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GALAXY: Gut-and-liver axis in alcoholic liver fibrosis

Periodic Reporting for period 3 - GALAXY (GALAXY: Gut-and-liver axis in alcoholic liver fibrosis)

Reporting period: 2019-01-01 to 2020-06-30

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/year globally, alcohol-related 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, over inflammation to progressive accumulation of scar tissue leading to cirrhosis.
Available treatments are 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 “bacterial gut imbalance”, targeting the gut-liver-axis, may represent a target for reversing scar accumulation. But ALD is a complex, multifactorial disease, in which no individual factors can explain disease phenotype. GALAXY explores 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 patients´ 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.
GALAXY objectives:
• Identify signatures of host-microbial cross-talk during disease development and progression.
• Translate this into biomarkers for diagnosis, stratification and treatment monitoring in patients with an excess use of alcohol.
• Evaluate new interventions to modulate gut microbiota towards prevention and mitigation of the disease in at-risk individuals.
• Study societal and economic impact of GALAXY biomarkers and treatments to accelerate future development.
GALAXY has used the past 18 months to put the multi-omics analyses in progress, collect sequencing data and start to combine the omics data with clinical study data and rodent studies.
We analyse the data collected in the two completed clinical cohorts of patients with ALD (GALA-ALD) and matched, healthy controls (GALA-HP). Results from the multi-omics profiling start to accumulate, with parallel completion of individual omics domains.
For the metabolomics part, we have finalized lipidomics profiling of liver and plasma, and are proceeding with urine and plasma metabolomics. Further, we have developed and tested the platform for stool metabolomics, and are proceeding with analysis of metabolic markers in stool. The genomics and transcriptomics analyses are similarly close to the finish line; we have analysed targeted circulating miRNA in a subgroup, which will complement the analysis of miRNA in liver samples that are close to completion as well. Similarly, the planned metagenomics and metatranscriptomics of stool samples are well underway.
Finally, we have extensively characterized study participants using neoepitope technology leading to a publication on the first commercial GALAXY biomarker, ProC3.
To expand the findings in the human studies, we have developed novel animal models of NAFLD and ALD and furthermore identified targets, which can be used as biomarkers as well as targets.
Our biomarkers development and pathofysiological investigations focus on mapping the microbiome taxonomy and metatranscriptomics, together with host metabolomics, genomics and transcriptomics. The omics domains are then correlated with histological liver lesions, patient outcomes and existing state-of-the-art serum and imaging biomarkers. Most of the data have been generated and next step is combining the omics domains, prioritizing biomarkers, identifying and testing potential targets for interventions, and finalizing the randomised controlled trials (RCT).
WP1. We await the completion of the RCTs GAB-ALD and SYN-ALD to analyse whether interventions targeting the gut microbiome alters ALD fibrosis. The results of the RCTs have the potential to reform the field and expand options for patients with progressive liver fibrosis due to excess drinking.
WP2. Individual omics domains have been put to use in upcoming publications regarding lipidomics in liver and circulation, and host transcriptomics in liver and circulation (miRNA and mRNA). Our lipidomics data indicate that sphingolipid levels decrease with severity of hepatic fibrosis, both in liver and plasma samples. Sphingolipids are involved in cell signalling and apoptosis, which indicate that disruption of the sphingolipid metabolic pathways, may be a key event for ALD progression.
WP3. We have evaluated the performance of existing, commercially available biomarkers, ELF (Enhanced Liver Fibrosis), FibroTest (Biopredictive), liver stiffness (elastography) and CAP (controlled attenuation parameter). Three manuscripts have been published: 1) Two manuscripts validating existing ALD markers to establish these markers in routine practice 2) Data on the novel MFAP4 marker.
WP4. Multiple omics techniques have been evaluated for their potential to yield biomarkers related to the progression and severity of alcohol-related liver fibrosis and steatohepatitis. It was possible to identify biomarkers related to metabolic risk factors, blood serum, and markers of extracellular matrix remodelling and wound healing. The results are being prepared for publication. The conclusion is that the different multi-omics method developed in GALAXY can yield biomarkers for the severity and progression of ALD.
WP5. GUF has developed new animal models that can be used in preclinical studies for NAFLD/ALD. To date, there is no drug approved by neither FDA nor EMA for the treatment of NAFLD and ALD. Therefore, animal models are mandatory to test new potential pharmaceuticals. Furthermore, putative biomarkers can be tested in our animal models for validation.
WP6. We have assessed circulating formation and degradation markers of collagen and the conclusion is that ALD is characterized by elevated collagen formation and degradation, which becomes increasingly dysbalanced with more severe disease. This has implications for early identification of those at highest risk of progressing to cirrhosis, and may pave a way for targets of future antifibrotic treatments and predictive markers.
WP7. We developed a model to test the cost-effectiveness and the outcome was that the most cost-effective strategy was to use the ELF test followed by liver stiffness measurement (LSM) if the test was positive, with incremental cost-effectiveness ratio [ICER] $5,387-$8,430/QALY. The strategy resulted in fewer QALYs due to more false negatives, but an ICER of $3,012, making this strategy suited for areas with restricted access to ELF and transient elastography or lower willingness-to-pay. Direct referral to LSM was highly cost‐effective in high‐prevalence cohorts with ICERs between $490 and $1,037/QALY. This is relevant for policy and if adopted may improve the cost-effectiveness.