Exploring the role of the gut microbiota in development of myocarditis related to immune checkpoint inhibitors

Introduction: Immune checkpoint inhibitor (ICI) therapy has revolutionized cancer treatment. However, ICIs are associated with immune-related adverse events (irAEs), including myocarditis, a severe and fatal condition. The clinical spectrum of ICI-associated myocarditis ranges from asymptomatic elevation of cardiac biomarkers to fulminant myocarditis. The mechanisms underlying susceptibility to ICI-related myocarditis are not well understood, but the gut microbiome, an important regulator of immune responses, may play a role. This study investigates whether gut microbiota influences the progression of ICI-related myocarditis in humans and in a transgenic mouse model.

Materials and Methods: A mouse model with a homozygous knockout of Pdcd1 and heterozygous deletion of Ctla4, mimicking ICI-associated myocarditis, was used. Mice were treated with antibiotics for two weeks and then underwent fecal microbiota transplantation (FMT) from patients who had developed myocarditis after ICI treatment or from control patients who did not develop myocarditis. Myocarditis severity was assessed by echocardiography, troponin I levels, and tissue analysis for myocardial inflammation and fibrosis. Gut microbiota composition was analyzed using 16S rRNA sequencing.

Results and Discussion: 16S rRNA sequencing revealed significant differences in gut bacterial composition between the myocarditis and control groups in both humans and mice, with specific bacterial species over-represented in the ICI myocarditis cohort. One month after FMT, mice which recieved FMT from ICI-myocarditis patients showed a significant decrease in global longitudinal strain (GLS) and left ventricular ejection fraction, alongside elevated troponin I levels, fibrosis, and inflammation markers compared to controls.

Conclusion: This study demonstrates that gut microbiota contributes to ICI-associated myocarditis, offering insights into the mechanisms behind this condition. The distinct microbial profiles observed in the ICI-myocarditis mice suggest potential microbiota-based interventions to mitigate irAEs. Further research is needed to explore these mechanisms and develop strategies targeting the gut microbiome to improve ICI therapy safety and efficacy.