Systematic Triangulation of Pathobiont-Host-Interactions

Informazioni relative al progetto

SOAR

ID dell’accordo di sovvenzione: 101115638

DOI

10.3030/101115638

Data della firma CE 29 Settembre 2023

Data di avvio 1 Gennaio 2024

Data di completamento 31 Dicembre 2028

Finanziato da

• European Research Council (ERC)

Costo totale

€ 1 993 688,00

Contributo UE

€ 1 993 688,00

Coordinato da

EBERHARD KARLS UNIVERSITAET TUEBINGEN
Germany

Periodic Reporting for period 1 - SOAR (Systematic Triangulation of Pathobiont-Host-Interactions)

Periodo di rendicontazione: 2024-01-01 al 2026-06-30

Sintesi del contesto e degli obiettivi generali del progetto

Rising incidences of chronic disorders and cancer have been linked to reduced microbial diversity. Genetic risk factors are also involved in the development of chronic disorders and cancer. The effect of both microbial and genetic factors is especially clear in inflammatory bowel disease (IBD) and colorectal cancer (CRC). The identification of specific bacteria that trigger/drive disease or modulate therapy efficacy in IBD and CRC is difficult, also due to a lack of comprehensive approaches. The paucity of so far identified disease relevant bacteria and their mode of action, likely lies in the complexity of both the microbiome and the host’s genetic risk factors. We hypothesize that specific bacteria, which do not harm the host under steady state conditions, hijack host pathways in the presence of certain genetic risk factors to drive inflammation, onset and progression of IBD and CRC.
It is our objective to identify these pathobionts and link them to host genetic risk. To do so, we have developed a method that utilizes immune responses against harmful bacteria to detect them. We want to further improve this method through developing a high throughput-pathobiont identification technology. We then aim to test the effect of isolated, harmful bacteria in animal models that have a defined genetic risk. Lastly, we will utilize the gained knowledge to identify the frequency and population of patients where the disease is driven through these harmful bacteria and genetic risks.
Identification of harmful bacteria in the context of the patients’ genetic risk factors will open the door to patient-specific therapeutic interventions.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

Our project in includes four work packages (WP).
WP 1 aims at isolating putative harmful bacteria from patients with inflammatory bowel disease (IBD) and colorectal cancer (CRC). From IBD patients we have sorted, isolated and cultured close to 80 unique bacterial taxa. From CRC patients we cultured close to 40 intratumoral bacterial species. Moreover, as outlined in WP1 we also planned to collect from an interventional clinical trial where IBD patients will receive exclusive enteric nutrition therapy. This trial is now finally approved and recruiting (NCT06953791. https://clinicaltrials.gov/study/NCT06953791)
WP2 aims to overhaul and reinvent the isolation approach for putative, harmful bacterial taxa to enable high-throughput approaches and conserves time and resources. To do so, we are developing a new, ground-breaking technology to isolate harmful bacteria. While still in development, we have made crucial advances such as developing specialized microfluidic chips for bacteria.
WP3 aims at linking genetic risk with putative harmful bacterial taxa. We have used bacterial taxa isolated in WP1 and hosts that carry defined genetic risk factors. Two harmful bacterial taxa induced disease only in mouse models carrying a genetic risk, but not wild type animals, showcasing the fidelity of our concept.
WP4 serves to use the gained knowledge on pathobiont-host risk interactions from WP1-3 to identify subpopulations in IBD and CRC that may respond well to future microbiome precision therapies. One harmful bacterium that we identified is present in increased abundance in patients with Crohn´s Disease and Ulcerative colitis in about 25-30% of patient, compared to healthy individuals. The other pathobiont shows a similar enrichment, but in a smaller subpopulation of about 5% of IBD patients. This revealed the heterogeneity of harmful bacterium occurrence in the general IBD population, as anticipated. Moreover, abundance of harmful bacteria correlated with inflammatory transcripts in IBD patients, highlighting their impact in a subpopulation of patients.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

Two aspects have the potential of going beyond the state of the art. On the one hand we have developed a pipeline that allows a patient-individual identification of specific bacterial drivers of diseases and even reveal compounds that selectively inhibit their growth. This opens the door for patient specific therapies using microbiome targeting strategies. Further demonstration in a larger cohort of patients will be required to bring this tool to a wider audience and to develop it commercially.
Secondly, we are developing a prototype for novel biomedical research to improve the identification of harmful bacteria. While this task is not completed yet, we have made important steps towards this goal and further research is required to finalize this device.