Leucine-Restricted Diet Attenuates Small Intestinal Tumorigenesis in Apc^{Min /+} Mice

Red and processed meats have been implicated in intestinal tumorigenesis; however, the roles of their main nutritional components, amino acids, in the modulation of adenoma development remain unclear. This study aimed to investigate the roles of various amino acids in intestinal tumorigenesis. Apc^Min/+ mice, as a model of spontaneous intestinal adenoma, were fed diets restricted to essential amino acids (leucine, lysine, valine), or the non-essential amino acid arginine to observe the modulation of tumorigenesis. The mice were fed diets with a reduction in each amino acid starting at 5 weeks of age and analyzed at 15 weeks of age. Among the diets tested, only the 90% leucine-restricted (Leu-R) diet dramatically reduced the size and number of small intestinal tumors. Mechanistically, both cell proliferation and mTORC1 pathway activation were reduced in tumors from the 90% Leu-R group. Further, Gene Set Enrichment Analysis (GSEA) showed that the 90% Leu-R diet affected pathways related to DNA repair and genome stability in small intestinal tumors. Notably, mismatch repair (MMR) genes, Mlh1, Msh2, and Pms2, were upregulated in small intestinal tumors from the 90% Leu-R group. Organoids derived from small intestinal tumors from the 90% Leu-R group exhibited fewer and smaller spherical structures. Leucine plays a key role in small intestinal tumorigenesis in Apc^Min/+ mice. The 90% Leu-R diet suppressed activation of the mTORC1 pathway and maintained genomic stability presumably via the MMR system. These findings suggest the potential for tumor prevention strategies targeting specific essential amino acids.