Influence of Probiotics on Infections in Cirrhosis (PIC)

Probiotic Modulation of Gut Microflora in Cirrhosis: Influence on Immune Function and Infections

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, the investigators hypothesize that probiotic treatment would restore neutrophil function and prevent infection in alcoholic cirrhosis.

The investigators hypothesize that administration of a probiotic mixture 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 probiotic mixture 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 mixture 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 oxidation, 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.

Study Overview

• Status: Completed
• Conditions: Liver Cirrhosis
• Intervention / Treatment: Dietary supplement: Winclove-849; Dietary supplement: Placebo

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
    • Department of Internal Medicine, Medical University of Geraz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria: • Patients aged between 18-80 years

• Clinical and radiological evidence of cirrhosis, and/or biopsy proven liver cirrhosis of any cause
• Informed consent

Exclusion Criteria:

• Child-Pugh score > 11
• Abstinence from alcohol for < 2 weeks at the time of screening for inclusion
• Clinical evidence of active infection
• Antibiotic treatment within 7 days prior to enrolment
• Gastrointestinal haemorrhage within previous 2 weeks
• Use of immunomodulating agents within previous month (steroids etc.)
• Use of proton pump inhibitors for preceding two weeks
• Concomitant use of supplements (pre-, pro-, or synbiotics) likely to influence the study
• Renal failure (such as hepatorenal syndrome), creatinine >1.7 mg/dL
• Hepatic encephalopathy II to IV
• Pancreatitis
• Other organ failure
• Hepatic or extra-hepatic malignancy
• Pregnancy
• Presumed non-compliance to the study medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Probiotic; 6 g of Winclove-849 containing Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, Lactococcus lactis W19, Lactococcus lactis W58 at a concentration of 2.5 x 10E9 cfu/g per day	Dietary supplement: Winclove-849; 6 g of Winclove-849 containing Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, Lactococcus lactis W19, Lactococcus lactis W58 at a concentration of 2.5 x 109 cfu/g
Placebo Comparator: Placebo; A similar looking and tasting powder	Dietary supplement: Placebo; A similar looking and tasting powder with no active substances

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in neutrophil phagocytic capacity	Percentage of neutrophil granulocytes showing phagocytosis of FITC (fluorescein isothiocyanate) -labelled E.coli bacteria	Change from baseline to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of clinically significant infections	Occurence of infections that require specific treatment and/or hospitalisation during the study period of 12 months	during 12 months
endotoxin levels	Endotoxin in serum (EU/ml)	0, 6, 12 months
neutrophil oxidative burst	percentage of neutrophil granulocytes showing oxidative burst with and without stimulation and mean fluorescence activity	0, 6, 12 months
neutrophil toll like receptor expression	percentage of neutrophil granulocytes showing TLR (Toll-like receptor) 2, TLR4 or TLR9 expression and mean fluorescence activity	0, 6, 12 months
albumin oxidation	oxidative status of albumin in the plasma (percentage of (human mercaptalbumin) HMA, (human non-mercaptalbumin) HNA1 and HNA2)	0, 6, 12 months
inflammatory response	elevation of one or more inflammatory markers: C reactive protein (mg/ml), lipopolysaccharide binding protein (ng/ml), soluble CD (cluster of differentiation) 14 (ng/ml)	0, 6, 12 months
bacterial flora	isolation of bacterial DNA and sequencing the gut microbiome from stool and duodenal aspirate	0, 6, 12 months
quality of life	(short form) SF-36 questionaire	0, 6, 12 months
nutritional status	subjective global assessment	0,6, 12 months
changes in gut permeability over time	elevated lactulose mannitol ratio, elevated zonulin	0, 6, 12 months

Collaborators and Investigators

• Sponsor: Medical University of Graz
• Collaborators: Austrian Science Fund (FWF)
• Investigators: Principal Investigator: Vanessa Stadlbauer-Köllner, MD, Medical University of Graz

Publications and helpful links

General Publications

• Stadlbauer V, Komarova I, Klymiuk I, Durdevic M, Reisinger A, Blesl A, Rainer F, Horvath A. Disease severity and proton pump inhibitor use impact strongest on faecal microbiome composition in liver cirrhosis. Liver Int. 2020 Apr;40(4):866-877. doi: 10.1111/liv.14382. Epub 2020 Jan 24.

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (Actual): March 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: April 13, 2012
• First Submitted That Met QC Criteria: May 24, 2012
• First Posted (Estimate): May 30, 2012

Study Record Updates

• Last Update Posted (Estimate): May 5, 2016
• Last Update Submitted That Met QC Criteria: May 4, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis
• Other Study ID Numbers: PIC-2010

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED