Probiotics in cirrhosis: do we expect too much?

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’, nonpharmacological 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 acuteon-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