Descripción del proyecto
Impulsores de la autoinmunidad asociados al intestino
La colangitis esclerosante primaria (CEP) es una enfermedad hepática crónica asociada a la inflamación de los conductos biliares, que pueden cicatrizar y bloquearse. Los pacientes con CEP son aptos para el trasplante de hígado, pero la enfermedad puede reaparecer. La hipótesis de trabajo del equipo del proyecto StopAutoinmunity, financiado con fondos europeos, es que la CEP está causada por señales intestinales del microbioma que conducen a la autoinmunidad. Los investigadores estudiarán los genes de las bacterias intestinales y los metabolitos que circulan por la sangre de los pacientes con CEP antes y después de un trasplante de hígado. Los resultados proporcionarán información importante sobre el mecanismo subyacente a la etiología de la CEP y podría identificar nuevas dianas terapéuticas.
Objetivo
Autoimmune disease is an increasing health concern. These diseases are strongly associated with altered gut microbiome. When immunosuppression fails there is little to offer in terms of therapy. In this project, I hypothesize that gut signals (microbial factors from the intestine) unaffected by immunosuppression are key drivers of autoimmune diseases. I propose to use recurrent autoimmune disease after organ transplantation as a human disease model to identify and stop these gut signals, providing a novel approach to close the gap between basic microbiome research and patient care in autoimmune diseases.
To identify autoimmunity-related gut signals, I will use patients with primary sclerosing cholangitis (PSC), an inflammatory disease of the bile ducts. PSC is a common indication for liver transplantation, but after transplantation there is high risk of recurrent PSC (rPSC). I recently showed that the PSC gut microbiome has low diversity and identified microbial metabolites associated with severe PSC. Preliminary data show that the post-transplant gut is even less diverse, suggesting that microbial factors drive autoimmunity.
In this project I will identify gut signals by in-depth investigation of gut bacterial genes and circulating metabolites in the blood. The outcome will be diagnostic and prognostic markers overlapping in PSC and rPSC, defined by changes in gut bacterial genes and concentrations of bacterial metabolites in the blood. Next, I will investigate if common drugs or interventions influence the identified autoimmunity-related gut signals. By generating a library of interventions influencing the gut microbiome it will be possible to select promising candidates for pilot treatment trials after liver transplantation.
The outcome of StopAutoimmunity will be gut signals useful as novel biomarkers and treatment targets. These may directly translate into improved patient care but also provide a foundation for understanding the mechanisms of autoimmunity.
Ámbito científico
- natural sciencesbiological sciencesmicrobiologybacteriology
- medical and health scienceshealth sciencesinflammatory diseases
- medical and health sciencesbasic medicineimmunologyautoimmune diseases
- medical and health sciencesclinical medicinetransplantation
- medical and health scienceshealth sciencespublic healthepidemiologymodeling of diseases spread
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
0313 Oslo
Noruega