ExoMod: Design of a targeted microbiome exometabolome modulation approach for the rational design of microbiome-based therapies for metabolic disease

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The microbiome is increasingly receiving attention as an important modulator of host health and disease. While a considerable number of links between changes in microbiome composition and disease processes in Type 2 Diabetes (T2D) have been identified, a key limitation in the translation of these findings into therapies is a lack of approaches for the targeted modulation of microbiome-host interactions. While the nutritional supplementation with fibers or probiotics has an effect on microbiome composition, this does not allow for a targeted modulation of individual microbial species or functions. Similarly, fecal microbiota transplants transfer entire microbial communities and thereby not only desired traits. The aim of this project is to overcome this limitation in the establishment of microbiome-based therapies by developing a combined experimental-theoretical workflow for the design of approaches for targeted modulation of metabolite production by the microbiota. For this purpose, we will focus on the production of nucleotides by the microbiota for which prior research by us and others indicates an important role in the pathogenesis of metabolic diseases. In our work, we will start with focusing on SIHUMIx, a minimal microbiome model community for which we will reconstruct accurate in silico models from a large array of experimental data in an iterative theoretical-experimental workflow. Using this in silico model, we will propose metabolite sets that can boost nucleotide production by the microbiota which will be tested experimentally. In parallel, we will establish in vitro as well as in silico models of the microbial communities T2D patients as a specific case of metabolic disease for which we will investigate changes in the microbial nucleotide production capacity. These communities will be used for further validation of the developed intervention approaches. Thus, this project aims to pave the way toward the development of targeted microbiome therapies as a novel therapeutic option in the treatment of T2D and other microbiome-driven diseases.