Abstract
Soybean meal‐induced enteritis (SBMIE) remains a major barrier to reducing fishmeal use in salmonid aquaculture. This study evaluated physiological and molecular responses associated with SBMIE resistance in rainbow trout (Oncorhynchus mykiss) by comparing a commercial strain (Com) and a selectively bred strain (Sel) with over two decades of selection for plant‐based diet tolerance. Both strains were fed either a traditional fishmeal‐based (FM) or high‐soybean meal plant‐based (PM) diet for 7 months. Growth performance was monitored monthly, and intestinal histology and proteomics were assessed at early (2‐month) and late (7‐month) timepoints. The Sel strain consistently outperformed the Com strain in final weight, weight gain and feed conversion ratio (p < 0.05), with no differences in feed intake or mortality (p > 0.05). Average weight gain was greatest in the Sel strain across diets (497.3 g on PM; 610.2 g on FM), while Com trout gained less, particularly when fed the PM diet (387.9 g on PM; 482.6 g on FM). Significant strain by diet interactions in distal intestinal histology (p < 0.05) indicated that only the Com strain developed SBMIE on the PM diet, characterized by shortened, widened villi, mucosal fold clubbing, and inflammatory infiltration. Ordinal histopathology scoring confirmed interactions for goblet cells, submucosa, lamina propria, and inflammatory cell counts (p < 0.05), confirming the SBMIE susceptibility in the Com strain. Label‐free proteomics identified only 18 significantly altered proteins (FDR ≤0.05, |log2FC| ≥1), exclusively in plasma, despite pronounced intestinal pathology in Com PM. Key plasma DEPs included upregulation of the inflammasome sensor Nlrp1 in Com PM relative to Com FM, providing molecular evidence for systemic inflammation linked to SBMIE. Exploratory gene set enrichment analysis revealed distinct functional profiles, notably heightened stress, DNA damage, and innate immune signaling (e.g., TLR pathways) in Com PM intestine, while inflammatory signatures were absent in Sel PM. These findings highlight coordinated histological and molecular adaptations underpinning SBMIE resistance in the Sel strain, demonstrate the utility of plasma proteomics for detecting systemic biomarkers like Nlrp1, and emphasizes the combined roles of diet and genetics in improving feed flexibility and sustainability in aquaculture.