Functional investigation of Salmonella-microbiota-host interactions by microaerobic intestinal organoid models from humans and chickens

• Applicant: Professor Dr. Thilo Martin Fuchs
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Metabolism, Biochemistry and Genetics of Microorganisms
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545894655

The composition, functionality, and activity of a healthy gut microbiota is a major pillar of the colonization resistance (CR) of humans and animals that protects against infection by foodborne pathogens. CR can be mediated via direct interbacterial mechanisms or indirect pathways involving the host. Importantly, this potential can be harnessed for the design of prevention and treatment strategies against diarrhoeal infections which represent a major cause of morbidity and mortality worldwide. To this aim, a thorough understanding of the functional and molecular mechanisms underpinning CR is vital. While studies using cancer-derived cell lines and mouse models have greatly contributed to current insights into the mechanisms of CR, the validity of these findings needs to be confirmed in appropriate human and animal models. Of particular promise are organoid systems which offer unprecedented insights into the interaction of Salmonella, the host and its microbiota. Here, we will focus on the major zoonotic pathogen Salmonella enterica which is commonly transmitted via chickens. In line with the research area “Integrative microbiome” of the BBSRC-UKRI-DFG call, we will (i) establish two physiologically relevant microaerobic organoid-based in vitro models which allow co-culture of human and chicken intestinal epithelia with oxygen-sensitive synthetic and complex microbial consortia. We will subsequently apply this novel system to ii) identify anaerobic bacteria with antagonistic activities against salmonellae in these models, and iii) to characterize activities of specific gut commensals mediating direct or indirect CR against salmonellosis in humans and chickens. By combining competitive growth experiments, novel human and chicken intestinal organoid models, Omics approaches, and bioinformatic data integration, we will be able to determine functional Salmonella-microbiome-host interactions. Taken together, this project will lead to the development of a new advanced in vitro model of the human and chicken intestinal epithelium which will enable the identification of functional host-pathogen-microbiota interactions, allow more reliable screening of probiotic candidates and reduce the animal use in microbiota research. In consequence, a better understanding of CR towards Salmonella in humans and chickens will inform strategies for targeted probiotic therapies which will benefit human and animal health and reduce antibiotic use according to the One Health approach.

• DFG Programme: Research Grants
• International Connection: United Kingdom
• Cooperation Partner: Dr. Stephanie Schüller