Gut bacteria-derived Metabolites and their Impact on the Pathogenesis of Primary Sclerosing Cholangitis

• Applicant: Professor Dr. Jörg Heeren
• Subject Area: Gastroenterology
• Term: from 2016 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 278045702

The relevance of the immuno-metabolic interplay for the pathogenesis of Primary Sclerosing Cholangitis (PSC) is not well understood. In the first funding period, we showed that cold exposure, feeding with cholesterol-enriched diet as well as inflammatory processes targeting biliary epithelial cells led to profound changes in bile acid and lipid metabolism that subsequently determined the composition of the gut microbiome. For the current project, we propose that known PSC-associated comorbidities including inflammatory bowel disease (IBD) and low bone mass result in distinctive serum lipid and bile acids signatures, reflecting altered metabolic processes in the liver, the vasculature and the gut of individual patients. By state of the art mass spectroscopy, we aim to identify subgroup specific metabolite signatures in PSC patients with high and low bone mass, as well as in PSC patients with and without concomitant IBD, respectively. Metabolites will be correlated by bioinformatics with the composition and/or metagenome of faecal and biliary microbiota, bone density, liver transcriptomics (if available) and clinical features of PSC such as IBD. To study the causal relationship between PSC-associated faecal dysbiosis and portal blood metabolites, we will quantify bile acids, short-chain fatty acids (SCFAs) and the lipidome in the caecum and portal blood of mice that were transplanted with faecal microbiota of healthy volunteers and PSC patients with or without concomitant IBD. Moreover, we will investigate whether bile acids and/or SCFAs influence the immune-modulatory functions of liver sinusoidal endothelial cells (LSECs). By the expression of typical and atypical adhesion molecules as well as cytokines, these liver cells regulate the recruitment of lymphocytes, their migration into the portal tract, and thus biliary inflammation. Here, we will investigate whether metabolite changes influence inflammatory signalling pathways that regulate the expression of adhesion molecules and cytokines in freshly isolated LSECs and in vivo PSC models. To define environmental factors that could contribute to PSC development, we will perform these studies in dependence on housing temperature, diet and the bacterial composition. Overall, these studies will show whether LSEC-dependent regulation of immune cell migration and portal tract inflammation observed in PSC patients is influenced by changes of gut-derived metabolites. To define the role of the G-protein coupled bile acid receptor 1 (GPBAR1, also known as TGR5) in this process, we will generate mice that lack TGR5 specifically in endothelial cells to test whether LSEC-dependent immune responses are altered by TGR5-dependent bile acid signalling. This broad experimental strategy will allow us to unravel whether e.g. by cold stress leading to increased energy expenditure modifies PSC and fibrosis.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 306: Primär Sklerosierende Cholangitis