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Gut microbiome and immune checkpoint inhibitor toxicity
Rik J Verheijden1, Mick J M van Eijs2, Fernanda L Paganelli3
1Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, PO box 85500, Utrecht 3584 CX, the Netherlands; Department of Epidemiology and Health Economics, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, PO box 85500, Utrecht 3584 CX, the Netherlands; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, PO box 85500, Utrecht 3584 CX, the Netherlands.
Background:
Multiple studies have suggested that gut microbiome may influence immune checkpoint inhibitor (ICI) efficacy, but its association with immune-related adverse events (irAEs) is less well studied. In this prospective cohort study, we assessed whether gut microbiome composition at start, or changes during ICI, are associated with severe irAEs.
Methods:
Stool samples of cancer patients treated with anti-PD-1 ± anti-CTLA-4 were analyzed using 16S rRNA gene sequencing and metagenomic shotgun sequencing. Differences in alpha and beta diversity between patients with and without severe irAE were assessed, as well as differential relative abundance (RA) of taxa, MetaCyc pathways, and seven prespecified literature-based bacterial groups including pathobionts and Ruminococcaceae.
Findings:
We analyzed 497 samples of 195 patients before and soon after starting ICI, at severe irAE onset and after starting immunosuppression. Mean RA of the pathobionts group was significantly higher in patients who developed a severe irAE (8.2 %) compared to those who did not (4.8 %; odds ratio 1.40; 95 %CI 1.07-1.87) at baseline, and also early during ICI treatment and at severe irAE onset. A significantly stronger decrease in RA of Ruminococcaceae after starting ICI was observed in patients who developed a severe irAE compared to those who did not. RAs of Ruminococcaceae, the genus Ruminococcus, and the species R. bromii and R. callidus were significantly lower at severe irAE onset compared to other time points.
Interpretation:
Gut microbiome dysbiosis signaled by higher RA of pathobionts and decrease in RA of Ruminococcaceae may predispose to severe irAEs.
Insights
Gut microbiome alterations, specifically increased pathobionts and decreased Ruminococcaceae, are linked to severe immune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitors (ICIs). These changes may predispose patients to these toxicities.
Area of Science:
- Oncology
- Immunology
- Microbiome Research
Background:
- The gut microbiome's influence on immune checkpoint inhibitor (ICI) efficacy is recognized, but its role in immune-related adverse events (irAEs) requires further investigation.
- Understanding the association between gut microbial composition and the development of severe irAEs is crucial for patient management.
Purpose of the Study:
- To prospectively assess the association between gut microbiome composition at baseline and during treatment with ICIs and the occurrence of severe irAEs.
- To investigate if alterations in specific bacterial taxa and pathways correlate with the development of severe irAEs in cancer patients.
Main Methods:
- Prospective cohort study analyzing stool samples from cancer patients treated with anti-PD-1 ± anti-CTLA-4 therapies.
- Utilized 16S rRNA gene sequencing and metagenomic shotgun sequencing to characterize the gut microbiome.
- Assessed alpha and beta diversity, differential relative abundance (RA) of taxa, MetaCyc pathways, and specific bacterial groups (pathobionts, Ruminococcaceae).
Main Results:
- Higher baseline and on-treatment relative abundance (RA) of pathobionts was significantly associated with the development of severe irAEs (OR 1.40; 95% CI 1.07-1.87).
- Patients who developed severe irAEs exhibited a significantly greater decrease in Ruminococcaceae RA after initiating ICI treatment.
- RAs of Ruminococcaceae, Ruminococcus, R. bromii, and R. callidus were significantly lower at severe irAE onset compared to other time points.
Conclusions:
- Gut microbiome dysbiosis, characterized by an increased relative abundance of pathobionts and a decreased relative abundance of Ruminococcaceae, may predispose patients to severe irAEs.
- These findings highlight the potential of the gut microbiome as a predictive biomarker for irAEs in patients undergoing immunotherapy.
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