SIBO and IBD modeled in the lab

March 4, 2019

The feats we’ve accomplished by bringing biology and engineering together are nothing short of impressive.  Recent technological advancements have brought together gut microbes, immune cells, intestinal epithelial cells, and mechanical forces in a laboratory setting in a way that accurately models the intestine and diseases centered in the intestine like inflammatory bowel disease (IBD) and small intestine bacterial overgrowth (SIBO).

Most of our knowledge about IBD and SIBO has been gathered through studies with patient data, patient samples, and animal models.  With these tools, scientists have built a basic understanding of IBD and SIBO, but the details that would lead to new effective therapies have been elusive.  The latest technology (gut-on-a-chip) allows researchers to learn how individual components, like certain pro-inflammatory signals, contribute to dysbiosis and the development of disease.

Gut-on-a-chip was developed from a push in the last few years to develop organs-on-chips.  The goal in designing these new systems for research was to be able to mimic the function of each organ on a small microfluidic device and then link the devices together in a way that reflects the cross-talk between the organs in the body.  In developing the gut-on-a-chip, scientists were able to successfully incorporate many of the components of the human intestine: the gut microbes, the immune cells, and the peristaltic motion.  Having all of these components allowed Drs. James Collins and Donald Ingber to investigate how they work together and what leads to bacterial overgrowth and inflammation.

When probiotic bacteria were added to the gut-on-a-chip, the intestinal cells remained healthy and the bacteria didn’t overgrow.  However, when a disease causing stain of E. coli was added to the gut-on-a-chip, the E. coli bacteria quickly overgrew and covered the intestinal cells.  Not only that, but the cellular architecture of the intestinal cells was destroyed, which increases the amount of material that passes through into the blood stream.  When immune cells were also added to the gut-on-a-chip, the amount of damage to the intestinal cells increased!  Scientists tested a panel of twelve factors that could be contributing and found IL-1β, IL-6, TNF-α and specifically IL-8 to be major culprits.  These four factors created a positive feedback loop, recruiting more immune cells and further increasing the inflammatory response to the pathogenic bacteria.  Interestingly, IL-1β, IL-6, and TNF-α are known players in Crohn’s disease and ulcerative colitis.  When the gut-on-a-chip had the probiotic bacteria, immune cells, and pathogenic E. coli, the immune response was still triggered and the intestinal cells were still damaged, but the damage was delayed.  This could mean that the probiotics have a protective effect!  More research will determine if the probiotics could be a treatment for early phase ulcerative colitis.

Researchers also modeled SIBO with the gut-on-a-chip.  When the mechanical forces where altered, the intestinal cells were overtaken by the bacteria.  Previous studies suggested that slow movement of material through the small intestine was responsible for bacterial over growth.  The work by the Ingber group suggests that it is actually proper peristaltic motion, the distortion of the intestinal cells, that is necessary to prevent bacterial overgrowth.

Gut-on-a-chip is clearly a powerful tool to study diseases like SIBO and IBD.  The current models have limitations though.  The next generation of gut-on-a-chip will have multiple intestinal cell types, which will make it an even better and more accurate model.  One way to achieve this is to use induced pluripotent stem cells like Dr. James Wells has done for a stomach-on-a-chip model.

Since both the gut-on-a-chip and stomach-on-a-chip models are relatively new, it will be a little while before they bring in more information about gut health and diseases.  We’ll be sure to keep you updated with the latest findings here on the ETP blog.

If you’re interested in the scientific details, check out the following scholarly articles.

Kim HJ, Li H, Collins JJ, Ingber DE. Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a human gut-on-a-chip. Proc Natl Acad Sci U S A. 2016 Jan 5;113(1):E7-15.

Lee KK, McCauley HA, Broda TR, Kofron MJ, Wells JM, Hong CI. Human stomach-on-a-chip with luminal flow and peristaltic-like motility. Lab Chip. 2018 Oct 9;18(20):3079-3085.

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