Navigating Through Cell-Based In vitro Models Available for Prediction of Intestinal Permeability and Metabolism: Are We Ready for 3D?

Traditionally, in vitro studies to quantify the intestinal permeability of drugs have relied on two-dimensional cell culture models using human colorectal carcinoma cell lines, namely Caco-2, HT 29 and T84 cells. Although these models have been commonly used for high-throughput screening of xenobiotics in preclinical studies, they do not fully recapitulate the morphology and functionality of enterocytes found in the human intestine in vivo. Efforts to improve the physiological and functional relevance of in vitro intestinal models have led to the development of enteroids/intestinal organoids and microphysiological systems. These models leverage advances in three-dimensional cell culture techniques and stem cell technology (in addition to microfluidics for microphysiological systems), to mimic the architecture and microenvironment of the in vivo intestine more accurately. In this commentary, we will discuss the advantages and limitations of these established and emerging intestinal models, as well as their current and potential future applications for the pre-clinical assessment of oral therapies.