To evaluate the impact of malnutrition on the developing gut, we studied small bowel structure, epithelial renewal, and enzymes in suckling rats deprived of adequate nutrient from birth. Rat pups were suckled by foster dams fedad libitumone of three isocaloric, semipurified diets containing 6,9, or 25% (control) protein throughout gestation and lactation. An additional control group consisted of pups raised with their natural, chow-fed mothers. Although survival of the pups, 98% in the chow-fed and 25% protein groups, decreased to 83% in the 9% groups and 53% in the 6% protein groups, body and gut weights were remarkably uniform within each study group. Mean body weight, gut weight, villus height, and crypt depth were markedly and significantly less in the 6 and 9% pups when compared with those in the chow and 25% control groups, the 6% group being significantly more affected was than the 9% group (P< 0.001). Pups raised by chow-fed mothers also weighed significantly less (P< 0.001) than did those raised by dams fed the 25% protein diet. Total small intestinal protein and DNA content of mucosal scrapings were less in 6 than 9% rat pups (P< 0.001), which in turn were less than those in the 25% group (P< 0.05). The protein/DNA ratio in the small intestine of the 6% animals only was reduced when compared with the 25% group (P< 0.05). Epithelial cell migration assessed by autoradiography with [3H]thymidine was significantly slower in both proximal and distal intestinal segments of the 6% animals when compared with those from the 25% group (P< 0.001). Incorporation of the3H, seen by autoradiography after 1 hr, was also signficantly decreased in the 6% group (P< 0.001). Calculated for the total small intestine, lactase, sucrase, alkaline phosphatase, and thymidine kinase activities were significantly diminished (P≤ 0.001) in the 6% animals compared with 25% controls. Calculated in relation to mucosal protein content and compared with 25% controls, sucrase and alkaline phosphatase activities were significantly decreased (P< 0.001) in both proximal and distal small intestinal segments of the 6% animals, but thymidine kinase activity was decreased only in the distal segment (P< 0.001). However, lactase specific activity was increased in both proximal and distal segments from the 6% group (P< 0.001). Further studies of this phenomenon demonstrated a significant increase in intracellular acid β-galac-tosidase (P< 0.001), particularly in the distal intestinal segment, but also a marked increase in brush border β-galactosidase.Our data demonstrate that in the small intestinal mucosa of the suckling rat, chronic malnutrition causes a decreased number of cells and impaired epithelial proliferation. These abnormalities reflect a profound direct impact of malnutrition on the gut of the young animal and demonstrate a delay in the normal pattern of postnatal maturation of the small intestinal epithelium.