One of the main objectives of the present study was an effective replacement of dietary fishmeal/fish oil (FM/FO) by new raw materials without negatively affecting European sea bass (Dicentrarchus labrax) performance and health status within a selection breeding context. The genomic selection of this species is still in its infancy if compared to salmonids and in particular, the role of D.labrax genome in shaping the gut microbiome, has been scarcely investigated. Wildtype (WT) and selected (GS) sea bass were fed with two diets: a control (20% FM/ 5–9% FO), and a “future” (F) diet, in which FM was decreased to 10% being replaced by poultry meal, whereas FO was completely replaced by a blend of rapeseed, poultry, and algae oils. The morphological evaluation of the intestine revealed a well-organized folding pattern and a conserved gut epithelial barrier for all fish groups. Despite a basal level of inflammation in the proximal intestine of WT fish, no differences were observed neither in the morphometric characteristics of goblet cells nor in the expression of GALT-related genes in response to fish genotype or diet. At distal intestine, WT fish showed a higher inflammatory status and larger goblet cells than GS fish and within the same genotype, fish fed the F diet had in general larger goblet cells. In distal intestine, a significant effect was found on the expression of 3 out of 7 target GALT genes. In particular, the expression of cytokines il-1β, tnf-α, and il-10 was different, showing an interaction effect diet x genotype. Diet had a lower influence upon gut bacterial composition than genotype. Indeed, regardless of the diet, WT fish showed higher species richness than GS genotype and this could be a direct consequence of selective breeding for multiple traits selection including growth, external morphology for lower abdominal fat deposition and adaptation to multiple and successive feed sources and composition across generations of selection. Furthermore, the gut microbiota of GS fish shared a reduced individual variability, indicating an enhanced capacity to cope with changes in diet composition. The less changes of GS sea bass at the level of gut bacterial composition in cumulating data collected with the feeds, demonstrate a capacity to reshape their microbiota thus better adapting to the diet, but with no negative impact on their growth performances, and even a better growth. A significant genotype effect was found for specific bacterial taxa, such as Paracoccus genus and other genera belonging to Moraxellaceae family, which were enriched in WT fish, regardless of the diet. Interestingly, the relative abundance of Paracoccus genus was positively correlated with higher proinflammatory cytokine il-1β expression found in distal intestine of wildtype sea bass.