Maintaining epithelial integrity and a well-orchestrated host-microbiome crosstalk is essential for organismal health and life span throughout the animal tree of life. In human deregulation of this complex interplay is associated with chronic inflammatory diseases of barrier epithelia including inflammatory bowel diseases and asthma. The conserved transcription factor FoxO is long recognized as a major life span regulator, yet its role in metaorganism homeostasis remains unknown. In Hydra FoxO controls both stem cell activity and expression of components of the innate immune system such as antimicrobial peptides (AMPs) (Boehm et al., 2012). Comparative microbiome analyses to reveal impact of FoxO signaling on microbial colonization and microbiome resilience in Hydra.