Periodic Reporting for period 3 - MICROB-PREDICT (MICROBiome-based biomarkers to PREDICT decompensation of liver cirrhosis and treatment response)
Reporting period: 2022-04-01 to 2023-09-30
Liver cirrhosis is the end-stage of any chronic liver disease and affects more than 2 million Europeans each year with increasing prevalence world-wide. Cirrhosis and its complications are responsible for 2% of global deaths world-wide. The main reason is the decompensation (aggravation) of disease and this is the case for 800,000 patients each year in Europe. When besides the liver, also other organs start to fail, then the so-called acute-on-chronic liver failure (ACLF) occurs. This happens to ca. 400,000 patients in Europe and ca. 160,000 (40%) will die within 28 days.
There are no specific therapies and also no markers to predict development of ACLF or success of treatments. Every treatment may interact with the microbes we carry in the gut and they may shape the effect of the respective treatment. 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 the following:
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 the 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 use these tools to personalize treatments for improved response to approaches modifying the microbiome and host co-factors in a clinical trial built in MICROB-PREDICT and to thereby decrease the social and healthcare burden of disease.
There are no specific therapies and also no markers to predict development of ACLF or success of treatments. Every treatment may interact with the microbes we carry in the gut and they may shape the effect of the respective treatment. 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 the following:
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 the 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 use these tools to personalize treatments for improved response to approaches modifying the microbiome and host co-factors in a clinical trial built in MICROB-PREDICT and to thereby decrease the social and healthcare burden of disease.
WP1 Clinical, genetic, expositional and geographic characterization of existing data
The CANONIC and PREDICT studies characterized in detail the European patients with liver cirrhosis. In addition, 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. In silico use of data has enabled the clinical and geographic characterization of cirrhosis patients and controls. Analyses include 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.
WP3 Proteomics and metabolomics of host and microbiome
Proteomics, metabolomics, and other omics-techniques have been implemented by WP3. Many proteins, metabolites and lipids point towards crucial pathways of decompensation and ACLF development. Especially, lipids seem to be relevant in the immunity, and specific mechanistic interventions are currently evaluated to fully uncover the pathomechanisms. In addition, other biomarkers may be used as biomarkers of response to treatment, or prediction of organ failure.
WP4 Data management, integration and systems modelling
The harmonization and integration tools have disclosed interesting scores and sets of biomarkers which are currently being evaluated for clinical use. In addition, novel tools have been established.
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. However, more confirmatory experiments are necessary to be done in the next funding period.
WP7 Clinical validation of signature guided interventions (ALB-TRIAL)
The protocol, eCRF and the planning of the logistics of the study and its design are finalized and the biomarkers are selected. The study has received regulatory approval and the sites are ready to start in the coming funding period.
WP8 Ethics, Health- and Socio-Economics
Substantial efforts were made in the field of ethics. We published information and an informed consent template for participation of human beings for using biological samples of human origin in research and for the use of personal data in research. A draft checklist for participants to assure informed consent was provided. Moreover, a Data Protection Impact Assessment (DPIA) was conducted and a corresponding report and action plan were drafted. The project has developed its privacy policy. Finally, MICROB-PREDICT offers several documents which will be useful for many projects, such as codes of conduct applicable and research integrity policy including publications in journals, policy for integrating the six agendas (ethics, gender equality, public engagement, governance, scientific education and open access) of responsible research and innovation and a public engagement strategy to design MICROB-PREDICT along with the need of patients.
WP9 Dissemination, training, communication, exploitation and guideline development
A large range of dissemination activities was implemented, including multiple talks and presentations at major European and other international conferences in the involved fields (liver, microbiota, medicine, biochemistry, nanotechnology, etc). Representatives of the European Liver Patient Associations were involved in all stages of research. Using different tools of social media (Twitter, LinkedIn) the coverage was very large. Several educational activities were implemented 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.
The CANONIC and PREDICT studies characterized in detail the European patients with liver cirrhosis. In addition, 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. In silico use of data has enabled the clinical and geographic characterization of cirrhosis patients and controls. Analyses include 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.
WP3 Proteomics and metabolomics of host and microbiome
Proteomics, metabolomics, and other omics-techniques have been implemented by WP3. Many proteins, metabolites and lipids point towards crucial pathways of decompensation and ACLF development. Especially, lipids seem to be relevant in the immunity, and specific mechanistic interventions are currently evaluated to fully uncover the pathomechanisms. In addition, other biomarkers may be used as biomarkers of response to treatment, or prediction of organ failure.
WP4 Data management, integration and systems modelling
The harmonization and integration tools have disclosed interesting scores and sets of biomarkers which are currently being evaluated for clinical use. In addition, novel tools have been established.
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. However, more confirmatory experiments are necessary to be done in the next funding period.
WP7 Clinical validation of signature guided interventions (ALB-TRIAL)
The protocol, eCRF and the planning of the logistics of the study and its design are finalized and the biomarkers are selected. The study has received regulatory approval and the sites are ready to start in the coming funding period.
WP8 Ethics, Health- and Socio-Economics
Substantial efforts were made in the field of ethics. We published information and an informed consent template for participation of human beings for using biological samples of human origin in research and for the use of personal data in research. A draft checklist for participants to assure informed consent was provided. Moreover, a Data Protection Impact Assessment (DPIA) was conducted and a corresponding report and action plan were drafted. The project has developed its privacy policy. Finally, MICROB-PREDICT offers several documents which will be useful for many projects, such as codes of conduct applicable and research integrity policy including publications in journals, policy for integrating the six agendas (ethics, gender equality, public engagement, governance, scientific education and open access) of responsible research and innovation and a public engagement strategy to design MICROB-PREDICT along with the need of patients.
WP9 Dissemination, training, communication, exploitation and guideline development
A large range of dissemination activities was implemented, including multiple talks and presentations at major European and other international conferences in the involved fields (liver, microbiota, medicine, biochemistry, nanotechnology, etc). Representatives of the European Liver Patient Associations were involved in all stages of research. Using different tools of social media (Twitter, LinkedIn) the coverage was very large. Several educational activities were implemented 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 three different tools to predict progression of disease, the success of treatment with Rifaximin and the success of treatment with albumin (see graph attached), and thereby improve outcome and reduce the health-care burden.