In vitro Models of the Small Intestine for Studying Intestinal Diseases

Abstract

The small intestine is a digestive organ that has a complex and dynamic ecosystem, which is vulnerable to the risk of pathogen infections and disorders or imbalances. Many studies have focused attention on intestinal mechanisms, such as host-microbiome interactions and pathways, which are associated with its healthy and diseased conditions. This review highlights the intestine models currently used for simulating such normal and diseased states. We introduce the typical models used to simulate the intestine along with its cell composition, structure, cellular functions, and external environment and review the current state of the art for in vitro cell-based models of the small intestine system to replace animal models, including ex vivo, 2D culture, organoid, lab-on-a-chip, and 3D culture models. These models are described in terms of their structure, composition, and co-culture availability with microbiomes. Furthermore, we discuss the potential application for the aforementioned techniques to these in vitro models. The review concludes with a summary of intestine models from the viewpoint of current techniques as well as their main features, highlighting potential future developments and applications.

Keywords: 3D culture; disease model; ex vivo model; host-microbiome interaction; in vitro model; intestinal glycans; small intestine.

Figure 1

Overall scheme of experimental model. Conventional 2D culturing is rather simple and has high productivity, but application is limited to target treatment experiments. In the Transwell system, the culture area is floated into the media and can simulate mass transfer or other activities. Many models try to simulate specific functions or structures using complex techniques, such as organoid differentiation, microfluidic devices, 3D scaffold fabrication, tissue engineering, etc. In animal models, the body represents a complete model, but there are problems with observation and ethical issues. In general, with increased complexity, the similarity of the model also increases.

Figure 2

Functions and compositions of intestinal glycan (mucin). A mucus layer covers the intestinal lumen. This thick layer prevents the epithelial cell layer from invading microbes. Glycan entraps pathogens and infectious microbes in its dense O-linked oligosaccharide chain.

Figure 3

Major intestinal models and their designs. (A) The ex vivo model uses intestine harvested from experimental animals and maintains its live state. It has high similarity, but the live state is hard to maintain. (B) Organoids are derived from pluripotent stem cells or cells harvested from in vivo tissue. The model has high similarity in function and cell composition but can only be maintained for a limited time. (C) Microfluidic devices can control the environment, are easy to observe and make it easy to focus on targets but have low productivity and a small area for experiments. (D) Three-dimensional (3D) cultures can provide large areas for experiments and high productivity but advanced techniques are required to simulate in vivo conditions and maintain a high level of uniformity.