Researchers may have uncovered a mechanism contributing to the development of colitis in patients with cancer receiving immunotherapy, as well as a novel strategy to deliver immune-based therapy without causing the adverse side effect, according to a recent study published by Lo et al in Science. In the study, the researchers created a new mouse model involving the injection of microbiota from wild-caught mice into the traditional mouse model. The researchers noted that the mice in the new model developed colitis following the administration of antibodies used for immunotherapy. They discovered that colitis may have developed in response to the composition of the gut microbiota, which caused immune T cells to become hyperactivated, whereas regulatory T cells responsible for inhibiting T-cell activation were deleted from the gut. The researchers revealed that this was occurring within a specific domain of the immune checkpoint antibodies—and upon removal of the domain, the mice continued to experience strong antitumor activity without developing colitis. To validate their findings, the researchers analyzed previously reported data from studies of human cells in patients treated with immune checkpoint antibodies, which reinforced the role of regulatory T cells in inducing colitis. In a companion press release on the findings from Michigan Medicine, the study authors concluded: “This work for the first time shows that microbiota are essential to develop colitis from immune checkpoint inhibition. Once we identified the mechanism causing the colitis, we could then develop ways to overcome this problem and prevent colitis while preserving the antitumor effect.”