Ligilactobacillus salivarius CCFM 1266 modulates gut microbiota and GPR109a-mediated immune suppression to attenuate immune checkpoint blockade-induced colitis

Abstract

The wide application of immune checkpoint blockade (ICB) therapy is impeded by the development of ICB-induced colitis, a condition intricately linked to alterations in the gut microbiota. In our previous study, Ligilactobacillus salivarius CCFM 1266 and Bacteroides fragilis HCK-B3 exhibited anti-inflammatory properties. In this research, treatment with both L. salivarius CCFM 1266 and B. fragilis HCK-B3 significantly ameliorated body weight loss and colonic inflammation in murine colitis models induced by intravenous ipilimumab injection, with L. salivarius CCFM 1266 demonstrating superior effectiveness. This amelioration was characterized by an augmented ratio of Treg cells and M2 macrophages, a diminishment in pro-inflammatory cytokines (IL-1β, TNF-α, IFN-γ, IL-23), and an elevation in the anti-inflammatory cytokine IL-10. The ingestion of L. salivarius CCFM 1266 exerted a discernible influence on the composition of the gut microbiota. Untargeted metabolomics revealed an increase in colonic nicotinic acid levels following the administration of L. salivarius CCFM 1266, potentially initiating the activation of the colonic GPR109a pathway. This mechanism likely serves as the fundamental basis for the protective capacity of L. salivarius CCFM 1266 against ICB-induced colitis. Importantly, L. salivarius CCFM 1266 did not interfere with the anti-tumor immune response elicited by ipilimumab. Probiotic intervention thus emerges as a promising approach for alleviating ICB-induced colitis.