Scientists Create a 'Gut-on-a-Chip' That Reveals Hidden Drivers of Inflammatory Bowel Disease : ScienceAlert

Inflammatory bowel disease (IBD) affects millions globally, yet the precise causes of the persistent inflammation that harms the gut are not fully understood by scientists. While treatments can alleviate symptoms, the exact mechanisms of disease onset and the varied progression among patients remain unclear.

A significant challenge has been replicating the disease in lab settings. Traditional cell cultures only capture isolated aspects of IBD, and animal models often do not accurately replicate human intestinal conditions. This has made it difficult for researchers to understand how different cell types contribute to inflammation, tissue damage, and an increased risk of colorectal cancer.

However, a study published in Nature Biomedical Engineering may bridge some of these knowledge gaps.

Crohn disease. Human large and small intestine with healthy segments and inflammation that affect layers of the intestinal wall. The affected segments are interspersed with unaffected ones. Close-up of a cross section of an intestinal wall with fat wrapping and fissures — Crohn’s disease is an inflammation of the intestinal wall, and one of the two main types of IBD. (CDC)

Researchers have developed what might be the most comprehensive human model of IBD on a chip, using cells from patients with Crohn’s disease and ulcerative colitis, the two primary 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.”

Differing from conventional lab models, the ‘Colon Chip’ device replicates multiple key features of the disease simultaneously, enabling researchers to observe complex interactions previously hard to capture.

Among the unexpected findings were fibroblasts—cells in connective tissue known for supporting organ structure and repairing tissue. Rather than being passive, these cells appeared to contribute actively to inflammation and weakening of the gut’s protective barrier.

To explore this, Özkan and his team paired fibroblasts from IBD patients with healthy intestinal cells from the same individuals on the chip. The results were significant.

Exposing healthy cells to these fibroblasts transformed them to mimic diseased tissue, showing a leakier intestinal barrier and heightened inflammatory responses.

Scientists Build an 'Inflammatory Bowel Disease-on-a-Chip' That Could Transform Research — The researchers added patient-derived cells to a commercially available chip device (left) to recreate features of IBD in the lab. (Özkan et al., *Nat. Biomed. Eng.*, 2026/Wyss Institute at Harvard University)

The findings indicate that fibroblasts might play a more significant 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 explained to ScienceAlert.

The chip also provided insights into another challenging area: the impact of normal bowel movement-induced stretching. Recreating these mechanical forces showed that inflammatory and fibrotic responses were more pronounced in chips made from IBD tissue.

Researchers also examined how pregnancy-related hormones affect the disease using the chip. When chips containing cells from female patients were exposed to these hormones, there were heightened inflammatory responses and increased collagen deposition, leading to tissue scarring, known as fibrosis.

A 2022 study published in PLOS Biology revealed that colon fibroblasts adopt inflammatory states during chronic intestinal inflammation and contribute to tissue remodeling. The new study advances this by demonstrating that fibroblasts from IBD patients alone could induce 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 noted. “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 focused on one of IBD’s most serious complications: colorectal cancer.

To study early cancer development, both healthy and diseased Colon Chips (each made from cells of different donors) were exposed to the carcinogen N-ethyl-N-nitrosourea (ENU). While both models reacted, the diseased chips showed significantly stronger cancer-associated molecular changes compared to healthy tissue.

The research showed that fibroblasts were key to this increased cancer risk. Healthy intestinal tissue only started expressing early cancer markers after being cultured with fibroblasts from IBD patients.

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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 detailed 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.