Approaching the Gut-Liver Axis’ is highly interdisciplinary and involves many different research areas, such as mucosal immunology, gastroenterology, microbiology, epithelial biology, imaging, and modelling. This diversity is challenging but also offers outstanding job opportunities for postdocs, doctoral students, Master students and technicians to develop a highly interdisciplinary and integrative mindset and to get into touch with a vast array of techniques.
We strongly encourage unsolicited applications! Please, directly contact the scientists in your project of interest or send your application to our Administrative Coordinator.
We currently offer PhD positions in six different projects of our CRC. All PhD projects will be carried out in Aachen and under the umbrella of our Graduate School IRTG ‘Gut-Liver Axis’.
Please see the job advertisement: in English and German here. You can directly upload your application via the online portal.
The six PhD projects are briefly summarized below:
Project A03: The role of proteomic stress in gut-liver axis
Alpha1-antitrypsin deficiency (AATD) arises due to inherited alpha1-antitrypsin (AAT) mutations. AAT constitutes a major serum anti-protease produced primarily in the hepatocytes, but also in the Paneth cells and inflammatory cells. A homozygous PiZ mutation, termed PiZZ, accounts for the major cause of severe AATD. PiZZ individuals are highly susceptible to the development of lung emphysema and liver cirrhosis, while inflammatory disorders or gallstone formation is less frequent. We are a worldwide leading center for study of AATD-associated liver disease that represents the second leading cause of AATD mortality. Using an unique set of human samples, we assess the high inter-individual variability as well as the impact of emerging treatment strategies. A particular focus is on the role of gut-liver axis-related factors in this process.
In your PhD thesis, you will investigate the impact of these factors on PiZ proteostasis/liver disease progression. You will analyse the role of inflammation, toxic bile acid overload, immune cells, intestinal metabolites in the PiZZ individuals as well as PiZ overexpressing animals. To that end, you will combine omics analyses with the work on transgenic animals and patient derived induced pluripotent stem cells (iPSCs).
Please contact Dr. hum. biol. Nurdan Güldiken or Prof. Dr. med. Pavel Strnad for further information!
Project A05: Functional analysis of lipid metabolism by the microbiome in gut-liver interactions
The gut microbiota and associated metabolites influence liver function. Project A05 focuses on the investigation of specific gut bacteria (in particular Coriobacteriia such as Collinsella aerofaciens) and their important within the gut-liver axis. In particular, we are interested in studying bacterial lipid metabolism (lipolytic activity and bile acid conversion). The work is based on anaerobic cultivation, molecular techniques to study microbial communities (high-throughput sequencing) and single species (genetic engineering), simplified models of the gut microbiota (synthetic communities), and gnotobiotic mice. The project is performed in close collaboration with the von Bergen lab at UFZ in Leipzig, contributing with further expertise in continuous culture systems and multi-omics approaches.
Please contact Prof. Dr. rer nat. Thomas Clavel for further information!
Project A08: Functional impact of genetic risk factors for disease progression within the gut-liver axis
Metabolic liver disease is a rising epidemic following the expansion of obesity in all parts of the world. Disease progression is associated with changes in intestinal microbiota as well as intestinal barrier function, suggesting a role for the gut-liver axis in metabolic liver disease.
Patatin-like phospholipase domain-containing protein 3 (Pnpla3) is a triacylglycerol lipase active in several cells involved in lipid metabolism, such as hepatocytes. A Pnpla3 polymorphism at position 148 is a well-established risk factor for metabolic liver disease. The farnesoid X receptor (FXR)-dependent regulation of BA synthesis via cholesterol 7alpha-hydroxylase (Cyp7A1) is a crucial determinant in predicting the outcome in patients with primary sclerosing cholangitis (PSC), a prototype disease of the gut-liver axis.
Our project will specifically focus on the risk factor PNPLA3I148M and gatekeepers of bile acid metabolism, e.g., FXR for disease progression within the gut-liver axis. These findings will direct our understanding towards novel therapeutic approaches.
In this PhD project you will
- Use genetic mouse models carrying the PNPLA3 polymorphism as well as organ specific FXR knockout mice to experimentally dissect the contribution of the intestinal microbiota, bile acid metabolism, diet and gut barrier integrity to liver disease.
- Analyze sex-specific differences determining FXR-mediated regulatory mechanisms between liver and intestine.
- Translate the experimental observations into the human situation and correlate them to clinical observations and outcomes in patients.
Please contact Dr. med. Lena Candels for further information!
