Using a gut-on-a-chip model to study intestinal inflammation

Intestinal inflammation involves a complex interaction between intestinal epithelial cells, intestinal microbiota and immune cells. Many factors are known to be involved in the onset of intestinal inflammation; however, an inciting factor responsible for triggering inflammation has not been identified. The ability to identify an inciting factor has been hampered by the lack of animal-based and cell culture-based models that allow individual factors to be effectively manipulated and their effects accurately measured.

Researchers at University of Texas at Austin have developed a human gut inflammation model to better study intestinal inflammation. Their findings were recently published in the Proceedings of the National Academy of Sciences.

Dr. Hyun Jun Kim’s lab previously developed a gut-on-a-chip microfluidic device capable of recapitulating the intestinal microenvironment. The device contains two microchannels, an upper channel and a lower channel, separated by a porous membrane. In this model, the upper channel represents the intestinal lumen that interacts with outside environmental factors such as the microbiota and dietary antigens. The lower channel represents capillaries that are the source of immune cells and other immune modulators. Human intestinal epithelial cells are grown in the upper channel forming a monolayer. Various factors can be added to both the upper channel and lower channel to influence the intestinal microenvironment.

The loss of intestinal barrier function is a critical component in the development of intestinal inflammation and the pathogenesis of diseases like Inflammatory Bowel Disease (IBD). The intestinal epithelium acts as a barrier to prevent harmful environmental components from entering the body. A common model used in animals to disrupt barrier function is treatment with DSS, a chemical that induces intestinal inflammation. DSS was applied to the lumenal channel resulting in changes in epithelial structure, mucus production and tight junction protein organization, yet no damage occurred to the individual epithelial cells. These negative effects to the intestinal barrier were reversed once DSS treatment ceased, similar to what would be seen in the wound healing process.

During inflammation, the production of radical oxygen species (ROS) damages adjacent cells. The researchers found that the accumulation of ROS increased when immune cells, peripheral blood mononuclear cells (PBMCs), interacted with DSS-treated intestinal epithelial cells. Direct contact of PBMCs with epithelial cells resulted in ROS from the PBMCs diffusing into the epithelial cells. These findings suggest that loss of barrier function promotes direct interaction between immune cells and epithelial cells that leads to oxidative stress.

Probiotics tested in models of intestinal inflammation and administered to individuals with IBD have provided conflicting results to its efficacy as a therapeutic. Models of intestinal inflammation have indicated great promise for probiotics as a therapeutic; however, clinical outcomes of probiotic treatment vary in patients with IBD. Probiotics have no effect in individuals with severe symptoms of IBD while those in remission seem to benefit from probiotic therapy. The researchers tested the effects of probiotics in the gut inflammation model and found the timing of treatment to yield different results. Probiotic treatment after DSS-induced barrier dysfunction led to an increase in inflammatory cytokine production. However, probiotic treatment prior to DSS prevented any release of inflammatory cytokines normally seen after DSS treatment.

This study provides evidence that gut inflammation-on-a-chip is an effective model of intestinal inflammation and allows the manipulation of the intestinal barrier. Furthermore, maintaining the integrity of the intestinal barrier is critical to preventing the onset of intestinal inflammation by preventing oxidative stress and interactions with immune cells as well as preventing the production of inflammatory cytokines.

These findings indicate that maintaining a healthy intestinal barrier through the use of probiotics may be an effective approach to preventing intestinal inflammation, and treatment with probiotics during the height of symptoms may actually worsen inflammation. As the technology advances, this model may be used to test an individual’s own cells and microbiota providing a personalized approach to treatment of intestinal inflammatory diseases.

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