Abstract
BackgroundImmune checkpoint inhibitor-related cardiotoxicity is one of the most lethal adverse effects, and thus, the identification of underlying mechanisms for developing strategies to overcome it has clinical importance. This study aimed to investigate whether microbiota-host interactions contribute to PD-1/PD-L1 inhibitor-related cardiotoxicity.MethodsA mouse model of immune checkpoint inhibitor-related cardiotoxicity was constructed by PD-1/PD-L1 inhibitor BMS-1 (5 and 10 mg/kg), and cardiomyocyte apoptosis and cardiotoxicity were determined by hematoxylin and eosin, Masson’s trichome and TUNEL assays. 16S rRNA sequencing was used to define the gut microbiota composition. Gut microbiota metabolites short-chain fatty acids (SCFAs) were determined by HPLC. The serum levels of myocardial enzymes (creatine kinase, aspartate transaminase, creatine kinase-MB and lactate dehydrogenase) and the production of M1 factors (TNF-α and IL-1β) were measured by ELISA. The colonic macrophage phenotype was measured by mmunofluorescence and qPCR. The expression of Claudin-1, Occludin, ZO-1 and p-p65 was measured by western blot. The gene expression of peroxisome proliferator-activated receptor α (PPARα) and cytochrome P450 (CYP) 4X1 was determined using qPCR. Statistical analyses were performed using Student’s t-test for two-group comparisons, and one-way ANOVA followed by Student–Newman–Keul test for multiple-group comparisons.ResultsWe observed intestinal barrier injury and gut microbiota dysbiosis characterized by Prevotellaceae and Rikenellaceae genus depletion and Escherichia-Shigella and Ruminococcaceae genus enrichment, accompanied by low butyrate production and M1-like polarization of colonic macrophages in BMS-1 (5 and 10 mg/kg)-induced cardiotoxicity. Fecal microbiota transplantation mirrored the effect of BMS-1 on cardiomyocyte apoptosis and cardiotoxicity, while macrophage depletion and neutralization of TNF-α and IL-1β greatly attenuated BMS-1-induced cardiotoxicity. Importantly, Prevotella loescheii recolonization and butyrate supplementation alleviated PD-1/PD-L1 inhibitor-related cardiotoxicity. Mechanistically, gut microbiota dysbiosis promoted M1-like polarization of colonic macrophages and the production of proinflammatory factors TNF-α and IL-1β through downregulation of PPARα-CYP4X1 axis.ConclusionsIntestinal barrier dysfunction amplifies PD-1/PD-L1 inhibitor-related cardiotoxicity by upregulating proinflammatory factors TNF-α and IL-1β in colonic macrophages via downregulation of butyrate-PPARα-CYP4X1 axis. Thus, targeting gut microbiota to polarize colonic macrophages away from the M1-like phenotype could provide a potential therapeutic strategy for PD-1/PD-L1 inhibitor-related cardiotoxicity.Graphical abstract
Highlights
Immune checkpoint inhibitor-related cardiotoxicity is one of the most lethal adverse effects, and the identification of underlying mechanisms for developing strategies to overcome it has clinical importance
The food intake by the mice treated with the programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitor BMS-1 (5 and 10 mg/kg) showed a decreasing trend compared with the control, there was no significant difference among the three groups (Fig. 1A)
Similar results were obtained in the activities of myocardial enzymes including creatine kinase (CK)-MB, aspartate transaminase (AST), CK and lactate dehydrogenase (LDH) in the peripheral blood of the mice treated with BMS-1 (Fig. 1D)
Summary
Immune checkpoint inhibitor-related cardiotoxicity is one of the most lethal adverse effects, and the identification of underlying mechanisms for developing strategies to overcome it has clinical importance. This study aimed to investigate whether microbiota-host interactions contribute to PD-1/PD-L1 inhibitor-related cardiotoxicity. PD-1/PD-L1 inhibitors induce a wide spectrum of immune-related adverse events (irAEs), with cardiotoxicity being the most lethal adverse effect [2]. ICI-related cardiotoxicity events occur in different forms, including myocarditis, cardiomyopathy and myocardial fibrosis, and myocarditis with evidence of cardiomyocyte apoptosis is one of the most important clinical and pathological features [3, 4]. It is essential to minimize systemic inflammation to overcome PD-1/PD-L1 inhibitor-induced cardiotoxicity, myocarditis. Whether manipulation of gut microbiota and its metabolites, including butyrate, prevents PD-1/PD-L1 inhibitor-induced cardiomyocyte apoptosis and cardiotoxicity is still not clear
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