to placebo. In a non-inferiority RCT comparing efficacy of probiotics with lactulose, Mouli et al. (2014) found MHE improvement rates and reduction in serum ammonia to be similar after 2 months of treatment in the two groups.

Role of probiotics in prevention of hepatic encephalopathy

Probiotics have been evaluated for prevention of first episode of HE (primary prophylaxis) and recurrence of HE (secondary prophylaxis) (Table 2). In a randomized controlled trial of probiotics vs. no treatment in 160 patients of cirrhosis and without prior history of HE, 3 months of probiotics administration resulted in significant improvement in levels of arterial ammonia, SIBO, OCTT, psychometric hepatic encephalopathy scores and critical flicker frequency thresholds compared with baseline. 8.8 % of patients in probiotics group and 20.3 % in no treatment group developed overt HE. In patients with MHE, the absolute risk reduction was 23.8 % and number needed to treat was 4.2. To study the effects of probiotics on prevention of recurrence of HE, Agrawal et al. (2012) randomized 235 patients to lactulose, probiotics or no treatment for one year. On follow up, 26.5 % of patients in lactulose group, 34.4 % in probiotics group and 56.9 % in no treatment group developed recurrence of HE. Probiotics were better than no treatment but as effective as lactulose in preventing recurrence of HE (Dhiman et al. 2014.

Table 2 Randomized controlled trials on probiotics in prevention of hepatic encephalopathy (HE)
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Systemic reviews and meta-analyses of studies on probiotics in treatment of minimal hepatic encephalopathy and overt hepatic encephalopathy

Critical analysis of collective data from different studies may give better evidence on the status of probiotics in management of HE and MHE (Dhiman 2013). Five meta-analyses have been published so far to evaluate the effects of prebiotics, probiotics and synbiotics on outcomes in patients with HE and MHE.

In a meta-analysis by Shukla et al. (2011) on the efficacy of prebiotics, probiotics and synbiotics in the management of MHE, nine studies were included with treatment duration varying from 2 to 14 weeks. Pooled relative risk (RR) of no improvement of MHE was significantly lower with use of prebiotics, probiotics and synbiotics (RR 0.40; P < 0.001). In this meta-analysis, five studies with lactulose showed significant reduction of risk of no improvement of MHE and four trials with use of probiotics and synbiotics were associated with significant reduction of risk of no improvement of MHE. Lactulose was better than probiotics and synbiotics in efficacy but was not well tolerated compared to probiotics and synbiotics, however no serious side effects were noted.

Another meta-analysis evaluated the beneficial and harmful effects of any probiotic in any dose compared with lactulose, L-ornithine-L-aspartate, placebo or no treatment in patients of HE (McGee et al. 2011). In this meta-analysis of seven trials involving 550 subjects, randomization was done to probiotic, placebo or no treatment in four trials including 245 patients, probiotic or lactulose in one trial including 40 participants, and probiotic with both placebo and lactulose in the remaining two trials including 265 participants. When probiotics were compared with no treatment, no significant differences were found in mortality (RR 0.72), lack of recovery (RR 0.72), quality of life, adverse events (RR 0.34), or change of/or withdrawal from treatment. Significantly lower plasma ammonia concentration was found in patients treated with probiotic at one month but not at two months. Most significant decrease in plasma ammonia was noted in the participants treated with probiotic at three months. In this meta-analysis lack of recovery, adverse events, change of/or withdrawal from treatment at one month, plasma ammonia concentration, or change in plasma ammonia concentration were similar.

Another meta-analysis assessed the role of probiotics and synbiotics in HE (Holte et al. 2012). This analysis comprising seven trials with 393 patients. Treatment with probiotics or synbiotics significantly improved hepatic encephalopathy as compared to placebo or lactulose. There was no significant difference in results of psychometry tests and side effects on treatment with probiotics or synbiotics versus placebo. This meta-analysis suggested that probiotics may be an effective treatment of hepatic encephalopathy.

In another meta-analysis (Xu et al. 2014) on effects of probiotic therapy on HE in patients with cirrhosis six RCT involving 496 patients were included. Treatment with probiotics was shown to significantly reduce the development of overt hepatic encephalopathy (OR 0.42, P = 0.0007). However, probiotics therapy did not affect mortality, levels of serum ammonia and constipation.

In a meta-analysis Ding et al. (2014) compared probiotics with lactulose in MHE and showed that rate of improvement of MHE was similar between probiotics and lactulose. As per this meta-analysis probiotics and lactulose were equally effective in the improvement of MHE but probiotics were relatively more safer to use.

Conclusions

Role of prebiotics, probiotics and synbiotics have been studied in various trials but results are inconclusive. In most of these trials number of patients is small, treatment is of short duration, there is variability in the HE/MHE related outcomes, differences in diet in different countries and variability in the type/strains/dose of probiotics used. The clinical implications of the findings should be strengthened and better characterized using meticulous methodological accuracy. Systemic reviews on use of probiotics in treatment of HE conclude that there is no definite evidence that probiotics have a significant effect on improvement in HE and mortality. Therapeutic efficacy of probiotics is still uncertain and hence cannot be recommended. There is a definite need to evaluate the therapeutic effects and safety of probiotics in randomized trials with low risk of systematic and random errors. Also comparative efficacy of various probiotics and optimal doses and duration of treatment needs to be evaluated.