Elucidating mechanisms of metabolic interaction and gene function in spatially interacting microbiome keystone bacteria

• Applicants: Professor Dr. Markus Ralser; Professorin Dr. Barbara Stecher-Letsch
• Subject Area: Metabolism, Biochemistry and Genetics of Microorganisms ; Microbial Ecology and Applied Microbiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 564414706

Gut microbes engage in critical interactions not only with their host but also with each other, driving microbiome functions essential for health and disease. Keystone species, such as Bacteroides caecimuris and Blautia coccoides, play pivotal roles in these processes. However, their functions and interactions are highly context-dependent, influenced by specific environmental and spatial conditions. Our preliminary data generated using our Oligo-Mouse-Microbiota (OMM12) model microbial community, suggest that metabolic pathways and cross-feeding interactions of these keystone species vary significantly across different media and gut regions. Moreover, as detected by proteomics, previously uncharacterized proteins were induced during species interactions. We hypothesize that keystone functions are modulated by environmental contexts, unannotated proteins mediate metabolite exchanges, and insights from OMM12 species can be extended to their human gut microbiota relatives. Our interdisciplinary team combines expertise in microbial ecology (Stecher lab) and metabolite exchange interactions as studied by advanced proteomic and metabolomic strategies (Ralser lab) to investigate the mechanisms underlying these microbial interactions and functions. We Aim to a) develop a comprehensive dataset of the OMM community under diverse nutritional, environmental, and spatial conditions, using in vitro cultivation systems and in vivo sampling from OMM colonies and disease models b) Identify molecular responses of keystone species to environmental variations, validating key pathways and metabolite exchanges through genetic and ecological perturbations. c) Assign roles to uncharacterized proteins in keystone species, validate up to five candidates, analyse proteomes of human gut bacteria, and create a web-based tool for data sharing and collaboration. By uncovering the context-dependent functions of keystone species and their interactions, this research will provide transformative insights into microbial community dynamics, advancing our understanding of their roles in gut health and disease.

• DFG Programme: Priority Programmes
• Subproject of: SPP 2474: Illuminating gene functions in the human gut microbiome
• Co-Investigators: Dr. Anna Georga Burrichter; Dr. Lisa Juliane Kahl