Ulcerative colitis (UC), a debilitating condition affecting millions globally, is characterized by inflammation of the large intestine. Sufferers experience pain, cramping, and frequent, often bloody, bowel movements. While periods of remission are possible, the disease is prone to sudden flare-ups, bringing renewed pain, diarrhea, and weight loss. Currently, there is no known cure for UC.
The intestinal flora, the community of microbes residing in the gut, plays a significant role in UC, though its precise involvement remains elusive. In healthy individuals, a diverse array of beneficial microbes aids digestion and supports overall bodily functions. Conversely, individuals with UC often exhibit an imbalanced intestinal flora, a condition known as dysbiosis, marked by a reduction in beneficial microbes and an increase in harmful ones.
A recent study, published in Science Immunology and spearheaded by researchers at The University of Osaka, has identified a synergistic relationship between dysbiosis, mutations in the OTUD3 gene, and STING signaling in exacerbating UC. Specific variations within the OTUD3 gene, referred to as single nucleotide variants (SNVs), are recognized as a risk factor for developing UC.
The research team’s breakthrough came from analyzing intestinal flora samples from both healthy individuals and those 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,” explained Bo Li, the study’s lead author.
Subsequently, the researchers investigated the connection between dysbiosis and OTUD3 gene mutations. Their findings pointed to STING, a protein that becomes activated by gut microbes when the OTUD3 gene is mutated.
“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,” stated Bo Li.
These findings underscore the interplay between genetic factors and the intestinal surroundings in the development of UC, suggesting that both might potentially be crucial targets for future therapeutic interventions.”We were able to elucidate the mechanism of onset and aggravation of UC, which involves OTUD3 gene mutations and disturbances in the intestinal flora,” commented senior author Hisako Kayama. “Our study suggests that dysbiosis and STING signaling might potentially be therapeutic targets for UC.We hope our results will lead to improved diagnosis and individualized treatment of UC.”
