December 19, 2019
Keio University School of Medicine
Japan Agency for Medical Research and Development (AMED)
A research group led by Professor Toshiro Sato of The Sakaguchi Laboratory (Organoid Medicine) at the Keio University School of Medicine has discovered that specific genetic mutations accumulate in the colonic tissue of patients with ulcerative colitis.
It is known that in normal human colonic epithelium, genetic mutations accumulate with age, causing colorectal carcinogenesis. Furthermore, the risk of colorectal carcinogenesis is also increased by various changes in the intestinal environment, such as diet quality and chronic inflammation. However, it remained unclear whether changes in the intestinal environment affect the accumulation of genetic mutations in the colonic epithelium.
In this study, we efficiently analyzed genetic mutations by culturing colonic epithelium obtained from patients and expanding the colonic epithelial cells. As a result, more genetic mutations were detected in the colonic epithelial cells of patients with long-standing ulcerative colitis compared to the colonic epithelium of healthy individuals. It was found that many of these genetic mutations were not those observed in colorectal cancer, but rather were related to chronic inflammation.
Furthermore, we determined the role of these genetic mutations using a technology called organoids, which involves culturing organs in a dish.
In ulcerative colitis, a chronic inflammatory signal called IL-17 (interleukin-17) is activated, and this stimulus damages the colonic epithelium. However, we found that the colonic epithelium in ulcerative colitis acquires IL-17-related genetic mutations not found in healthy individuals, allowing it to escape cell damage from chronic inflammation. In other words, it became clear that in the colons of patients with ulcerative colitis, epithelial cells with genetic mutations that make them more likely to survive in an inflammatory environment are selectively expanded, replacing normal colonic epithelial cells.
While it has already been reported that the human colon develops colorectal cancer through the accumulation of genetic mutations (Fearon ER, et al. Cell 1990), this study revealed that mutations also accumulate to adapt to changes in the intestinal environment, such as chronic inflammation.
Future research is expected to clarify how the accumulation of colonic epithelial cells with genetic mutations affects the pathology and carcinogenesis of ulcerative colitis.
The results of this research were published in the online edition of the British scientific journal "Nature" on December 18, 2019 (UK time).
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