Profermin®: Prevention of progression in alcoholic liver diseases by modulating dysbiotic microbiota - a randomised controlled clinical trial
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.
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.
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.
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
Nordisk Rebalance A/S, Allerød, Denmark.
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
VLV Bio, Peviva AB, Nacka, Sweden
- Managing Director Richard Hermann
Manatee APS, Aarhus C
Siemens Healthcare A/S, Ballerup
Department of Pathology, Odense University Hospital
- Associate professor Sönke Detlefsen, MD
Department of Pathology, University Paris-Diderot, France
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
Steno Diabetes Center, Gentofte
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
European Molecular Biology Laboratory, EMBL, University of Heidelberg, Germany
- Postdoctoral fellow Michael Kuhn
Department for Visceral Surgery and Medicine, University Hospital Bern, Switzerland
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
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