Gut microbiota dysbiosis at the onset of immune checkpoint inhibitor-mediated colitis impacts risk of disease and associated cancer prognosis
Introduction
Immune checkpoint inhibitors (ICIs) target many advanced malignancies with high efficacy but also predispose cancer patients to immune-related adverse events, such as immune-mediated colitis (IMC). IMC is a common side effect following treatment with immune checkpoint inhibitors (ICIs), affecting approximately 50% of treated cancer patients. Standard intervention following IMC diagnosis includes halting ICI therapy and administering immunosuppressants that may compromise cancer outcomes. Additionally, chronic inflammation is a known risk factor for cancer development and progression; finding novel, feasible ways to reduce IMC risk and severity are imperative for both patient quality of life and reduction of cancer risk factors. Studies have highlighted roles of the gut microbiota in ICI efficacy and toxicity but less is known regarding how the microbiota impacts cancer prognosis in IMC.
Methods
We retrospectively investigated the microbiota of patient stool samples collected at ICI-mediated colitis onset using 16S rRNA sequencing and clinical outcomes (n=31). Unsupervised hierarchical clustering based on the beta diversity of patients was used to identify distinct clusters based on microbial composition. Additionally, we used the same patient stool samples to perform targeted liquid chromatography-mass spectrometry (LC-MS) metabolomics to determine short chain fatty acid (SCFA) concentrations.
Results
Select results from the study revealed lower alpha diversity (p=0.001) and greater dysbiosis measured by the distance of beta diversity from healthy volunteers (p=0.01). The patients with severe dysbiosis also showed significantly lower levels of common SCFAs by metabolomic analysis of stool. Interestingly, the patients with greater dysbiosis showed significant increase in infectious events (p=0.05) and worse cancer-related mortality (p=0.05), suggesting severe dysbiosis may be a novel prognostic factor in cancer patients with IMC.
Conclusion
The data from this study give insight into the unique microbial signatures and metabolites that may play a critical role in the risk for IMC development and cancer-related outcomes for IMC patients. Infectious events at IMC onset may contribute to both IMC risk as well as decreased survival potentially due to increased clinical complications and increased antibiotic exposure during ICI treatment. Reducing the risk of IMC development can lead to decreased adverse side effects from ICI therapy and better survival outcomes. Manipulation of the gut microbiota in patients represents a precise, feasible, and high-throughput option for treatment.