New Insights Into Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) impacts millions globally, yet the mechanisms behind the chronic gut inflammation remain elusive. Researchers have long struggled to fully decipher how the disease develops and varies from patient to patient, even with symptom-controlling treatments available.

One major challenge has been replicating the disease in laboratory settings. Traditional cell cultures often only depict fragments of IBD, while animal models frequently fail to accurately reflect human intestinal conditions. This discrepancy has made it hard for scientists to understand the interactions among various cell types that contribute to inflammation and tissue damage, as well as the heightened risk of colorectal cancer.

A recent study in Nature Biomedical Engineering could provide crucial insights into these issues.

Researchers have developed what might be the most comprehensive human model of IBD yet, utilizing cells from patients diagnosed with Crohn’s disease and ulcerative colitis, which are the two primary types of IBD.

“To the best of my knowledge, this model is the first to fully reproduce, in vitro, the exacerbations that pregnant women with IBD may experience,” noted first author Alican Özkan, a bioengineer at Harvard University.

“Perhaps more significantly, our system facilitates the investigation of the initial stages of cancer development within tissues that grow in a context relevant to an organ,” he added.

The ‘Colon Chip,’ as this innovative model is named, differs from standard laboratory setups by mimicking multiple key aspects of the disease simultaneously. This allows researchers to observe interactions that have been challenging to study until now.

One intriguing finding involved fibroblasts, which are connective tissue cells known for their organ-supporting functions. Rather than merely serving a passive role, these cells seemed to actively contribute to inflammation and compromised the gut’s protective barrier.

Özkan and colleagues tested this hypothesis by combining fibroblasts from IBD patients with healthy intestinal cells on the same chip. The results were compelling.

The mere presence of those fibroblasts prompted healthy cells to behave like diseased tissue, exhibiting a leaky intestinal barrier and heightened inflammatory responses.

These discoveries imply that fibroblasts may carry more weight in IBD development than previously thought. “By integrating matched epithelial cells, stromal fibroblasts, immune cells, and mechanical forces resembling normal bowel movements, the Colon Chip allows researchers to evaluate each element’s role in the disease,” Özkan shared.

The chip enabled exploration of another factor that had been difficult to model: the slight stretching that normal bowel movements cause. The scientists found that recreating these gentle movements intensified inflammatory and fibrotic responses in chips composed of IBD tissue.

Additionally, the chip was employed to study how hormones related to pregnancy might affect the disease. When chips constructed from cells of female patients were exposed to these hormones, they showed increased inflammatory responses and greater collagen buildup, both signs of tissue scarring known as fibrosis.

A 2022 study demonstrated that fibroblasts in the colon assume inflammatory roles during chronic inflammation and aid in repairing damaged tissue. The recent study takes this further, showing that IBD-derived fibroblasts alone can induce disease-like changes in healthy intestinal tissue grown on the chip.

This understanding may be difficult to achieve with traditional organoids or animal models, according to Özkan, who remarked, “The major advancement here lies in moving past mere replication of IBD pathology to uncovering the mechanisms driving disease progression using a fully human, patient-derived system.”

The team’s research also ventured into addressing one of the most severe long-term effects of IBD: colorectal cancer.

In their investigation of early cancer development stages, they subjected both healthy and diseased Colon Chips, derived from different donors, to a carcinogen, N-ethyl-N-nitrosourea (ENU). While both types responded, the IBD chips exhibited significantly stronger molecular changes associated with cancer.

Remarkably, the study indicated that fibroblasts are central to this increased susceptibility to cancer. Healthy intestinal tissue only began expressing early cancer markers when grown alongside IBD-derived fibroblasts.

“The strength of this platform lies in its ability to accurately recreate the dynamic environment of the human intestine while enabling the analysis of individual disease drivers independently and collectively,” Özkan explained.

Overall, the integration of patient-derived cells with immune cells and peristalsis-like mechanical forces structures the key aspects of IBD that are often missing from most existing models.

These findings are detailed in Nature Biomedical Engineering.