Former associated PhD Students

The Impact of the microbiome-bile acid axis on Barrett Esophagus (BE) and Esophageal Adenocarcinoma (EAC)

Technical University of Munich
Klinikum rechts der Isar
Gastroenterology

Supervisor
Prof. Dr. med. Michael Quante (Z02)

Description

The main precursor condition of Esophageal Adenocarcinoma (EAC) is Barrett´s Esophagus (BE). BE is mainly attributed to inflammation due to chronic reflux of gastric and bile acid. Risk of progression to EAC correlates with obesity and a western-style diet, which further affects the gut microbiome, including bile acid metabolizing bacteria. We could show by 16s sequencing and metabolomic analyses that high fat diet in mice leads to an altered microbiome and thus to altered bile acid metabolites in the blood, which correlate with accelerated malignant progression. Also, in humans we could show that different diagnoses are correlating to shifts in microbiome and serum bile acids. Gene expression analyses demonstrated that the nuclear bile acid receptor FXR, a key regulator in bile acid, metabolic and inflammatory signaling, was upregulated in BE but downregulated in EAC in humans and mice. A germline knockout FXR in IL-1ß mice accelerated malignant progression of BE. In intestinal cancer, changes in FXR expression had a strong impact on intestinal barrier function (Ting et al. 2019). This leads us to the suggestion that loss of FXR expression also increases barrier permeability in EAC, thereby enhancing the damaging effects of bacteria and bile acids. FXR, on metaplastic BE cells seems to be an important player to regulate the inflammatory effects of microbiome regulated bile acid exposure and the differential potential of progenitor cells at the gastro-esophageal junction. Obeticholic acid (OCA), a selective FXR agonist, has a protective function in organoids treated with the secondary bile acid deoxycholic acid (DCA). Interestingly, in mice treated with CD, HFD or HFD + OCA, histopathologic scoring showed a significant reduction of dysplasia in L2-IL-1b mice treated with HFD and OCA compared to mice on HFD only at the 9 month timepoint. This fits our primary hypothesis that activation of FXR prevents microbial effects and bile acid induced cell damage and thus disease progression. We are now aiming to investigate the local and systemic effect of bacteria on mice treated with different diets with or without OCA. Generally we plan to further elucidate the systemic impact of diet and the thereby affected microbiome – bile acid axis on disease progression in BE and EAC.

Publications

• Fu, Ting, et al. "FXR Regulates Intestinal Cancer Stem Cell Proliferation." Cell 176.5 (2019): 1098-1112

Improvement of Porcine Models for Cancer Research and Immunology

Technical University of Munich

Chair of Livestock Biotechnology

Supervisor

Prof. Dr. Angelika Schnieke (P12)

Description

There is a growing need for preclinical trial data from non-rodent species that the pig is well placed to fulfill as it provides a good representation of key aspects of human physiology, pathophysiology and anatomy and immunology. Our aim is to provide porcine models for colorectal cancer (CRC) and elucidate the interplay between genetic predisposition, inflammation and the microbiome in CRC. To this end we will refine an existing porcine model of colorectal cancer based on an APC¹³¹¹ mutation.

Pigs carrying an engineered truncating mutation in the endogenous APC gene (APC¹³¹¹, orthologous to human APC¹³⁰⁹) recapitulate all major features of familial adenomatous polyposis (FAP), an inherited human CRC predisposition disorder. These animals will be used to investigate the effect of changes in the gut microbiota on cancer progression and regression. The effects of additional oncogenic mutations known to play a role in the human adenoma-adenocarcinoma sequence, will be studied by ex vivo manipulations of polyp derived colonic organoids.  Organoids with APC¹³¹¹  and KRAS^G12D mutations in combination with various inactivated tumour suppressor genes will be generated, their proliferation, and altered pathways analysed and transplanted back into the same animal from which they were derived, to test the effect of mutation load on the microbiome. Manipulated organoids will also be co-cultured with bacteria, toxins and metabolites in vitro to elucidate host-pathogen interactions and analyse their transformation status.

Technical University of Munich
TUM School of Medicine
Institute of Pathology
Trogerstr. 18, 81675 Munich

Supervisor:
Dr. med. vet. Katja Steiger (Z02)

Description of Thesis 

Genetically engineered mouse models (GEMMs) are the most frequently employed animal models for human colorectal cancer (CRC) research. However, there are tumor characteristics which are different in mice and humans, whereas spontaneous tumors of companion animals (e.g., cats) resemble the human phenotype more closely. This project addresses the need for a standardized and comparative histological classification and grading system for animal models of human CRC. Following this comparative approach, we aim at further deciphering the role of different mast cell subtypes and the microbiome within the intestinal tumor microenvironment during adenoma-carcinoma progression by comparing diverse GEMMs for intestinal cancer, spontaneous feline, and human colorectal neoplasia.

Development and Application of System Medicine Tools for Knowledge Discovery in Microbiome Data

Technical University of Munich
TUM School of Life Sciences Weihenstephan
Chair of Experimental Bioinformatics

Supervisor
Prof. Dr. Jan Baumbach (INF01)

Description

coming soon

Microbiome in Covid-19 patients

Technical University of Munich
Klinikum rechts der Isar
Klinik und Poliklinik für Innere Medizin II
Ismaninger Str. 22, 81675 München

Supervisor
Dr. med. Moritz Middelhoff (Z02)

To investigate the role of the gut microbiome in the development of colorectal cancer we use classical cultivation approaches and simplified bacterial communities to dissect targeted meachanism involved in tumor progression

University Hospital of RWTH Aachen
Institute of Medical Microbiology
Functional Microbiome Research Group
Pauwelsstr. 30, 52074 Aachen

Supervisor
Prof. Dr. rer. nat. Thomas Clavel (P14)