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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - GALAXY (GALAXY: Gut-and-liver axis in alcoholic liver fibrosis)

Teaser

Summary

Alcohol overuse is the leading cause of cirrhosis, a disease with poor prognosis due to late diagnosis and sparse treatment options. Claiming more than 500.000 lives per year globally, alcoholic liver disease (ALD) represents a huge unmet social challenge due to the high morbidity associated with the disease. ALD covers a disease spectrum from simple fat accumulation in the liver (steatosis), over inflammation (steatohepatitis) to progressive accumulation of scar tissue leading to manifest cirrhosis.
Available treatments include lifestyle interventions; however they are insufficient due to limited efficacy, frequent failure and poor compliance. Current available pharmacological treatments have limited effects.
GALAXY aims at understanding the key networks in the development and progression of ALD, to identify and test novel drug targets and describe the socioeconomic burden of the disease. The hypothesis is that gut bacterial composition determines susceptibility to liver disease and that cross talk between the gut microbiome and the liver drives the disease progression. As liver fibrosis is associated with a â€œbacterial gut imbalanceâ€, targeting the gut-liver-axis, may represent a target for reversing scar accumulation. However, ALD is a complex, multifactorial disease, in which no individual factors can explain disease phenotype. GALAXY will explore the inter-dependencies between the individual host, the gut and the liver, by using a systems medicine approach. This allows us to integrate extensive phenotypic data from the individual patients with characteristics of the patientsÂ´ genome and gut microbiome. Ultimately, this leads to optimized personalized healthcare, by stratifying individuals who would benefit from targeted healthcare efforts, and thus reduce the economic burden for health care systems and to improve health outcome for the patients.
The GALAXY objectives:
1. To identify signatures of host-microbial cross-talk during disease development and progression.
2. To translate this into biomarkers for diagnosis, stratification and treatment monitoring in alcohol over users.
3. Evaluate new interventions to modulate gut microbiota towards prevention and mitigation of the disease in at-risk individuals.
4. Study societal and economic impact of GALAXY biomarkers and treatments to accelerate future development.

Work performed

GALAXY has initiated four clinical trials, of which two are finalised with 463 alcohol-overusing individuals, and a corresponding age â€“ and gender matched healthy control group of 100 participants. Of the excess drinkers, 328 with biopsy-verified alcohol-related liver fibrosis were offered participation in a randomised, placebo controlled trial, directly targeting the gut microbiome using the gut-selective antibiotic Rifaximin. Inclusions are ongoing untill 136 patients have been randomised. The fourth study is a randomised controlled trial comparing a special food for medical purposes, the synbiotic Profermin, with a general food for medical purposes, Fresubin. We will randomise the first ALD patient in March 2019.
During the first three years of GALAXY, we have assembled an extensive data warehouse and gathered a large biobank from the clinical studies, including blood, urine, stool and liver specimens. The two finalised cohort studies have so far been used for discovery and validation of biomarkers for diagnosis and prognosis of fibrosis, hepatic inflammation, and fatty liver. We also generate data to further understand the pathology of progression of alcohol-related liver fibrosis, including remodelling of the hepatic scar tissue in alcoholic liver disease.
As data from the multi-omics profiling start to accumulate, we have set up bioinformatics procedures to integrate and analyse the large data sets. We are thereby getting closer to develop a set of multi-omics biomarkers that may be used in ALD. For example, we have analysed the cellular signalling molecules (RNA and miRNA) in livers and circulating blood from the cohort of ALD patients. Preliminary data show good correllation between standard genes for fibrosis and the histological fibrosis stage. These data are being merged with analyses of collagen degradation and formation epitopes, human GWAS analyses and analyses of liver specimen and corresponding blood samples by means of lipid profiling and metabolites.
To further explore the key signatures and networks in alcohol related disease progression, we have explored the mechanisms involved in a series of animal studies. We have described animal models for ALD and non-alcoholic fatty liver disease (NAFLD) which surpass existing models. This was reached through extensive testing of various animal models using combinations of ethanol-, CCl4- and high-fat diets. We found that the phenotypes of these two models match with the phenotypes of human ALD and NAFLD. Therefore, results gained in these rodent models, e.g. therapeutic experiments, might be more reliable and may easily be transferred to humans.
For dissemination, a project website and twitter profile have been established (www.livergalaxy.eu, @liverGALAXY).

Final results

Our biomarkers development and pathofysiological investigations focus on mapping the microbiome taxonomy (metagenomics) and metatranscriptomics, together with host metabolomics, genomics and transcriptomics. These -omics domains are then correlated with histological liver lesions, patient outcomes and existing state-of-the-art serum and imaging biomarkers. These data are being generated and we expect results in the next period of GALAXY.
During the first three years, we evaluated the performance of two existing, commercially available serum fibrosis markers, ELF (Enhanced Liver Fibrosis test, Siemens) and FibroTest (Biopredictive), and compared the tests with six indirect markers of fibrosis from routine biochemistry and liver stiffness (elastrography). We found a similar diagnostic accuracy in patients from primary and secondary health care, and that a low ELF test in primary care has a high diagnostic accuracy to exclude significant liver fibrosis. We were also able to conclude that indirect indices of liver fibrosis from routine liver biochemistry could be important as first-line diagnostic tools. The results are published in Gastroenterology 2018, 154(5):1369-79. We also assessed the accuracy of controlled attenuation parameter (CAP), a novel imaging method for steatosis detection, for diagnosing alcohol-related fatty liver. This result is published in Journal of Hepatology 2018, 68(5):1025-32. Furthermore, we have manuscripts in preparation regarding novel single-protein biomarkers for diagnosing alcohol-related hepatic inflammation (cytokeratin-18 degradation products) and alcohol-related fibrosis (MFAP4, ProC3), and for prognostication of liver-related clinical outcomes in excess drinkers (ELF, elastography, FibroTest, MFAP4, ProC3).
We have also evaluated the socio-economic impact of early disease detection and assessed different screening strategies for referral of patients from primary to secondary care. Our economic model of costs and benefits for diagnosis of alcohol-related advanced liver fibrosis is the first ever. In it, we show that early disease detection is cost-effective, even across a spectrum of abstinence/ongoing drinking rates. The manuscript is submitted. When published, it will allow policy makers to make more informed decision about the best strategies to adopt.