Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy

Myocarditis can develop into inflammatory cardiomyopathy through chronic stimulation of myosin heavy chain 6-specific T helper (T_H)1 and T_H17 cells. However, mechanisms governing the cardiotoxicity programming of heart-specific T cells have remained elusive. Using a mouse model of spontaneous autoimmune myocarditis, we show that progression of myocarditis to lethal heart disease depends on cardiac myosin-specific T_H17 cells imprinted in the intestine by a commensal <i>Bacteroides</i> species peptide mimic. Both the successful prevention of lethal disease in mice by antibiotic therapy and the significantly elevated <i>Bacteroides-</i>specific CD4⁺ T cell and B cell responses observed in human myocarditis patients suggest that mimic peptides from commensal bacteria can promote inflammatory cardiomyopathy in genetically susceptible individuals. The ability to restrain cardiotoxic T cells through manipulation of the microbiome thereby transforms inflammatory cardiomyopathy into a targetable disease.