Periodic Reporting for period 1 - ENDOTARGET (Systemic Endotoxemia as the driver of chronic inflammation - Biomarkers and novel therapeutic targets for Arthritis)
Période du rapport: 2023-01-01 au 2024-06-30
Rheumatic diseases (RDs) and musculoskeletal disorders affect more than 40% of the European population, causing significant disability, pain, reduced life expectancy and a very high economic burden of around 240 billion euros per year. The available therapies focus on addressing the symptoms, often accompanied by severe side effects. Currently, these diseases are considered incurable, and to date, their exact causes remain largely unknown.
In this project, the ENDOTARGET consortium is investigating the importance of the gut microbiota as a driver of chronic systemic inflammation and its role in the pathogenesis of RDs, with a special focus on osteoarthritis (OA), rheumatoid arthritis (RA) and spondylarthritis (SpA).
We are studying the events leading to disease onset by
i. taking advantage of 12 geographically diverse large cohorts with available blood and faeces samples (HUS, UTARTU, SERGAS/FIDIS, iMM, UH, UNICAM),
ii. search for novel risk biomarkers for RA, SpA, and OA by using high-throughput OMICS-based analyses (UTARTU, SERGAS/FIDIS, UH),
iii. conducting targeted clinical studies (HUS, UH, UNICAM, iMM),
iv. performing in vitro mechanistic studies to explore the gut-joint axis using tissue explants, cultures, and organ-on-chip models (SERGAS/FIDIS, UH, ETHZ, TUW),
v. conducting three interventional proof of concept studies: dietary intervention in RA (TASTY study; iMM), faecal transplantation (FMT study; UH) and a gut permeability decreasing drug in RA (LARA study; iMM, HUS, UNICAM, EBRIS),
vi. exploring in vitro new potential drugs or nutraceuticals (SERGAS/FIDIS)
By combining all these results, a machine learning and AI-informed rheumatic disease prediction tool will be developed by NEC and SIB for the use of clinicians to predict the health-to-disease transition of RDs and their severity. Furthermore, by the analysis of a wide variety of possible risk factors (genetic, lifestyle, biological) and their association towards developing RDs from collected data, we will help to educate and empower patients and to contribute to an holistical approach for RDs. This will significantly reduce the burden of disease on RD patients.
Simultaneously, the ENDOTARGET project will also have a positive economic impact by reducing healthcare costs and enabling efficient allocation of these saved healthcare costs.
In this project, the ENDOTARGET consortium is investigating the importance of the gut microbiota as a driver of chronic systemic inflammation and its role in the pathogenesis of RDs, with a special focus on osteoarthritis (OA), rheumatoid arthritis (RA) and spondylarthritis (SpA).
We are studying the events leading to disease onset by
i. taking advantage of 12 geographically diverse large cohorts with available blood and faeces samples (HUS, UTARTU, SERGAS/FIDIS, iMM, UH, UNICAM),
ii. search for novel risk biomarkers for RA, SpA, and OA by using high-throughput OMICS-based analyses (UTARTU, SERGAS/FIDIS, UH),
iii. conducting targeted clinical studies (HUS, UH, UNICAM, iMM),
iv. performing in vitro mechanistic studies to explore the gut-joint axis using tissue explants, cultures, and organ-on-chip models (SERGAS/FIDIS, UH, ETHZ, TUW),
v. conducting three interventional proof of concept studies: dietary intervention in RA (TASTY study; iMM), faecal transplantation (FMT study; UH) and a gut permeability decreasing drug in RA (LARA study; iMM, HUS, UNICAM, EBRIS),
vi. exploring in vitro new potential drugs or nutraceuticals (SERGAS/FIDIS)
By combining all these results, a machine learning and AI-informed rheumatic disease prediction tool will be developed by NEC and SIB for the use of clinicians to predict the health-to-disease transition of RDs and their severity. Furthermore, by the analysis of a wide variety of possible risk factors (genetic, lifestyle, biological) and their association towards developing RDs from collected data, we will help to educate and empower patients and to contribute to an holistical approach for RDs. This will significantly reduce the burden of disease on RD patients.
Simultaneously, the ENDOTARGET project will also have a positive economic impact by reducing healthcare costs and enabling efficient allocation of these saved healthcare costs.
• The ENDOTARGET consortium has started evaluating samples from population cohorts for gut permeability and endotoxemia associated biomarkers. Currently 10,000 samples have been measured with at least 6,000 samples left to be analyzed during 2024. Currently, preliminary data indicate an association between systemic endotoxemia biomarkers, as well as correlation between gut permeability, and endotoxemia in certain patient’s disease subsets. Final results for these tasks, inserted in the WP1: Population cohort analysis to explore biomarkers and lifestyle factors influencing health to disease transition, are expected by the end of 2026.
