Medizinische Klinik
Innere Medizin I
Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie

Cancer immunotherapy with immune checkpoint inhibitors or CAR-T cells are becoming a standard-of-care for an increasing number of cancer entities, and are a viable option for a dozen of other tumor diseases. Despite promising results, these emerging new therapies necessitate precise biomarkers and predictors for treatment response and immune-related adverse events. The gut microbiome has recently emerged as a major factor determining host immunity, and previous studies have collected strong evidence that gut commensal microbes and their metabolites affect immunotherapy outcomes in mice and humans. However, the exact mechanisms and requirements remain unclear. 

Together with colleagues at the Universities of Tübingen as well as national and international collaborations, we are studying the role of the gut microbiome in the efficacy and development of toxicities of CD19-targeting CAR-T cell therapies against hematologic malignancies and of immune checkpoint inhibitors against solid tumors. We are using mouse models and conduct collaborative clinical biomarker studies. Our research focuses on the effects of diets and antibiotics on microbiome compositions, and how microbial dysbiosis can affect antitumor immunity and immune cell regulations through signaling of microbial metabolites. 

One of the most important challenges in translational microbiome research is to go beyond association and study causality. A major achievement to prove causation and study mechanisms lies within the transfer of individual microbes or whole microbiome configurations into germ-free mice. Within the new M3 – Institute at the University of Tübingen and its germ-free and gnotobiotic animal facility we are probing into mechanisms of microbe-host interactions in development of pancreatic and colon cancers and in metastasis. We have also a particular interest in the effects of the microbiome on regulation the action and toxicities of chemotherapies against these tumor entities.

Treatment with antibiotics can destroy the intestinal microbiome rendering patients vulnerable to expansion and/or colonization with Enterococcus, Klebsiella, Pseudomonas and other pathogenic gut residing bacterial species. Such a dysbiosis increases the risk for bloodstream infections in immunocompromised hosts, e.g., in patients undergoing cancer therapies. We are studying how microbiome injuries through antibiotics or diets can facilitate pathobiont expansion and colonization processes in mouse models and how these bacteria, specifically enterococci, affect mucosal homeostasis and T cell biology of the host. In clinical studies, we investigate environmental sources and transmission processes of these pathogenic bacteria within clinical settings and in vulnerable, highly immunocompromised patient cohorts. In our laboratory, we are also interested in the interaction of the microbiome with virus infections, primarily COVID-19, and microbe – immunity cross-talks that may facilitate long-term sequelae of virus infections.

Important challenges in microbiome sciences relate to targeted modulations of the gut microbiome in clinical settings. This is of particular importance for either preventing dysbiosis or restoring gut microbial homeostasis in patients receiving antibiotic treatments. In the Stein-Thoeringer laboratory we are working on identifying clinical factors, e.g., diets or chemotherapy, that are linked to antibiotic-induced microbiome dysbiosis in various patient cohorts. We are also probing into microbiome interventions through fecal microbiota transfers, dietary modifications or small molecules to change the microbiome and/or restore homeostasis as well as to modulate clinical outcomes.