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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.
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