Fast development of the aquaculture sector in the last decades conducted to a shortage in traditional ingredients (fishmeal and fish oil) that were not anymore avaible in sufficient quantity to purvey such growing aquafeeds needs. Ingredients of plant-derived raw materials, thus started to be preferentially incorporated into aquafeed formulas, and are nowadays being routinely used in most fish feed formulas. However, the total replacement of fishmeal and fish oil has not yet been reached due to negative impacts on feed intake and feed efficiency, perturbations of metabolic and health status, impacts on flesh quality, and growth performances slowdown. Single cell protein sources such as yeast protein products could be an alternative solution to complement and mitigate detrimental effects of plant proteins. This was assessed in a 12 weeks trial in which rainbow trout (Oncorhynchus mykiss) juveniles were fed with a plant-based diet (totally devoid of fishmeal and fish oil), containing 0, 5, 10 or 15% of a protein-rich yeast fraction and microalgae as DHA source. Results indicated that a 15% protein-rich yeast fraction inclusion may upgrade growth performance of trout fed plant-based diets by improving feed conversion ratio and body nitrogen retention. Surprisingly, 5% yeast incorporation in the diet leaded to enhanced accumulation of DHA in whole body that could be linked to a higher expression of the fatty acid elongase 2. Immune status and gut health of fish were also assessed through histological analyses and transcript expression level measurements of immune-related genes in distal intestine complemented by measurement of some plasma immune-related parameters. A lower score of lymphocytes infiltrates in lamina propria of fish distal intestine was observed from 10% inclusion level of the yeast fraction and the calculated overall inflammation score was greatly reduced with 15% inclusion level. In fish fed diets containing 5% and 15% yeast fraction, a higher internal perimeter: external perimeter ratio was measured compared to fish fed the control plant-based group. Inclusion of 15% yeast fraction in the plant-based diet also lead to an increased expression of mucin 5 and claudin a compared to 5% inclusion level. A statistically negative linear correlation was revealed between plasma neutrophils proportions and dietary yeast content. Plasma lysozyme concentration was lower in trouts fed diets containing 10% and 15% yeast fraction. All together, those results revealed that inclusion of yeast in a plant-based diet enables to improve rainbow trout gut health and global immune status