Gut microbiota and metabolite signatures predict severe immune-related adverse events in advanced hepatobiliary cancers.

[INTRODUCTION] Immune checkpoint inhibition (ICI) has proven to be a major breakthrough in hepatobiliary cancers treatment. However, immune-related adverse events (irAEs) remain a major concern. The gut microbiome has been implicated in ICI efficacy; however, specific alterations in the multi-kingdom gut microbiota associated with severe irAEs are not well understood.

[OBJECTIVES] We aimed to identify the signatures of gut microbiota, fungi, and metabolites in patients with advanced hepatobiliary cancers with severe irAEs compared to those in patients experiencing mild or no irAEs.

[METHODS] We enrolled 168 patients with advanced hepatobiliary cancers between June 2018 and June 2022 (72 in the train set, 31 in test set 1, and 65 in test set 2). Multi-kingdom microbiota profiles were investigated using metagenomic, ITS2, and metabolomic datasets.

[RESULTS] The presence of severe irAEs was associated with significantly longer overall survival compared with the irAE-Mild and irAE-No groups. Patients with severe irAEs showed significant differences in the composition of bacteria and metabolites, but relatively few differences in fungi, and had more complex network associations of multi-kingdom gut microbiota compared with the irAE-Mild and irAE-No groups. A predictive model based on four bacteria and six metabolites simultaneously discriminated irAE-Severe from irAE-Mild and irAE-No with high accuracy.

[CONCLUSION] Patients with severe irAEs exhibited unique changes in microbiota-fungi-metabolite interactions. Gut microbiota- and/or metabolite-based algorithms could be used as additional tools for predicting severe irAEs and as potential prognostic markers in advanced hepatobiliary cancers.