Periodic Reporting for period 4 - MICROB-PREDICT (MICROBiome-based biomarkers to PREDICT decompensation of liver cirrhosis and treatment response)
Okres sprawozdawczy: 2023-10-01 do 2025-03-31
Liver cirrhosis is the end-stage of any chronic liver disease and affects more than 2 million Europeans each years with increasing prevalence worldwide. Cirrhosis and its complications are responsible for 2% of global deaths worldwide. The main reason is the decompensation (aggravation) of disease and this is the case for 800,000 patients each year in Europe. If other organs besides the liver also begin to fail, this is known as acute-on-chronic liver failure (ACLF). This happens to approx. 400,000 patients in Europe and about 160,000 (40%) will die within 28 days.
There are no specific therapies for ACLF and no markers to predict development of ACLF or success of treatments for underlying cirrhosis or systemic inflammation. It is also well-established that the microbes of the gut (microbiota) may influence the outcome in cirrhosis.
Therefore, the aims of our project are:
1. To understand in depth and to better explain the interaction of human microbiome with host and medication, as well as their exact contribution to the development of decompensation and ACLF, and thereby to provide important foundations for the development of future prevention and treatment strategies modifying the microbiome and host co-factors;
2. To validate biomarkers and develop (i) novel microbiome-based nanobiosensors connected to smartphones and other easy-to-use tools for end-users of such markers and (ii) treatment approaches modifying the microbiome and host co-factors;
3. To properly (controlling for confounders) identify major taxonomic and functional microbial traits and their interaction with the host, which are associated with the development of decompensated cirrhosis and progression to ACLF;
4. To personalize treatments using these tools in clinical trials, aiming to improve outcomes and reduce the social and healthcare burden.
There are no specific therapies for ACLF and no markers to predict development of ACLF or success of treatments for underlying cirrhosis or systemic inflammation. It is also well-established that the microbes of the gut (microbiota) may influence the outcome in cirrhosis.
Therefore, the aims of our project are:
1. To understand in depth and to better explain the interaction of human microbiome with host and medication, as well as their exact contribution to the development of decompensation and ACLF, and thereby to provide important foundations for the development of future prevention and treatment strategies modifying the microbiome and host co-factors;
2. To validate biomarkers and develop (i) novel microbiome-based nanobiosensors connected to smartphones and other easy-to-use tools for end-users of such markers and (ii) treatment approaches modifying the microbiome and host co-factors;
3. To properly (controlling for confounders) identify major taxonomic and functional microbial traits and their interaction with the host, which are associated with the development of decompensated cirrhosis and progression to ACLF;
4. To personalize treatments using these tools in clinical trials, aiming to improve outcomes and reduce the social and healthcare burden.
WP1 Clinical, genetic, expositional and geographic characterization of existing data
PREDICT identified three different courses of decompensation apart from ACLF, pre-ACLF being the most relevant one, as well as the main precipitants of ACLF. With the inclusion of other relevant cohorts, an in silico cohort of over 3,500 patients was created, which enabled the clinical and geographical characterisation of cirrhosis patients and control subjects. Analyses include age and gender as well as geographical and drug effects on the microbiome and on progression of disease.
WP2 Characterization of the Microbiome
Characterization of the microbiome (bacteria, fungi, viruses) at different levels of the body (stool, gut-biopsies, blood, saliva, etc.) has been finalized. The results uncover numerous novel combinations of (sub)-species and microbiome signals and elaborate on the tight interaction between the host and microbiome in the development of ACLF. Presence of specific phages and bacterial species have been associated with severity of disease, while compartmentalization of the microbiome revealed interesting data to better understand physiological situation and pathophysiological changes during progression of cirrhosis. Key manuscripts of WP2 are under revision or about to be submitted to leading international journals.
WP3 Proteomics and metabolomics of host and microbiome
WP3 has used proteomics, metabolomics, and other omics techniques to identify proteins, metabolites, and lipids involved in decompensation and ACLF. Lipids are especially important in immunity, and current studies are exploring their mechanistic roles. Metabolites can effectively distinguish different stages and predict ACLF development. Other biomarkers may also help monitor treatment response and organ failure. Key manuscripts from WP3 are at an advanced stage and will be submitted soon.
WP4 Data management, integration and systems modelling
The harmonization and integration of the various data sets (e.g. proteomics, metagenomics, lipidomics) generated in the project have produced interesting scores and sets of biomarkers which are currently being evaluated for clinical use. Various machine learning approaches were tested to analyse the large amount of data. The technological knowledge gained from this can also be applied to other clinical conditions.
WP5 Validation of biomarker candidates and biosensor development
Preparatory work to test the techniques and devices, which may be used for the biomarkers, has started and several approaches have been tested. First validation approaches were successful and pave the way to the final design and development of a PoC.
WP6 In-vitro and in-vivo experimental validation of targets
The work to identify the effects of Rifaximin and Albumin with the host and the microbiota continues and interesting first results elucidate the role of rifaximin in the gut. The substitution of albumin also shows a favourable effect on liver cells. However, more confirmatory experiments are necessary to be done in the next period.
