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Soy protein is the major source of protein as fishmeal replacement in fish feed because of its worldwide availability and low price. However, the presence of high carbohydrate content along with saponins, lectins, and phytates can have a negative impact on fish gut health. Based on the literature and our lab studies, dietary soybean meal can cause a dose-dependent type of distal intestine inflammation called enteritis in commercial fish species including salmonids. This leads to reduced absorptive capacity, increased mucus secretion, hyperpermeability, and leucocyte infiltration in the lamina propria and submucosa, also inducing the pro-inflammatory cytokine genes expression, including Il-1β, Il-8, and Tnf-α. In addition, dietary soy may alter the composition and population of the gut microbiota via providing nutrients and energy that preferentially support the growth of some gut bacteria. This chapter summarizes the current knowledge of the effects of soy protein on the enteritis and gut microbiota.