Immunocompetent Human Intestinal Models in Preclinical Drug Development

The intestinal epithelial barrier, together with the microbiome and local immune system, is a critical component that maintains intestinal homeostasis. Dysfunction may lead to chronic inflammation, as observed in inflammatory bowel diseases. Animal models have historically been used in preclinical research to identify and validate new drug targets in intestinal inflammatory diseases. Yet, limitations about their biological relevance to humans and advances in tissue engineering have forced the development of more complex three-dimensional reconstructed intestinal epithelium. By introducing immune and commensal microbial cells, these models more accurately mimic the gut's physiology and the pathophysiological changes occurring in vivo in the inflamed intestine. Specific advantages and limitations of two-dimensional (2D) and three-dimensional (3D) intestinal models such as coculture systems, organoids, and microfluidic devices to study inflammatory and immune-related responses are highlighted. While current cell culture models lack the cellular and molecular complexity observed in vivo, the emphasis is put on how these models can be used to improve preclinical drug development for inflammatory diseases of the intestine.