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The molecular basis for the carnosine-induced activation of intestinal epithelial cells was studied and subsequently we focused on whether carnosine stimulates a brain–gut interaction. To assess this, we investigated changes in intestinal epithelial cells induced by carnosine. Our results showed that carnosine activated Caco-2 cells, resulting in the secretion of various factors (including neurotrophic factors), and leading to the induction of neurite growth in SY-SY5Y cells. We then conducted DNA microarray analysis to reveal global changes in Caco-2 cells via treatment with carnosine. The expression of 745 genes significantly changed upon carnosine treatment. Furthermore, cluster analysis showed that several of these genes were related to secretory proteins, membrane protein/transporters, and calcium channel/transport protein. Some of these genes would explain the mechanism of carnosine action, especially considering stimulation of the brain–gut interaction.