WP7 Clinical validation of signature guided interventions (ALB-TRIAL)
Following the successful completion of all regulatory requirements, the study was launched in February 2024 and 14 clinical centres are involved in the recruitment of patients. Measurement of the two biomarkers is carried out centrally by UM for all participating centres.
WP8 Ethics, Health- and Socio-Economics
Substantial efforts in ethics included publishing an informed consent template for using human biological samples and personal data in research. A draft checklist for informed consent was provided, and a Data Protection Impact Assessment was conducted with an action plan. The project developed a privacy policy and offers useful documents such as codes of conduct, a research integrity policy, and a public engagement strategy aligned with responsible research principles. Additionally, health and socio-economic models are continuously expanded with new data from WP7.
WP9 Dissemination, training, communication, exploitation and guideline development
A wide range of dissemination activities included talks at major European and international conferences across fields like liver, microbiota, medicine, biochemistry, and nanotechnology. European Liver Patient Associations were involved throughout the research. Social media platforms (Twitter, Bluesky, LinkedIn, YouTube) ensured broad coverage. Additionally, educational activities were organized for early-career scientists.
WP10 Project Management
The project management required a very good interaction of all involved partners, which is a challenge in such a large consortium, but was so far very successful, and we thank all partners for the cooperation.
WP11 Ethics requirements
See WP8.
PREDICT identified three different courses of decompensation apart from ACLF, pre-ACLF being the most relevant one, as well as the main precipitants of ACLF. With the inclusion of other relevant cohorts, an in silico cohort of over 3,500 patients was created, which enabled the clinical and geographical characterisation of cirrhosis patients and control subjects. Analyses include age and gender as well as geographical and drug effects on the microbiome and on progression of disease.
WP2 Characterization of the Microbiome
Characterization of the microbiome (bacteria, fungi, viruses) at different levels of the body (stool, gut-biopsies, blood, saliva, etc.) has been finalized. The results uncover numerous novel combinations of (sub)-species and microbiome signals and elaborate on the tight interaction between the host and microbiome in the development of ACLF. Presence of specific phages and bacterial species have been associated with severity of disease, while compartmentalization of the microbiome revealed interesting data to better understand physiological situation and pathophysiological changes during progression of cirrhosis. Key manuscripts of WP2 are under revision or about to be submitted to leading international journals.
WP3 Proteomics and metabolomics of host and microbiome
WP3 has used proteomics, metabolomics, and other omics techniques to identify proteins, metabolites, and lipids involved in decompensation and ACLF. Lipids are especially important in immunity, and current studies are exploring their mechanistic roles. Metabolites can effectively distinguish different stages and predict ACLF development. Other biomarkers may also help monitor treatment response and organ failure. Key manuscripts from WP3 are at an advanced stage and will be submitted soon.
WP4 Data management, integration and systems modelling
The harmonization and integration of the various data sets (e.g. proteomics, metagenomics, lipidomics) generated in the project have produced interesting scores and sets of biomarkers which are currently being evaluated for clinical use. Various machine learning approaches were tested to analyse the large amount of data. The technological knowledge gained from this can also be applied to other clinical conditions.
WP5 Validation of biomarker candidates and biosensor development
Preparatory work to test the techniques and devices, which may be used for the biomarkers, has started and several approaches have been tested. First validation approaches were successful and pave the way to the final design and development of a PoC.
WP6 In-vitro and in-vivo experimental validation of targets
The work to identify the effects of Rifaximin and Albumin with the host and the microbiota continues and interesting first results elucidate the role of rifaximin in the gut. The substitution of albumin also shows a favourable effect on liver cells. However, more confirmatory experiments are necessary to be done in the next period.
WP7 Clinical validation of signature guided interventions (ALB-TRIAL)
Following the successful completion of all regulatory requirements, the study was launched in February 2024 and 14 clinical centres are involved in the recruitment of patients. Measurement of the two biomarkers is carried out centrally by UM for all participating centres.
WP8 Ethics, Health- and Socio-Economics
Substantial efforts in ethics included publishing an informed consent template for using human biological samples and personal data in research. A draft checklist for informed consent was provided, and a Data Protection Impact Assessment was conducted with an action plan. The project developed a privacy policy and offers useful documents such as codes of conduct, a research integrity policy, and a public engagement strategy aligned with responsible research principles. Additionally, health and socio-economic models are continuously expanded with new data from WP7.
WP9 Dissemination, training, communication, exploitation and guideline development
A wide range of dissemination activities included talks at major European and international conferences across fields like liver, microbiota, medicine, biochemistry, and nanotechnology. European Liver Patient Associations were involved throughout the research. Social media platforms (Twitter, Bluesky, LinkedIn, YouTube) ensured broad coverage. Additionally, educational activities were organized for early-career scientists.
WP10 Project Management
The project management required a very good interaction of all involved partners, which is a challenge in such a large consortium, but was so far very successful, and we thank all partners for the cooperation.
WP11 Ethics requirements
See WP8.
We hope to offer the European patients and the patients world-wide four different tools to predict progression of disease, the success of treatment with Rifaximin, the success of treatment with albumin and the success of treatment with Terlipressin (see graph below), and thereby improve outcome and reduce the health-care burden. The technological and conceptual knowledge gained in this consortium will also make a contribution to other clinical conditions.