Low input farming occurs under non-SPF (specific pathogen free) conditions. The European ban on in-feed antibiotics exposes the piglets to a higher microbial environmental pressure. The postnatal priming of piglets with a diverse microbiota may affect the development of the piglet’s host-defense and gut functionality. By reversal, the piglets developing host-defense may affect the development of the gastro-intestinal microbiota. Moreover, this intricate interplay between gut microbiota and its host during the early phases of life is expected to also affect animal health and performance later in life. The gut microbiome is an immensely diverse ecosystem that has co-evolved with its host. Recent research on microbe-host interactions has provided novel insights into the role of commensal intestinal microbes in several physiological processes, i.e., from epithelial barrier development to immune development as well as neurological aspects. Nevertheless, we only start to understand the molecular mechanisms of the host microbe cross-talk. Recent conceptual as well as technological advances have set the stage for the integrated application of a complementary set of high throughput approaches for the comprehensive profiling of GIT microbiota composition and functionality as well as the animal’s intestinal function. In a multidisciplinary consortium, comprising 11 public and private partners from across and beyond Europe with complementary expertise in gut microbiomics, immunology and physiology, and animal genomics and nutrition, INTERPLAY will apply an integrated approach to arrive at a sound understanding of the interaction of early colonization of the intestine and the development of gut function. This knowledge will be exploited for the identification of innovative management strategies that address host genotype as well as nutritional means to provide a framework for sustainable animal production at high food and consumer safety and improved animal health and welfare.