A new organ-on-a-chip device confirms that damage to the intestinal barrier triggers gut inflammation, which could lead to Crohn’s disease and ulcerative colitis.
A new study of an organ-on-a-chip device has confirmed that damage to the thin, delicate intestinal barrier triggers gut inflammation. The intestinal epithelial layer is a critical single-cell barrier that blocks potentially harmful bacteria from reaching the rest of the body. When this barrier is damaged, it catalyzes a condition called leaky gut, which is associated with inflammatory bowel disorders such as Crohn’s disease and ulcerative colitis.
“We wanted to find out what triggers chronic inflammatory bowel disorder in patients,” said Hyun Jung Kim, assistant professor in the Department of Biomedical Engineering at the University of Texas at Austin Cockrell School of Engineering who led the study.
Kim is a leading researcher in the development of human organs-on-chips. He developed the first human gut on-a-chip in 2012 at Harvard University’s Wyss Institute for Biologically Inspired Engineering. His latest research was supported in part by the Alternatives in Scientific Research of The International Foundation for Ethical Research Graduate Fellowship and the National Research Foundation of Korea, Bio Grand Challenge program.
Organ-on-a-chip devices are lined with living human cells and serve as models of organ functions in a controlled environment. This study is the first to leverage an organ-on-a-chip to identify how disease—in this case, gut inflammation—is initiated in the human body. Kim and Woojung Shin, a biomedical engineering Ph.D. candidate, recently published their findings in Proceedings of the National Academy of Sciences (PNAS).
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The device helped the engineers understand the mechanisms that initiate chronic intestinal ailments. The chip has three major components that represent the key cellular players in inflammation: the epithelial layer, the microbiome, and the immune cells. These components engage in highly complex intercellular “cross-talk,” so it’s difficult to tease out cascades of disruption that can initiate gut inflammation.
Animal modeling is limited, mainly because researchers can’t fully manipulate the three independent, yet intertwined gut components that drive inflammation. For instance, it’s not possible to remove the entire immune system from a mouse.
The inflammatory gut-on-a-chip model, however, allows researchers to study the immunological effects of these components by sequentially changing variables.
“We can co-culture multiple types of the cells and manipulate the gut complexity by adding or removing cell types at different times and spaces,” Kim said.
The device includes two micro-channels where scientists grow cells. Each channel is about 1-millimeter wide and 1-centimeter long. A stretchable porous membrane separates the microchannels into the lumen and the blood cell layers. The device deploys repeated vacuum suctions to mimic cyclic human bowel movements.
“We found that keeping the good barrier function of the epithelial layer is the most critical factor to suppress possible inflammation in the human gut,” Kim said. “There are only three primary components that work and interact with each other in the gut. So we co-cultured the epithelium, the microbiome, and immune cells, and then we could add other elements such as toxic chemical, bacterial toxin, or probiotic bacteria.”
The team used dextran sodium sulfate, a chemical normally applied to animal models to induce and study gut inflammation, to mimic the leaky gut.
“Then we sequentially added different components at different concentrations and temporal simulations, changing the variables,” Kim said. “We added different bacterial cells or microbial toxins to elicit strong immune responses.”
Through their research, the engineers discovered that damage to the epithelium is the driver of inflammatory gut disease.
“There can be many causes of inflammation of the barrier function, including environmental factors, genetic susceptibility, or long-term drug treatment,” Kim said. “No matter what the cause, once a person has compromised barrier function, that is a red flag.”
The results of the study also casts doubt on common nutritional advice to take probiotics (live bacteria considered healthy for the gut) on a regular basis. If the gut wall is healthy, probiotics can be beneficial, but if the intestinal barrier is damaged, probiotics can enter the rest of the body and potentially cause harm.
Eugene B. Chang, professor of medicine at the Knapp Center for Biomedical Research at the University of Chicago, said the researchers “are making strides in developing a model to look at multicellular interactions and paths of physiological events.
“Maybe this particular set of experiments might not be definitive in telling everybody that this is what happens in actual patients,” he added. “But it’s a step in the right direction in developing model systems to interrogate specific roles of cells and how they interact under certain conditions and to study human disease.”
The researchers are now working on customized human intestinal disease models for colorectal cancer to study metastasis and the efficacy of cancer immunotherapy. They are collaborating with clinicians in the Dell Medical School at the University of Texas at Austin to collect biopsied tissues or blood samples from patients after cancer surgery. The goal is to isolate a person’s immune and other cells and study them in a cancer-on-the-chip device. Treatments could be customized for personalized medicine. Each chip device could be used as an avatar for each patient.
John Tibbetts is an independent writer who focuses on technology.
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