Systemic Endotoxemia as the driver of chronic inflammation - Biomarkers and novel therapeutic targets for Arthritis

Informations projet

ENDOTARGET

N° de convention de subvention: 101095084

DOI

10.3030/101095084

Date de signature de la CE 15 Novembre 2022

Date de début 1 Janvier 2023

Date de fin 31 Decembre 2026

Financé au titre de

• Health

Coût total

€ 6 756 911,24

Contribution de l’UE

€ 6 756 911,24

Coordonné par

HUS-YHTYMA
Finland

Periodic Reporting for period 2 - ENDOTARGET (Systemic Endotoxemia as the driver of chronic inflammation - Biomarkers and novel therapeutic targets for Arthritis)

Période du rapport: 2024-07-01 au 2025-12-31

Résumé du contexte et des objectifs généraux du projet

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, we are investigating the importance of the gut microbiota and intestinal permeability 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, GIMM, 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, GIMM),
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 two interventional proof of concept studies: dietary intervention in RA (TASTY study; GIMM) and faecal transplantation (FMT study; UH) in AS
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.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

• The ENDOTARGET consortium has performed the biomarker analysis of blood samples from population cohorts for gut permeability and endotoxemia associated biomarkers. In total, more than 15,000 samples were measured during 2023-2025. 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 exploitation will take place during 2026 and associated tasks of WP5.
• Clinical trial TASTY, a 12-week diet intervention in RA patients, is currently ongoing and expected to conclude during Q2 2026. 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.
• ENDOTARGET continued collaborating with other sister-call projects, particularly the EU-HORIZON sister call project GLYCANTRIGGER and IMMEDIATE, in order to test the added value ENDOTARGET proposed biomarkers, particularly the LPS bioactivity biomarker that received wide attention, in another health-to-chronic disease transition, such as the GLYCANTRIGGER target disease, the Crohn’s disease. During 2026 a co-authored scientific article s expected to be submitted with GLYCANTRIGGERS researchers, and second one is currently being drafted with IMMEDIATE researchers.
• ENDOTARGET in vitro studies have also identified fibronectin acts as a biological "sponge," binding to these bacterial toxins and preventing them from triggering inflammation. This discovery, alongside computer modeling of how existing drugs like naloxone might block these toxic pathways, offers a promising roadmap for new therapies.
• ENDOTARGET mechanistic and cell-based studies, have observed indications that, beyond inter-species differences in endotoxemia-related effects, intra-species variability may also be biologically relevant. Preliminary experimental data suggest that different serotypes within the same bacterial species may differentially modulate cellular responses
• ENDOTARGET developed preclinical animal models to study the role of LPS in OA progression. These models were used to assess the effects of systemic and local LPS, revealing that systemic LPS did not cause significant cartilage damage but resulted in subtle changes in cartilage surface integrity and minimal synovial inflammation. In contrast, intra-articular LPS significantly elevated synovial inflammation.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

To achieve the aims and objectives of the ENDOTARGET project, different scientific and clinical work is planned during the project. As the work has not yet been completed, some of the expected results and impacts are still pending. Nevertheless, many findings were already shared through scientific papers on our website, with more planned during 2026. Furthermore, we continued extensive collaborations with sister-call projects (e.g. IMMEDIATE, GlycanTrigger) by participating in joint events, social media campaigns or newsletters/ blog articles.

ENDOTARGET goes beyond the current state of the art by adopting a holistic approach to understanding chronic inflammation in rheumatic diseases, with a particular focus on the gut–joint axis. While many of the results are still being exploited, the project has already established novel findings, as well as novel scientific, methodological and translational foundations that exceed existing knowledge and approaches. Some of them have already been shared via scientific publications and other communication & dissemination activities.
In terms of impact, our expected results will contribute to the creation of high-quality scientific knowledge, strengthen interdisciplinary research capacity, and support open science practices. Societally, they align with EU priorities on personalised prevention, healthy ageing and chronic disease management, empowering citizens and healthcare professionals with actionable insights. Economically, the project lays the groundwork for innovation in digital health, predictive diagnostics and experimental platforms.

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