DFG Research Unit RU 5042: The microbiome as a therapeutic target in inflammatory bowel diseases, Project 6: Cultivation and characterization of IBD-relevant microbes

Single microorganisms as well as the dynamics in microbiome composition play an essential role in maintaining gut homeostasis and are known to be altered in IBD. While changes in microbiota compositions have been well-investigated on a genetic basis, functional data on its disease-modulating potential are largely missing and its usefulness as a discriminative marker for IBD needs improvement. To date, it is largely unknown how functional profiles change in single members of the microbiota and complete bacterial communities at IBD initiation, progression and during therapeutic interventions. Defining detailed metabolite and protein profiles and gaining knowledge about bioactivities of specific molecules in their direct interaction with the host within bacterial communities is a pre-requisite for a better functional understanding of the gut microbiome in IBD. Qualitative and quantitative proteome analyses in single bacteria and complex bacterial communities isolated from environmental or medical samples have been shown the central functions of the proteomes which fulfil and orchestrate biological processes in cells and finally also define the composition of their metabolomes. Metaproteomic studies led, for example, to the identification of proteins and pathways involved in bacterial oxidative stress response in microbiomes of IBD patients. However, both due to the complexity of microbiomes and the relatively superficial coverage of metaproteomes by bottom-up proteomics data, an in-depth elucidation of the molecular mechanisms triggering the interorganism-interactions can only be deduced indirectly. Here, the in-depth characterization of defined bacterial co-cultures (including proteogenomic approaches), with its potential to study defined environmental conditions, offers improved possibilities in understanding the respective functional interdependence. Such studies have up to now not been systematically performed. Within this project we aim to improve the understanding of the functional relevance of microbiota changes in IBD patients upon disease initiation, progression and treatment responses. To do so we will correlate the molecular patterns of single bacterial isolates with their (either beneficial or non-beneficial) role in IBD, decipher the molecular potential of single microorganisms altered in the presence of other bacteria (co-cultures), and elucidate whether the interaction with the host is mediated for single bacteria, how is this interaction is triggered in bacterial communities. Comparing single-bacteria analyses with bacteria-bacteria and bacteria-host interactions in vitro and ex vivo will deliver a broad experimental data base for deciphering the situation in vivo in IBD patients and healthy controls. Defining regulatory and compensatory mechanisms in microbial communities of IBD patients on a functional level will provide novel biomarkers for disease activity and progression and may result in therapeutic options in the future.