Fly projects

Cross-regulation of metabolism, innate immunity and the gut microbiome

Metazoans are in continuous contact with microorganisms which have co-evolved with plants and animals. They are important determinants for the range of diet supply for the host, they shape its immune system and they also restrict the uncontrolled proliferation of pathogenic bacteria in the symbiontic microbial community. The interactions of the host with its microbiota occur primarily at epithelial/mucosal surfaces such as in the gut or the skin. These tissues generate barriers that prevent the invasion of the pathogens into the body cavity, but they also provide beneficial physiological conditions that support commensal growth. Immune responses are tightly linked to energy homeostasis and it is well established that metabolic dysregulation e.g. due to overeating or genetic predisposition can cause inflammation in fat and other metabolic tissues. How energy metabolism, local immune regulation and microbiota functions in digestion and gut physiology are interconnected and cross-regulated in health and disease is, however, only beginning to emerge. One important research lines in the lab is to use Drosophila as a model organism to investigate how metabolism, innate immunity and the microbiome are crossregulated in Drosophila gastrointestinal physiology.

Towards this goal, we  have recently discovered a novel link between metabolic and stress signaling, and innate immune effector pathways (Becker et al., Nature 2010). We could demonstrate that fasting or starvation induces the expression of antimicrobial peptides in epithelial tissues such as the gut and that this innate immune response is observed under non infectious conditions independent of pattern recognition receptors. In fact, starvation, which is sensed through the absence of insulin, triggers the activation of the transcription factor FOXO, which, in turn, initiates antimicrobial immune response. These findings establish an entirely novel perspective in immune sensing by directly linking the metabolic or stress status of tissues with innate effector functions of the immune system. Of note, this newly identified connection goes beyond a modulatory role of metabolic or stress signaling for immune functions, as metabolic or stress signaling pathways had not been implicated as initiators of immune effector functions per se. Understanding the molecular mechanisms of phenomena, such as the relationship of fasting to reduced inflammation, or the loss of appetite associated with infection, are future and timely challenges. We are currently studying the crossregulation of metabolism and innate immunity in several Drosophila projects, including a putative significance of the FOXO-dependent mechanism for lifespan regulation.

Selected recent publication:

Becker T, Loch G, Beyer M, Zinke I, Aschenbrenner AC, Carrera P, Inhester T, Schultze JL, Hoch M. 2010. FOXO-dependent regulation of innate immune homeostasis. Nature 463: 369-73