Project description
Linking gut bacteria to fibrosis in heart and liver disease
Fibrosis is a condition where excessive scar tissue forms, leading to organ damage. It plays a major role in heart failure and liver disease, but the underlying aetiology remains poorly understood. The ERC-funded IMPACT project aims to investigate the role of imidazole propionate (ImP), a molecule produced by gut bacteria and linked to diabetes and heart disease. Researchers will study how ImP levels relate to fibrosis and uncover the molecular pathways involved. The work will also involve the development of inhibitors to block ImP production and treat fibrosis. By uncovering how gut bacteria affect organ health, this project could lead to better treatment for heart and liver diseases.
Objective
Fibrosis is a pathological feature caused by excessive extracellular matrix secretion, resulting in scar tissue that causes thickening and loss of tissue mobility, culminating in impaired organ function. It is a common feature of heart failure and non-alcoholic steatohepatitis and an important determinant of morbidity and mortality. However, relatively little is known about the underlying aetiology.
We and others have mapped alterations in the gut microbiota in different cardiometabolic diseases, focusing on the functions performed by the microbiota. IMPACT builds on our work showing that humans with type 2 diabetes have high plasma levels of the microbial metabolite imidazole propionate (ImP) and that ImP impairs insulin signalling through p38gamma. We also resolved the X-ray crystal structure of urocanate reductase (UrdA), the bacterial enzyme responsible for ImP production. Our recent work showed that ImP is more strongly associated with heart failure and that treatment of mice with ImP promotes both cardiac and liver fibrosis, consistent with studies showing that p38gamma signalling is implicated in fibrosis development.
IMPACT will first use state-of-the-art clinical assessments to determine how circulating levels of ImP correlate with fibrosis in heart and liver. Second, we will explore the kinetics by which ImP induces fibrosis in mice and how this process is associated with immune cell infiltration and disease progression. Third, to provide mechanistic understanding, we will perform similar experiments in mice lacking key target signalling components (e.g. p38gamma), combined with single cell sequencing that will guide us in producing tissue-specific knockouts to elucidate the cellular cross-talk. Fourth, we will generate UrdA inhibitors and test their potential to reduce ImP production in isolated bacteria, complex microbial communities, and colonised mice. Thus, IMPACT has the potential of generating new therapies to diseases with unmet clinical needs.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- social sciences sociology demography mortality
- natural sciences biological sciences microbiology bacteriology
- medical and health sciences clinical medicine endocrinology diabetes
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2022-ADG
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405 30 Goeteborg
Sweden
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