Project B06: Topology and function of secretory antibodies in gut-liver communication
Secretory immunoglobulins (SIg) confer protection against toxins and pathogens. Additionally, SIg binds to gut microbiota affecting microbial metabolism, growth, motility, bile acid sensitivity and host-microbe interaction. The main antibody isotype produced in the gut-liver system is IgA. Yet, pathways inducing IgA responses to the microbiota and their coordination are only emerging.
In this project we are investigating the coordination of IgA responses in the gut-liver system. Combining single cell sequencing, bulk repertoire sequencing, flow cytometry and in vivo cell tracking, we investigate the contribution of different inductive compartments to generate IgA secreting plasma cells. In vivo cell tracking allows to follow the migration of individual cells from inductive compartments into gut and liver. Repertoire and single cell sequencing will allow to define their exact properties and to generate recombinant monoclonal antibodies to study their specificity for the microbiota and other intestinal antigens.
Further reading: IgA and the intestinal microbiota: the importance of being specific – PubMed (nih.gov)
Please contact Prof. Dr. rer. nat. Oliver Pabst for further information!
Project B08: Effects of the gut microenvironment on liver during cancer
Gut-liver communication is critical for immune homeostasis. However, the gut-liver axis also contributes to pathogenesis in cancer, where pathways of tissue regeneration and immune tolerance are exploited to favour tumour growth and dissemination.
Liver metastasis and cachexia associated with liver dysfunction are major factors in the pathogenesis induced by intestinal tumours in humans. The inflammatory mechanisms driving these processes most likely run in parallel and influence each other. In Project B08, we aim to use a combined approach employing mouse models and human tissue samples to address how tumours manipulate immune gut-liver communication.
This project relies on the side-to-side comparison of preclinical mouse models and human clinical samples. One PhD student will focus on the mouse models, while the other one will focus on the analysis of human material. Continuous exchange between the two arms of the project is a must.
The project relies on preclinical animal models, human material, high end flow cytometry, next generation sequencing, bioinformatics and a broad range of immunological and metabolic techniques.
Please contact Dr. rer nat. Ana Izcue or Prof. Dr. med. Ulf Neumann or further information!
Project B09: Elucidating microbiota-dependent and independent functions of inflammasome -mediated innate immunity during Hepatocellular carcinoma development
Hepatocellular carcinoma (HCC), the most common primary malignant liver tumor with rising incidence and still limited treatment options. Recent data demonstrate that HCC is significantly influenced by gut microbiota and the gut-liver axis, which may offer a new angle to treatment strategies. Previous research from our group has been investigating the role of the inflammasome sensor molecules, NLRP3 and NLRP6, and their interaction with the gut microbiota in the development of HCC. We have discovered that certain unfavorable microbiota can induce a TLR4-dependent expansion of hepatic monocytic myeloid-derived suppressor cells and suppression of T-cell abundance (Schneider et al., Nat. commun. 2023).
Building on our previous work, we hypothesize that the gut microbiota plays a significant role in shaping the inflammatory microenvironment of the liver, which critically affects the progression of liver disease towards cancer. We aim to characterize the impact of NLRP3 and NLRP6-inflammasome signaling and their downstream targets, IL-18R and IL-1R, on the hepatic tumour microenvironment and intestinal tissue and systematically dissect the microbiota-dependent and independent functions of inflammasome signaling in parenchymal and non-parenchymal cells.
These experiments may lead to new microbiota-dependent treatment strategies for HCC. Our project will employ a wide range of techniques such as general molecular biology techniques (e.g., PCR, Western blotting), microbiome analysis, in vivo and in vitro experiments, working with human specimen, flow cytometry, advanced microscopy and bioinformatic analyses.
This project provides an opportunity to learn and apply a range of advanced experimental techniques, contribute to a clinically relevant basic research, and potentially shape future HCC therapy and prevention strategies. As part of our team, you’ll work in a dynamic, collaborative environment, have the opportunity to present your findings in top-tier scientific meetings, and publish in high-impact journals.
This project offers a strong foundation for a career in either academia or the biotech and pharmaceutical industry, with an emphasis on translational research, immuno-oncology, and the increasingly recognized field of the microbiome in human health and disease.
Together, we aim to fill a critical gap in our understanding of the HCC pathogenesis and the influence of gut microbiota on the inflammatory response in the liver. Your work could significantly contribute to the development of novel therapeutic strategies for preventing or treating HCC and potentially other inflammatory and malignant diseases influenced by the gut microbiome.
Please reach out for more information! Contact: Prof. Dr. med. Dr. rer. nat. Kai Markus Schneider