Open positions in the following projects:
Project: Functional analysis of bile acids and the gut microbiome as important mediators of gut-liver interactions (PI: Prof. Dr. rer. nat. Thomas Clavel)
Bile acids are produced in the liver and regulate the resorption of lipids in the gut. Moreover, they alter the composition and functions of the gut microbiota, some members of which are able to metabolize them via deconjugation, dehydroxylation, or dehydrogenation with consequences on their bioavailability, biological properties, and metabolic functions in the liver. Hence, the crosstalk between bile acids and gut bacteria plays an important role in gut-liver interactions. However, little is known about the impact of specific secondary bile acids on liver physiology and about different bile acid types and levels on the gut microbiota and its metabolic activities. In this project, we will therefore focus on the following research questions using continuous culture and gnotobiotic mice:
1) By which mechanisms do bile acid compositions and concentrations impact gut microbiota community structure and functions in minimal and complex microbial communities?
2) What are the mechanisms underlying the impact of specific bile acid-metabolizing bacteria (Coriobacteriaceae) on microbial community functions and on the host?
3) What is the basis of host species-specific features of the gut microbiota-bile acids crosstalk?
Our findings will deliver novel insights into the ecology of microbiota-bile acids interactions and their contribution to liver pathophysiology.
Project: Consequences of bile salt signalling for liver regeneration and pathophysiology (PIs: Prof. Dr. med. Steven Olde Damink, Frank Schaap,Ph.D.)
Besides facilitating lipid absorption, bile salts activate membrane-bound and intracellular receptors, thereby regulating gut barrier integrity, metabolic liver functions, hepatic bile salt levels, and the regenerative response of the liver following parenchymal injury or surgical resection. A balanced and coordinated response involving the innate immune system and bile salt signalling in both small intestine and liver is required for normal progression of liver regeneration after partial hepatectomy. Disruption of enterohepatic bile salt circulation often occurs in patients with malignancies that obstruct bile flow. Post-operative complications are relatively more frequent and more severe, following extended liver resection for perihilar cholangiocarcinoma (pCCA). This seems to relate to infectious complications, and abrogated bile salt signalling and/or bile salt toxicity in the remnant liver, resulting in defective recovery of liver function, with frequent lethal outcome.
Bile salt signalling is interwoven with the gut microbiota: bile salts are actively metabolized by the gut microbiota with functional impact for the host, and bile salts have direct antimicrobial properties. The gut microbiota modulates liver regeneration in animal models of partial hepatectomy. In this project we will study the interaction between the gut microbiota and innate immunity in the context of liver regeneration. The proposal is largely based on studies in patients and analysis of patient materials, thus, adding a strong translational aspect to the gut-liver axis studies of the consortium. Specific aims are:
1) To acquire in-depth insight into enterohepatic fluxes of bile salts and regeneration-related signalling molecules in patients with normal and abrogated enterohepatic circulation, under basal and stimulated conditions.
2) To study the consequences of an abrogated enterohepatic circulation on bile salt signalling in the human intestine and liver.
3) To improve regeneration of the post-cholestatic human liver.
4) To study the effect of gut microbiota modification on bile salt signalling in the human liver.
5) To improve therapeutic strategies in animal models of post-resectional liver failure.
The combined studies provide in-depth insight into the gut-liver axis of bile salt signalling in humans, and modulating effects of disease and antibiotic treatment. This theoretical framework is used to rationalize novel approaches to prevent/treat post-resectional liver failure.
Project: Enterohepatic cooperation in the postnatal establishment of immune homeostasis (PI: Prof. Dr. med. Mathias Hornef)
With birth, the neonate organism becomes exposed to maternal and environmental microorganisms that rapidly generate a dense and highly dynamic enteric microbiota. Concomitantly, the intestinal epithelium matures and the liver undergoes functional transition from a hematopoietic organ to a central organ of metabolic regulation and immune surveillance. Together, the intestinal mucosa and the liver form a barrier to maintain host-microbial homeostasis and shield the systemic circulation from gut-derived microbial and environmental stimuli. The structural and functional mechanisms that facilitate the establishment of this barrier during the postnatal period are ill-defined. Failure to generate a cooperative gut-liver barrier and to separate the densely colonized enteric lumen from the systemic circulation might, however, exert lasting influence on the liver function as well as systemic immune homeostasis. Aim of the present study is the identification and characterization of both adaptive and developmental mechanisms that facilitate postnatal establishment of the gut-liver barrier, prevent an inappropriate immune response to postnatal microbial exposure and shape bacterial colonization. Specifically, we will work on the following aims:
1) Characterize the postnatal establishment of the gut-liver barrier.
2) Define adaptive responses of the hepatic tissue to postnatal microbial exposure.
3) Analyse the influence of the excretory liver function on neonatal host-microbial homeostasis.
Project B01 aims at a comprehensive characterization of the structural and functional changes of the intestinal epithelium and hepatic tissue during the transition from foetal to postnatal life.
Project: Tissue regeneration as a critical component of gut‐liver homeostasis (PI: Prof. Dr. rer. nat. Christian Liedtke, Dr. nat. med. Yulia Nevzorova)
The intestinal epithelium is characterized by a high cell turnover involving proliferation of progenitor cells and apoptosis of differentiated enterocytes. Any disturbance of this homeostasis e.g. through impaired proliferation or by toxic agents may result in increased intestinal permeability, translocation of bacterial products from the gut to the liver and secondarily to chronic liver disease. E-type Cyclins (Cyclin E1, Cyclin E2) are regulatory subunits of the Cyclin-dependent kinase 2 (Cdk2) and mediate the transition of resting cells into cell cycle progression. In the last decade we have uncovered several important functions of Cyclin E1 in the setting of chronic hepatic and intestinal injury. We provided evidence that Cyclin E1 is essential for initiation of liver fibrosis and hepatocellular carcinoma and plays a role for the prevention of intestinal permeability in the setting of excessive alcohol challenge. In this project we hypothesize that the Cyclin E/Cdk2 complex is important for the maintenance of a functional intestinal barrier and aim to determine the consequences of a de-regulated cell cycle for the intestinal permeability and subsequent crosstalk with the liver. The following aims will be addressed:
1) To evaluate the impact of E-type Cyclins and Cdk2 for basal intestinal regeneration and maintenance of gut- liver homeostasis.
2) To analyse the impact of Cyclin E1-complexes for gut-liver communication upon alcoholic challenge.
3) To define the role of E-type cyclins for development of colorectal cancer (CRC) and gut-liver metastasis.
In summary this project will identify the essential core cell cycle machinery in the intestine required for barrier homeostasis and balanced versus imbalanced gut-liver interactions in stages of health and disease.