Beyond immunity: The Imd pathway as a coordinator of host defense, organismal physiology and behavior

The humoral arm of host defense in Drosophila relies on two evolutionarily conserved NFκB signaling cascades, the Toll and the immune deficiency (Imd) pathways. The Imd signaling pathway senses and neutralizes Gram-negative bacteria. Its activity is tightly adjusted, allowing the host to simultaneously prevent infection by pathogenic bacteria and tolerate beneficial gut microbiota. Over-activation of Imd signaling is detrimental at least in part by causing gut dysbiosis that further exacerbates intestinal pathologies. Furthermore, it is increasingly recognized that the Imd pathway or its components also play non-immune roles. In this review, we summarize recent advances in Imd signal transduction, discuss the gut-microbiota interactions mediated by Imd signaling, and finally elaborate on its diverse physiological functions beyond immunity. Understanding the multifaceted physiological outputs of Imd activation will help integrate its immune role into the regulation of whole organismal physiology.