Short summary

We want to influence the gut microbiota in patients with alcoholic liver disease in a randomized controlled clinical trial. We hypothesize that the alcohol-related dysbiosis seen in these patients can be changed and disease progression haltered by modulating microbiota with probiotics during 6 months. 

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Rationale

Liver fibrosis is a wound healing response due to hepatic inflammation. A variety of conditions may cause the hepatic inflammation, with alcohol as a common exemplar. Sustained liver inflammation leads to progressive fibrosis, the precursor of cirrhosis and alcohol is also here the main cause of liver cirrhosis, which accounts for 0,7-0,9% of all deaths in the world

and 4,2% of all deaths in Europe. In 2010, alcoholic liver cirrhosis led to nearly 500.000 deaths

worldwide and compared to other common chronic diseases, mortality from alcoholic liver cirrhosis

is on the rise. 

At present the only curative treatment for fibrotic end-stage liver disease is liver transplantation, but this treatment is only available for a selective minority of patients. Therefore, there is a need for anti-fibrotic treatment strategies to slow down fibrogenesis, preserve liver function and reduce the burden on health care systems.

Gut microbiota:

Bacteria, viruses and fungi inhabit the human gastrointestinal tract, where they contribute to the

normal human physiology. Together they form a gut microbiota comprising an ecosystem with more than 2000 different species and 150-fold more genes than their human host. The study of microbiota (incl. virome and mycobiota) and its role in health and disease is still at its infancy, but an increasing body of evidence suggests that the overall microbiota is a co-evolved partner that significantly impact host metabolic and immunological functions, and thereby is involved in human extra-intestinal diseases like diabetes and liver cancer.

The Gut and liver axis:

Intestinal blood from the small and large intestine returns to the liver by the portal vein. Consequently, the liver is the first organ to encounter bacteria and bacterial components from the

gut. Under normal conditions, an effective gut barrier limits the entering of bacterial products

from the gut to the circulation, and the capacity of the liver to eliminate bacterial products is not overloaded. However, chronic alcohol overuse is associated with increased gut permeability, qualitative changes in the intestinal microbiota (dysbiosis) and bacterial overgrowth.

Alcoholic liver disease thereby favors a microbiota with increased invasive potential while

simultaneously compromising the gut barrier. As a consequence, this increased load of

bacterial products ultimately cause fibrogenesis. The cross talk between the intestinal microbiota and the liver constitute a gut-liver axis, which is increasingly recognized as a key mechanism in the progression of liver disease and development of liver related complications.

Aim of study:

In this study, we wish to investigate the role of probiotics/synbiotics on gut microbiota and

particularly gut dysbiosis seen in liver disease. We hypothesize that the gut microbiota and its

metabolites are major drivers of fibrosis in human liver disease and that modulating the intestinal

flora by Profermin® (a food for special medical purposes) will halter disease progression by

changing the alcohol-related dysbiotic signatures in the microbiota towards eubiosis.

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Description of the cohort

We aim to include 40 patients with alcoholic liver disease in a randomized clinical trial. 

Patients will be randomized 1:1 to receive Profermin® versus a general food suply Fresubin®, for 24 weeks. The randomisation will be stratified according to whether patients are abstaining or have an ongoing use of alcohol at inclusion. The study will be performed as an open-label trial. Outcome assessment of liver biopsies will be performed by our pathologist blinded for treatment group allocation.

Data and biological material

Blood, feces, urine, hair, sputum, liver biopsies, bloodsamples (peripheral and liver adjacent)

Food questionnaires, baseline questionnaires, quality of life, sickness questionnaires

Collaborating researchers and departments

Odense Patient Data Exploratory Network (OPEN), University Hospital

• Lars Søgaard

Nordisk Rebalance A/S, Allerød, Denmark.

• CEO Hans Israelsen

Department of Clinical Biochemistry and Pharmacology, Odense University Hospital

• Professor of Clinical Biochemistry Lars Melholt

Department of Clinical Biochemistry, Odense University Hospital Svendborg

• Chief concultant Steen Antonsen

Nordic Bioscience A/S, Herlev, Denmark

• Professor Morten Karsdal

VLV Bio, Peviva AB, Nacka, Sweden

• Managing Director Richard Hermann

Manatee APS, Aarhus C

• CEO Kristian Nordahl

Siemens Healthcare A/S, Ballerup

• Merete Askestad

Department of Pathology, Odense University Hospital

•  Associate professor Sönke Detlefsen, MD

Department of Pathology, University Paris-Diderot, France

• Professor Pierre Bedossa

The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and University College London Institute for Liver and Digestive Health, London, UK

• Associate Professor: Emmanuel Tsochatzis, MD

Novo Nordisk Center for Protein Research, Copenhagen N and Max Planck Institute of Biochemistry, Department of Proteomics and Signal Transduction, Mu?nchen, Germany

• Professor Matthias Mann

Steno Diabetes Center, Gentofte

• Professor Peter Rossing

Novo Nordisk Center for Basic Metabolic Research, University of Copenhagen

• Professor, PhD Torben Hansen, MD

Department of Biochemistry and Molecular Biology, University of Southern Denmark

• Professor Susanne Mandrup

Biomedical Research Foundation, Academy of Athens, Greece

• Ema Anastasiadou

European Molecular Biology Laboratory, EMBL, University of Heidelberg, Germany

• Postdoctoral fellow Michael Kuhn

Department for Visceral Surgery and Medicine, University Hospital Bern, Switzerland

• Professor Reiner Wiest

Laboratory for Fibrosis and Portal Hypertension, Department of Internal Medicine 1, University of Bonn, Germany

• Adjunct Professor Jonel Trebicka

Department of Health Management and Health Economics, University of Oslo, Norway

• Associate Professor Hans Melberg

Department of Health Economics, Universitet Pompeu Fabra, Barcelona, Spain

• Professor Miquel Serra

NNF Center for Proteine Research, Disease Systems Biology Program, Copenhagen

• Professor Lars Juhl Jensen

NNF Center for Basic Metabolic Research, University of Copenhagen

• Associate Professor Manimozhian Arumugam