A Novel Microphysiological Colon Platform to Decipher Mechanisms Driving Human Intestinal Permeability

Area of Science:

• Gastroenterology and Hepatology
• Biotechnology and Bioengineering
• Cell Biology and Histology

Background:

• Limited availability of human intestinal epithelium models hinders therapeutic development and physiological studies.
• Organ-on-a-chip technology offers a promising avenue for creating more physiologically relevant models.
• Previous organoid systems lacked the complexity to fully mimic in vivo intestinal architecture.

Purpose of the Study:

• To develop a microphysiological system that accurately mimics human intestinal epithelium.
• To gain insights into intestinal barrier integrity and function.
• To investigate the mechanisms underlying cytokine-induced barrier disruption.

Main Methods:

• Combined human biopsy-derived organoids with Organ-on-a-chip technology to create a Colon Intestine-Chip.
• Utilized RNA sequencing to characterize model proximity to human tissue and organoids.
• Assessed differentiation of intestinal epithelial cells and donor variability under various conditions.
• Applied the system to study epithelial barrier function and cytokine-induced disruption.

Main Results:

• The Colon Intestine-Chip successfully established a tight monolayer of differentiated, polarized intestinal epithelial cells.
• Confirmed interferon-gamma's effect on the colonic barrier, involving junctional complex reorganization and apoptosis.
• Demonstrated that interleukin-22 disrupts the human epithelial barrier, contrasting findings in mouse models.

Conclusions:

• A human Colon Intestine-Chip platform was successfully developed and validated.
• The platform is valuable for characterizing cytokine mechanisms, such as interleukin-22's effect on the human epithelial barrier.
• This system can elucidate leaky gut mechanisms and identify potential biomarkers in a time- and challenge-dependent manner.