Probiotics in Cirrhosis: Do We Expect Too Much?

German Soriano; Carlos Guarner

Disclosures

Liver International. 2013;33(10):1451-1453. 

Probiotics are life micro-organisms that produce a beneficial effect to the host when administered in an adequate amount.[1] Interest in probiotics has grown in recent years, partly because they are an 'ecologic', non-pharmacological and relatively cheap approach to prevent and treat a variety of diseases. The main properties underlying their beneficial effects are the ability to modify the intestinal microbiota, to improve the intestinal barrier and to modulate inflammatory response. With these properties, the potential areas of applicability are wide.[1,2] Evidence for their usefulness is still low, however, and mainly limited to only a few entities, such as necrotizing enterocolitis and acute infectious diarrhoea in children, and antibiotic-associated diarrhoea, pouchitis and lactose maldigestion in adults.[1]

The above-mentioned properties make probiotics an attractive option in liver diseases, including cirrhosis.[2,3] There is an increasing evidence that the sequence linking alterations in gut microbiota and intestinal permeability with bacterial translocation, pro-inflammatory state and hyperdynamic circulation play a relevant role, not only in the development of bacterial infections but also in the pathogenesis of other complications of cirrhosis, such as variceal bleeding, ascites, hepatorenal syndrome, hepatic en-cephalopathy (HE) and acute-on-chronic-liver failure.[4,5] Antibiotics can successfully modify this sequence, mainly through their effect on intestinal microbiota.[4,5] However, infections caused by multiresistant bacteria are a growing threat in patients with cirrhosis because their incidence is increasing and they are associated with high mortality rates.[6] As previous antibiotic administration is strongly related to the development of such infections,[6] alternatives to antibiotics are urgently needed in the prevention of bacterial translocation and its consequences.[2]

Several studies in animal models of non-alcoholic fatty liver disease have reported beneficial effects of certain probiotics on liver damage.[2,3] However, most studies evaluating probiotics in experimental models of cirrhosis and portal hypertension have yielded disappointing results. No benefits on intestinal microbiota or bacterial translocation have been observed with Lactobacillus GG[7] and L. johnsonii La1[8] administration in rats with carbon tetrachloride-induced cirrhosis, or with L. acidophilus and Lactobacillus GG in rats with portal vein ligation.[9]

We should take into account that research with probiotics is hampered by two main limitations that especially affect clinical studies. First, as probiotics are not considered drugs, their regulations are not necessarily the same as those for medications. This could partly explain the shortage of high-quality trials[10,11] and favour the influence of the dairy industry on research. Second, the high variety of probiotics and the heterogeneity in their effects makes it difficult to extrapolate the results between different probiotics and different experimental or clinical situations.[1–3]

The usefulness of probiotics in patients with cirrhosis has been evaluated in several clinical studies, mainly in the field of HE. In an interesting randomized study performed by Liu et al.[12] in China, patients with cirrhosis and minimal HE treated for 1 month with a probiotic combination (Pediacoccus pentoseceus 5–33:3, Leuconostoc mesenteroides 32–77:1, L. paracasei spp. paracasei 19 and L. plantarum 2592) associated with prebiotics (i.e. non-digestible food-ingredients that beneficially affect the host by modifying the intestinal microbiota)[2] showed an increase in lactobacilli and a decrease in Escherichia coli fecal concentrations, a decrease in endotoxemia, and an improvement in liver function and cognitive tests. Unfortunately, potential mediators of these beneficial effects, such as inflammatory response, were not evaluated. Large randomized clinical trials from India have also reported positive results in the treatment of minimal HE[13] or in the prevention of HE recurrence[14] with other combinations of probiotics. In contrast, in Western countries, clinical studies are scarce, some of them are non-randomized,[15] the trials usually include a low number of patients,[15,16] and some administered probiotics together with prebiotics.[17] A recent Cochrane review on probiotics for patients with HE stated that '…we are unable to conclude that probiotics are efficacious in altering clinically relevant outcomes…Further randomized clinical trials are needed'.[11]

