Targeting the cellular fatty acid metabolism in intestinal infection and inflammation

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Targeting the intracellular metabolism of immune cells is a promising emerging strategy for immunomodulation. Our previous work suggested that intracellular de novo fatty acid synthesis represents an important metabolic checkpoint for the reciprocal differentiation of Th17 versus regulatory T(reg) cells. The intestine serves as a major site for the induction of both Th17 and Treg cells, and the optimal regulation of the Th17/Treg balance is vital for normal intestinal homeostasis, resistance against infection and prevention from detrimental inflammation. It is the main objective of this proposal to study the impact of the two central processes of the cellular fatty acid metabolism, de novo fatty acid synthesis and fatty acid oxidation (FAO), on intestinal immune responses under in vivo conditions. To achieve this goal, we will use established as well as newly generated genetic mouse models that allow for the deletion of the key enzymes of fatty acid synthesis and FAO in specific immune- and non-immune cells, including T cells, innate lymphoid cells (ILC) and intestinal epithelial cells. This genetic approach will enable us to study the role of the cellular metabolism under infectious and inflammatory conditions in vivo, and to dissect the molecular and metabolic mechanisms by which the fatty acid metabolism influences immune cell fate and function in the intestine. In addition, we will assess the potential of pharmacological modulation of the fatty acid metabolism using specific inhibitors and translate these findings into the human system by analyzing the impact of the fatty acid metabolism in cells isolated from human intestinal tissues. The results of this work may not only lead to significant conceptual advances in the field of immunology, but will also offer an immediate therapeutic perspective for the treatment of gut-associated infectious and inflammatory diseases in humans