Probiotic modulation of gut flora in cirrhosis

Liver cirrhosis is the 10th most common cause of death in the western world. Infection is the most common precipitant of deterioration of liver function in cirrhosis. Endotoxin, derived from gram-negative organisms in the gut, can enter the circulation due to increased gut permeability and contributes to neutrophil dysfunction, infection risk and mortality in alcoholic cirrhotics. As probiotics decrease gram-negative organisms in the gut and/or decrease gut permeability, we hypothesize that probiotic treatment would restore neutrophil function and prevent infection in alcoholic cirrhosis. We hypothesize that administration of a probiotic in patients with liver cirrhosis will improve innate immune function through alteration of the gut bacterial flora and gut barrier integrity. The aim of this randomised, double- blinded placebo-controlled study is to assess whether food supplementation with a probiotic improves neutrophil phagocytic capacity in patients with cirrhosis and decreases the incidence of significant infections. 92 patients with alcoholic cirrhosis will be included according to a sample size calculation from preliminary data. Patients will be randomized in two groups: Group 1 receives a probiotic Group 2 receives a similar looking and tasting placebo without bacteria. The recruited patients will be treated for 6 months. Besides routine clinical and laboratory assessments, neutrophil function, toll-like receptor expression, endotoxin levels, bacterial DNA, cytokine levels, albumin oxdiation, gut permeability and analysis of gut microflora will be performed. Furthermore nutritional status and quality of life will be assessed. Primary endpoints will be neutrophil phagocytosis. Secondary endpoints will be significant infection, neutrophil oxidative burst, neutrophil toll-like receptor expression, endotoxin levels, bacterial DNA; cytokine levels, albumin oxidation, gut barrier function and bacterial flora, nutritional status and quality of life. If our hypothesis holds true, probiotics will provide an easily applicable and cost effective method to improve immune function and to prevent infection in liver cirrhosis. It is possible that this can improve survival of patients with liver cirrhosis.

Liver cirrhosis is the 10th most common cause of death in the western world. Infections due to an impaired immune response are the most common complication. In many cases the gut is the driver of these infections. Patients with liver cirrhosis have a disturbed gut flora leading to a leaky gut and the influx of bacterial products. This causes a chronic exhaustion of the immune system and leads to immune dysfunction. Strategies to influence this gut-liver axis may have the potential to break this vicious cycle. Probiotics (live micro-organisms which, when administered in adequate amounts, confer a health benet on the host) can influence the gut-liver axis. We hypothesize that administration of a probiotic in patients with liver cirrhosis will improve innate immune function through alteration of the gut bacterial flora and gut barrier integrity. During this FWF project we tested the effect of a specially developed probiotic mixture in a randomized, double-blind, placebo controlled study in patients with liver cirrhosis. We assessed the effect on the gut flora, the gut-liver axis and the liver function. Patients with liver cirrhosis showed changes in gut flora composition, which was most prominent in patients taking proton pump inhibitors. These changes could be at least partially reverted by the probiotic. We could also prove that the lactic acid bacteria from the probiotic could be found in the stool of patients, which implies that the probiotic bacteria can stay in the gut for some time. The most important result of our study was that the liver function improved during the probiotic was taken. We also found an improvement in some immune function markers. Patients who took then probiotic furthermore reported a better quality of life. Clinical data and the biological material collected in this study also helped us to better understand the development of complications of cirrhosis. We could show that the intake of proton pump inhibitors causes dysbiosis, inflammation and a leaky gut, which was associated with the development of complications and mortality in cirrhosis. In conclusion, we could show that probiotics are a possible way to improve liver function, immune function and quality of life in liver cirrhosis