• We have also started the study the effects of endotoxemia in OA animal preclinical models. Namely we are currently analyzing serum samples from studies where OA animals were subjected to diet-induced obesity. Furthermore, in two separate studies we are evaluating the protective effects of fiber supplementation and exercise on the knee health and evaluate if the gut permeability and endotoxemia are modulated by such factors. The results from these studies are expected to be completed by 2025.
• The ENDOTARGET consortium has started the clinical trial TASTY, a 12-week diet intervention in RA patients. This trial studies whether nutritional intervention based on the Mediterranean diet with fermented products can influence the gut microbiota, gut permeability and thereby modulate the disease activity and quality of life of RA patients. The trial started recruiting the 1st patients in June 2023 and is currently ongoing. Final results from this study are expected to be completed by 2025.
• The consortium started a close scientific collaboration with the GlycanTrigger EU sister call project. GlycanTrigger aims to study the main causes of the uncontrolled inflammation of the gastrointestinal (GI) tract in Crohn’s disease (CD) and ulcerative colitis (UC). Together, the two EU projects are now analyzing endotoxemia and gut permeability associated biomarkers in CD and UC diseases to study their potential contribution to the disease mechanisms and the health-to-chronic inflammation transition. Current Preliminary results indicate that gut permeability (zonulin biomarker) is altered prior to CD onset. Furthermore, preliminary results indicate a clear impact of the patient sex on gut permeability and endotoxemia status. Final results from these studies are expected to be completed by 2025.
• We have conducted in vitro and in vivo studies on the effects of LPS derived from different strains of the same bacteria using various joint cell types. This serves as a reference for comparison with LPS from other bacteria potentially linked to gut dysbiosis and endotoxemia associated with rheumatic diseases. Through this process, we have identified for the first time that, beyond the pathogenic role of certain bacterial types, the bacterial strain type could play a crucial role in the development of inflammation. This finding highlights the complexity of identifying pathogenic intestinal bacterial species and suggests the possibility of fine-tuning the intestinal microbiota at the strain level. These results are expected to be available by the end of 2025.
• We have also started the study the effects of endotoxemia in OA animal preclinical models. Namely we are currently analyzing serum samples from studies where OA animals were subjected to diet-induced obesity. Furthermore, in two separate studies we are evaluating the protective effects of fiber supplementation and exercise on the knee health and evaluate if the gut permeability and endotoxemia are modulated by such factors. The results from these studies are expected to be completed by 2025.
• The ENDOTARGET consortium has started the clinical trial TASTY, a 12-week diet intervention in RA patients. This trial studies whether nutritional intervention based on the Mediterranean diet with fermented products can influence the gut microbiota, gut permeability and thereby modulate the disease activity and quality of life of RA patients. The trial started recruiting the 1st patients in June 2023 and is currently ongoing. Final results from this study are expected to be completed by 2025.
• The consortium started a close scientific collaboration with the GlycanTrigger EU sister call project. GlycanTrigger aims to study the main causes of the uncontrolled inflammation of the gastrointestinal (GI) tract in Crohn’s disease (CD) and ulcerative colitis (UC). Together, the two EU projects are now analyzing endotoxemia and gut permeability associated biomarkers in CD and UC diseases to study their potential contribution to the disease mechanisms and the health-to-chronic inflammation transition. Current Preliminary results indicate that gut permeability (zonulin biomarker) is altered prior to CD onset. Furthermore, preliminary results indicate a clear impact of the patient sex on gut permeability and endotoxemia status. Final results from these studies are expected to be completed by 2025.
• We have conducted in vitro and in vivo studies on the effects of LPS derived from different strains of the same bacteria using various joint cell types. This serves as a reference for comparison with LPS from other bacteria potentially linked to gut dysbiosis and endotoxemia associated with rheumatic diseases. Through this process, we have identified for the first time that, beyond the pathogenic role of certain bacterial types, the bacterial strain type could play a crucial role in the development of inflammation. This finding highlights the complexity of identifying pathogenic intestinal bacterial species and suggests the possibility of fine-tuning the intestinal microbiota at the strain level. These results are expected to be available by the end of 2025.
To achieve the aims and objectives of the ENDOTARGET project, different scientific and clinical work is planned during the project. As the project is still in the early stages and most of the work has not yet been completed, expected results and impacts are still pending. Nevertheless, some of the findings were already shared through scientific papers on our website, with more coming. Furthermore, ENDOTARGET has established collaborations with similar projects (e.g. IMMEDIATE, GlycanTrigger) by organizing joint events, social media campaigns or newsletters/blog articles.