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Inflammatory bowel disease affects millions of people worldwide, yet scientists still don't fully understand what drives the chronic inflammation that damages the gut.
Although treatments can help control symptoms, exactly how the disease develops – and why it progresses differently from one patient to another – remains poorly understood.
One of the biggest obstacles has been recreating the disease in the laboratory. Conventional cell cultures capture only isolated pieces of inflammatory bowel disease (IBD), while animal models often fail to faithfully mirror what happens in the human intestine.
As a result, researchers have struggled to untangle how different cell types interact to drive inflammation, tissue damage, and the increased risk of colorectal cancer.
Now, a study published in Nature Biomedical Engineering may help fill some of those gaps.
Researchers created what may be the most complete human model of IBD on a chip yet, using cells donated by patients with Crohn's disease and ulcerative colitis, the two main types of IBD.
"To my knowledge, this is the first model that has recapitulated in vitro the disease exacerbations that pregnant women with IBD often can experience," says first author Alican Özkan, a bioengineer at Harvard University.
"Perhaps even more importantly, we showed that our system enables studying the earliest stages of cancer formation within human tissues growing in an organ-relevant context in vitro."
Unlike conventional laboratory models, the miniature device called a 'Colon Chip' recreates many of the disease's key features at once, allowing scientists to study interactions that have long been difficult to observe.
Among the biggest surprises were fibroblasts – connective tissue cells best known for supporting the structure of organs and helping repair damaged tissue.
Instead of acting as passive bystanders, the cells appeared to help drive inflammation and weaken the gut's protective barrier.
To test the idea, Özkan and colleagues paired fibroblasts from people with IBD with healthy intestinal cells from the same people on the same chip.
The results were striking.
Simply exposing healthy cells to those fibroblasts was enough to make them behave like diseased tissue, with a leakier intestinal barrier and stronger inflammatory responses.
Together, these findings suggest fibroblasts may play a much bigger role in IBD than previously thought.
"By combining matched epithelial cells, stromal fibroblasts, circulating immune cells, and physiologically relevant mechanical forces, the Colon Chip enables researchers to determine the contribution of each component to disease," Özkan told ScienceAlert.
The chip also allowed the researchers to explore another factor that has been difficult to study in the lab: the constant stretching caused by normal bowel movements.
By recreating those gentle mechanical forces, the researchers found that inflammatory and fibrotic responses became even stronger in chips built from IBD tissue.
The researchers also used the chip to investigate how pregnancy-related hormones might influence the disease.
When chips built from cells donated by female patients were exposed to those hormones, they observed stronger inflammatory responses and increased collagen deposition – changes associated with tissue scarring, known as fibrosis.
A 2022 study published in PLOS Biology showed that fibroblasts in the colon adopt inflammatory states during chronic intestinal inflammation and help remodel damaged tissue.
The new study goes a step further by showing that fibroblasts taken from patients with IBD were, on their own, enough to trigger disease-like changes in healthy intestinal tissue grown on the chip.
"This mechanistic insight would be difficult to obtain using conventional organoids or animal models," Özkan said.
"The most important advance is that this model moves beyond replicating IBD pathology to uncovering the mechanisms that drive disease progression in a fully human, patient-derived system," he added.
The team also turned to one of IBD's most serious long-term complications: colorectal cancer.
To investigate the earliest stages of cancer development, they exposed both healthy and diseased Colon Chips (each using cells from different donors) to the carcinogen N-ethyl-N-nitrosourea (ENU).
While both models responded, the diseased chips exhibited far stronger cancer-associated molecular changes than healthy tissue.
The researchers also found that fibroblasts appeared to be central to this increased cancer susceptibility.
Healthy intestinal tissue only began expressing early cancer-associated molecular markers after being grown alongside fibroblasts taken from patients with IBD.
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"The strength of this platform lies in its ability to faithfully recreate the dynamic human intestinal microenvironment while allowing individual disease drivers to be studied in isolation and in combination," Özkan told ScienceAlert.
"The integration of patient-derived epithelial and stromal cells with circulating immune cells and peristalsis-like mechanical forces captures key features of inflammatory bowel disease that are absent from most existing models."
The findings are reported in Nature Biomedical Engineering.
This article was fact-checked by Clare Watson and edited by Rebecca Dyer. While we pride ourselves on our process, we are only human. If you spot a mistake, please let us know.
