Probiotics for patients with liver cirrhosis
Authors: Tetsuji Fujita
Journal: Journal of Hepatology (2008)

Following their previous study showing decreased neutrophil phagocytic activity and an increased oxidative burst in response to a stimulus in patients with alcoholic hepatitis on cirrhosis [[1]Mookerjee R.P. Stadlbauer V. Lidder S. Wright G.A. Hodges S. Davies N.A. et al.Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome.Hepatology. 2007; 46: 831-840Crossref PubMed Scopus (250) Google Scholar], Dr. Stadlbauer and colleagues revealed similar neutrophil dysfunction and beneficial effects of probiotic treatment with lactic acid-type bacteria on the restoration of neutrophil phagocytic capacity in 12 stable out-hospital cirrhotic patients [[2]Stadlbauer V. Mookerjee R.P. Hodges S. Wright G.A. Davies N.A. Jalan R. Effect of probiotic treatment on deranged neutrophil function and cytokine responses in patients with compensated alcoholic cirrhosis.J Hepatol. 2008; 48: 945-951Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar]. In their open-label study, in addition to measurements of neutrophil function using commercially available kits, ex vivo production of soluble tumor necrosis factor receptors (sTNFRs), interleukin (IL)-10 upon a high dose endotoxin (500 ng) and the expression of toll-like receptor (TLR)-2, 4, and 9 of neutrophils were determined. sTNFRs and IL-10 levels were significantly elevated in cirrhotic patients as compared to 13 healthy controls at the beginning of the study, and patients' sTNFRs and IL-10 levels were significantly decreased following probiotic treatment. The expression of TLR-4, which is thought to recognise exclusively Gram-negative microbial stimuli including endotoxin, was significantly elevated in patients as compared to controls, and patients' TLR-4 levels on the surface of neutrophils were significantly decreased on the completion of the study as compared to baseline. The authors mention that no significant change in the expression of TLR-2 and TLR-9, which are surface or intracellular receptors that are known to recognise mainly Gram-positive bacteria or bacterial DNA, was observed during the study. Improvements in Child's class, hepatic function and mean serum ALT concentrations were not accompanied by the recovery of neutrophil phagocytic activity. First, I would like to address a question about the results of statistical analysis and their clinical relevance. Is an increase by about 25% in neutrophil phagocytic capacity resulting from probiotic treatment, as shown in Fig. 1, clinically relevant? I would like to know a true p value rather than p < 0.05. In Fig. 2 showing the change in TLR-9 expression level, it appears that each pretreatment level decreased at the end of the study. I wonder why there is no statistical difference between pre- and post-treatment expression levels of TLR-9. Recent findings suggest that Gram-positive bacteria, their components or products, and their receptors such as TLR-2 and TLR-9 rather than endotoxin and TLR-4 have more important roles in the development of bacterial infection associated with cirrhosis [[3]Riordan S.M. Williams R. The intestinal flora and bacterial infection in cirrhosis.J Hepatol. 2006; 45: 744-757Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar]. Next, I would like to raise an issue regarding the method for ex vivo endotoxin-stimulated cytokine production. The endotoxin concentration used for the study appears extremely high, more than 1000-fold higher than endotoxaemia observed in patients with cirrhosis. I would like to ask the authors the reason for using clinically irrelevant high dose endotoxin in the study. In the section of discussion, the authors mention that the lack of adverse events associated with the administration of probiotic preparation is evidenced by no change in clinical and laboratory parameters during the study. I think that no alteration in hepatic function during the study period may have to be attributed to the insufficient clinical efficacy of probiotic administration. As well as with liver cirrhosis, bacterial overgrowth and reduced barrier function in the gut are associated with severe acute pancreatitis, predisposing to the development of infectious complications. In 2008, a randomised clinical trial (RCT) assessing the effects of probiotic prophylaxis in 296 patients with predicted severe acute pancreatitis resulted in unexpected increased 90-day mortality associated with probiotic administration (16% versus 6% in control patients) [[4]Besselink M.G.H. van Buskens H.C. Buskens E. Boermeester M.A. van Goor H. Timmerman H.M. et al.Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial.Lancet. 2008; 371: 651-659Abstract Full Text Full Text PDF PubMed Scopus (1064) Google Scholar]. Although the exact mechanism is uncertain, fatal bowel ischaemia contributed to increased deaths in the probiotic group. I agree with the need for RCT to evaluate the efficacy of probiotics or probiotic cocktails in cirrhosis, but it should be done with caution.