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In the last decades, processed animal proteins, such as poultry by-product meal (PBM) and insect meals have received great attention as sustainable and nutritious aquafeed ingredients. The aim of the present study was to evaluate growth performances, liver and gut histology, macromolecular composition and inflammatory response in rainbow trout (Oncorhynchus mykiss) fed diets deprived of fish meal, where graded levels of vegetable protein-rich ingredients, were replaced by defatted Hermetia illucens pupae meal (HM) or PBM, singly or in combination. To this end eight grossly iso‐proteic (45% DM), isolipidic (26% DM) and isoenergetic (23.5 MJ/kg DM) were offered each to triplicated groups of juveniles' fish in a 91 days feeding trial. A diet rich in vegetable protein derivatives high in soybean meal (CV) was prepared to have a 10:90 and 20:80 fish to vegetable protein and lipid ratios respectively. By contrast, a fish-based diet (CF) was formulated with opposite fish to vegetable protein and lipid ratios. Six more diets, were obtained by replacing graded levels of protein (10, 30 and 60%) of diet CV , by protein from a defatted Hermetia illucens pupae meal and/or poultry by-product meal, singly or combined, while maintaining the same vegetable to fish lipid ratio as in the CV diet. Relative to diets CV and CF , a medium to high substitution (30 and 60%) of dietary vegetable protein-rich ingredients, with HM and/or PBM resulted in improved growth performance as well as in a minor incidence of distal intestine morphological alterations. The diet including both the test animal proteins led to nearly the best overall response in terms of growth and gut/liver health. Both HM and PBM when included at moderate or high levels in the diet, resulted in a downregulation of the expression of inflammatory-related genes relative to diet CV. This effect was greater with HM than that observed with PBM and goes beyond the parallel reduction of vegetable protein and SBM levels in the same diets, suggesting a beneficial role of insect meal that warrant further investigation. The results obtained so far, provide support to a reliable use of alternative/underexploited protein and lipid sources [(HM) or (PBM)] in developing a new generation of sustainable and healthy trout diets that meet the circular economy principles. • Insects and poultry by-product meal are suitable aquafeed ingredients. • A combination of poultry by-product and H. illucens resulted in better fish welfare. • H. illucens meal elicited an anti-inflammatory response in distal intestine. • FTIR resulted as a reliable technique to investigate fish metabolic responses. [ABSTRACT FROM AUTHOR]