Accumulation of Specific Gene Mutations Found in Patients with Ulcerative Colitis Elucidating the Mechanism of Onset and Exacerbation of Intractable Diseases
December 27, 2019
Keio University School of Medicine
Japan Agency for Medical Research and Development
A research team led by Professor Toshiro Sato at the Keio University School of Medicine Sakaguchi Laboratory has discovered that specific gene mutations accumulate in the colonic epithelium of patients with ulcerative colitis.
In normal human colon epithelium, gene mutations accumulate with age and are known to cause carcinogenesis in the colon. Changes in the intestinal environment, such as dietary quality or chronic inflammation, can also increase the risk of carcinogenesis in the colon. However, it has remained unclear whether changes in the intestinal environment affect the accumulation of gene mutations in the colon epithelium.
In this study, the research team cultivated colon epithelium obtained from research participants and amplified colonic epithelial cells to efficiently analyze gene mutations. Results showed more gene mutations in colonic epithelial cells of patients with chronic ulcerative colitis than in the colons of healthy individuals. The team found that many of these gene mutations were related to chronic inflammation and were not those found in colorectal cancer.
The team identified the role of these gene mutations by using an organoid culture, a culture method for producing simplified versions of organs.
When an inflammatory molecule called IL-17 (interleukin-17)induces chronic inflammation in colonic epithelium, the stimulation damages the colon mucosa. The team found that the colonic epithelium of ulcerative colitis patients had acquired IL-17-related gene mutations that do not occur in healthy individuals, making it resistant to cell damage caused by chronic inflammation. In other words, the team clarified that in the colon of patients with ulcerative colitis, the number of epithelial cells with gene mutations that are likely to survive in an inflammatory environment increases selectively, replacing normal colonic epithelial cells.
While previous papers have stated that the human large intestine develops colorectal cancer through the accumulation of gene mutations (Fearon ER, et al., Cell, 1990), this study found that mutations also accumulate in order to adapt to changes such as chronic inflammation in the intestinal environment.
Future research is expected to reveal how the accumulation of colonic epithelial cells with gene mutations affects the pathogenesis and cancerization of ulcerative colitis.
The results of this research were published online in the online edition of the British journal Nature on December 18(GMT), 2019.
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