Taking the sting out of ulcerative colitis

Osaka, Japan – Ulcerative colitis (UC) causes misery for millions worldwide. It affects the large intestine, causing pain, cramping, and frequent bowel movements with bloody diarrhea. Although some people go through periods when they feel well, the disease will suddenly flare up, causing another cycle of pain, diarrhea, and weight loss. There is currently no cure.

The intestinal flora plays a vital role in UC, but the exact role is unclear. In healthy people, the intestinal flora contains a wide variety of microbes that help digestion and provide benefits for the whole body. In contrast, the intestinal flora of people with UC is unbalanced, with fewer beneficial microbes and more harmful microbes. This condition is known as dysbiosis.

In a new study published in Science Immunology, a multi-institutional research team led by The University of Osaka revealed that a combination of dysbiosis, mutations of the OTUD3 gene, and STING signaling aggravate UC. These specific mutations of the OTUD3 gene, known as a single nucleotide variants or SNPs, are considered as a risk factor for UC.

The key to the team’s discovery lay in studying intestinal flora from healthy people and people with UC. “We transplanted the intestinal flora of healthy individuals and of patients with UC into mice with mutant OTUD3 and mice with normal OTUD3. The only mice that developed symptoms of UC were the ones with mutant OTUD3 that received UC flora,” says lead author of the study Bo Li.

The researchers then looked for the link between dysbiosis and the OTUD3 gene mutation. The answer lay in STING, a protein that is activated by microbes in the intestinal flora when mutated OTUD3 is present.

“We found that dysbiosis in people with UC leads to activation of STING signaling, leading to inflammation in the colon. When we transplanted UC intestinal flora into OTUD3 mutant mice without the STING gene, we saw no symptoms of UC,” explains Li.

The research team’s results show that genes and the intestinal environment work together in UC, and that both may be important in the search for new UC treatments.

“We were able to elucidate the mechanism of onset and aggravation of UC, which involves OTUD3 gene mutations and disturbances in the intestinal flora," says senior author Hisako Kayama. “Our study suggests that dysbiosis and STING signaling may be therapeutic targets for UC. We hope our results will lead to improved diagnosis and individualized treatment of UC.”

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The article, “OTUD3 prevents ulcerative colitis by inhibiting microbiota-mediated STING activation,” will be published in Science Immunology at DOI: https://doi.org/10.1126/sciimmunol.adm6843.

About The University of Osaka

The University of Osaka was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world. Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.

Website: https://resou.osaka-u.ac.jp/en

About Immunology Frontier Research Center (IFReC), Osaka University 
IFReC was established by the support of the World Premier International Research Center Initiative (WPI) in 2007. IFReC aims to overcome immune-related diseases by clarifying the whole picture of the immune system, and has promoted globally competitive fundamental research with excellent researchers from overseas. 
Website: https://www.ifrec.osaka-u.ac.jp/en/