Jong Hwan Sung

The human gut extracts nutrients from the diet while forming the largest barrier against the outer environment. In addition, the gut actively maintains homeostasis through intricate interactions with the gut microbes, the immune system, the enteric nervous system, and other organs. These interactions influence digestive health and, furthermore, play crucial roles in systemic health and disease. Given its primary role in absorbing and metabolizing orally administered drugs, there is significant interest in the development of preclinical in vitro model systems that can accurately emulate the intestine in vivo. A gut‐on‐a‐chip system holds great potential as a testing and screening platform because of its ability to emulate the physiological aspects of in vivo tissues and expandability to incorporate and combine with other organs. This review aims to identify the key physiological features of the human gut that need to be incorporated to build more accurate preclinical models and highlights the recent progress in gut‐on‐a‐chip systems and competing technologies toward building more physiologically relevant preclinical model systems. Furthermore, various efforts to construct multi‐organ systems with the gut, called gut–organ‐axis‐on‐a‐chip models, are discussed. In vitro gut models with physiological relevance can provide valuable platforms for bridging the gap between preclinical and clinical studies.