Researchers find a link between gut bacteria and genes in colitis flare-ups
Ulcerative colitis is a chronic disease that affects more than 1.2 million people in the United States, according to a 2023 study of medical claims data. It falls under the umbrella of inflammatory bowel disease, or IBD — a group of conditions that includes Chron's disease and is marked by unpredictable flare-ups, long-term discomfort, and treatments that often work inconsistently.
'This study demonstrates that it's not just an imbalance of microbes in your gut or genetics that induce intestinal inflammation — but the interaction between the two,' said Hisako Kayama, an associate professor of immunology at Osaka University and co-senior author of the study.
At the center of that inflammatory response is a protein called STING that helps the body recognize the DNA of bacteria and viruses and mount an immune response. Healthy people are able to keep this response under control with the help of a gene called OTUD3, which acts as a biological brake. But in some people, their OTUD3 gene variant leads that brake to fail — causing the immune system to treat harmless bacteria as a threat. Unchecked, the protein can drive chronic inflammation, particularly in the gut, which is home to many different types of 'good' bacteria.
The protein STING is very important in fighting bacterial infections, said co-author Dr. Kiyoshi Takeda, a professor of immunology at Osaka University. 'But the problem is that the overactivation of STING causes inflammation.'
To explore how this interaction plays out, the researchers studied mice bred specially to have a genetic vulnerability to colitis similar to humans. When feces from the ulcerative colitis patients was transferred to the colons of the mice, they developed more severe colitis symptoms than mice with a normal version of the gene. If they didn't have the gene variant or the microbial trigger, the disease didn't develop.
In total, researchers used tissue and gut bacteria from 124 patients — including 65 with ulcerative colitis and 59 with colorectal cancer — plus 12 healthy people as controls.
The culprit was a molecule called cGAMP, which is made by certain gut bacteria. In healthy mice, researchers know that OTUD3 helps break down excess cGAMP so the immune system doesn't overreact. But in mice without a working version of that gene, cGAMP built up, overactivating STING and causing inflammation.
The findings could help explain why some patients respond poorly to current ulcerative colitis treatments, which typically suppress the immune system as a whole. By pinpointing a single inflammatory pathway, the study opens the door to more precise, personalized therapies — especially for patients who carry this specific gene variant.
Still, the researchers caution that any treatment targeting the STING protein directly must be used carefully, since suppressing it too much could leave patients vulnerable to infection. Alternative approaches, such as targeting cGAMP-producing bacteria, could allow STING to keep doing its job in the rest of the body while dialing down inflammation in the colon.
The variant gene that colitis sufferers have is common. According to past genome-wide studies, it appears in about 53% of Europeans, 52% of Americans and 16% of Japanese people. Not everyone with it develops the disease, lending credence to the idea that it's the interaction between genes and microbes that triggers inflammation.
'This study is helpful in demonstrating a specific example — a genetic variant and a microbial signal — that leads to inflammation,' said Dr. Jonathan Jacobs, a gastroenterologist and microbiome researcher at UCLA who was not involved with the study. 'That's exciting,' he said, because it offers a clear mechanism that ties together many of the risk factors scientists have long observed in inflammatory bowel disease.
Even if it turns out not many people are vulnerable to this particular gut-genetic interaction, he said, the research could lead to more personalized treatment. 'It moves us closer to precision medicine,' Jacobs said.
The shift toward more targeted treatment could make a world of difference for patients like Anderson Hopley, a volunteer with the Orange County and Los Angeles chapter of the Crohn's and Colitis Foundation who was diagnosed with Crohn's this year.
'I know people who have medication that'll work for a couple years, maybe even just a couple months, and then it kind of randomly stops,' he said. 'They have to adjust everything.'
Although Hopley has Crohn's, not ulcerative colitis, he said the new study still resonates.
'I think it'd be really nice to know what causes this,' he said. 'Even if there's not a cure yet, just having an answer — some clarity — would be a step in the right direction.'
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