VSL#3 is a multispecies probiotic consisting of a combination of 8 strains of bacteria (L. paracasei,L. plantarum,L. acidophilus,L. delbrueckii spp. bulgaricus,Bifidobacterium longum,B. breve,B. infantis and Streptococcus salivarius spp. thermophilus). The rationale for the combined use of several microorganisms is that such combinations can have a more marked effect than a single strain because of their potentially synergistic or additive effects on the physiopathological sequences.[1–3,12,15] VSL#3 has been observed to decrease fibrosis in an experimental model of non-alcoholic steatohepatitis in mice[18] and to improve liver function tests, pro-inflammatory cytokines and oxidative damage in patients with different liver diseases including cirrhosis in a non-controlled study.[15] It has also shown to be useful in the prevention of HE in cirrhotic patients with previous HE episodes.[14] Furthermore, a large open-label randomized controlled trial in patients with cirrhosis and no history of previous overt HE – presented at the EASL International Liver Congress 2013 – showed that VSL#3 was useful in the prevention of HE and the treatment of minimal HE.[19]

In this issue of Liver International, Jayakumar et al.[20] present their data from a randomized, double-blind placebo-controlled trial in patients with decompensated cirrhosis. They evaluated the effect of VSL#3 treatment (3600 billion bacteria daily) for two months on portal pressure, assessed by the hepatic venous pressure gradient (HVPG). In concordance with a previous pilot study from the same authors including 8 patients, 5 decompensated and 3 compensated,[21] VSL#3 failed to significantly decrease HVPG. However, it should be noted that the median change in HVPG was -11.6% in the VSL#3 treated group and +2.8% in the placebo group, and the lack of statistical significance could be because of the small sample size, as only 15 patients were included: 7 treated with VSL#3 and 8 with placebo. Again in concordance with the previous pilot study, the authors observed a decrease in plasma aldosterone levels in patients treated with VSL#3. Nevertheless, although this change reached statistical significance (P = 0.046), the magnitude of this variation did not seem to be clinically relevant and was not associated with a decrease in plasma renin activity or an increase in systolic blood pressure. Although a more accurate evaluation of systemic hemodynamics was not performed, these data suggest that VSL#3 did not produce relevant changes in the hyperdynamic circulatory state.

Previous studies in patients with inflammatory bowel disease showed that VSL#3 increases the mucosal or fecal concentration of lactobacilli and bifidobacteria.[22,23] In the study of Jayakumar et al.,[20] however, no significant changes were observed with VSL#3 treatment in the stool microbiota evaluated by terminal restriction fragment length polymorphism (TRFLP). As commented by the authors, this finding could be because of different effects of VSL#3 on fecal microbiota in patients with decompensated cirrhosis, to the use of a different microbial detection technique, or again to the small sample size.

On the other hand, perhaps the target of a HVPG decrease in patients with cirrhosis and clinically significant portal hypertension was too ambitious for a probiotic treatment alone. We must keep in mind here again that probiotics are not drugs but combinations of bacteria. Their use has therefore been recently proposed as adjunctive therapy in addition to drugs.[24,25] In patients on primary prophylaxis of variceal bleeding receiving propranolol, adjunctive treatment with VSL#3 (900 billion bacteria daily) increased the rate of hemodynamic response evaluated by HVPG from 31% to 58%, similar to the results observed with propranolol associated with norfloxacin (54%).[24] However, in a study that used a combination of Enterococcus faecalis JPC, Clostridium butyricum,Bacillus mesentericus JPC and Bacillus coagulans, this approach of using probiotics as adjunctive therapy did not improve the efficacy of norfloxacin in the primary or secondary prophylaxis of spontaneous bacterial peritonitis.[25]

Probiotics in liver diseases is a promising field, but further studies are needed for several reasons. First, the mechanisms implicated in their effects are not yet well understood. Emerging molecular techniques could be of great help here to study the changes in gut microbiota induced by probiotics.[20,23] Second, safety should always be borne in mind, especially in critically ill patients because probiotics are not devoid of risks, as has been observed in severe acute pancreatitis.[26] Although studies to date including patients with cirrhosis suggest that treatment with probiotics is safe, they did not include critically ill patients.[12–17,19–21,24,25] Finally, the interesting data provided by studies from India and Eastern Asia should be confirmed in clinical trials in other populations, such as in Western countries, including a high number of patients.

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