Gut-microbiota-derived indole sulfate promotes heart failure in chronic kidney disease

Heart failure (HF) is highly prevalent in chronic kidney disease (CKD) and associates with alterations in gut microbiota, although the underlying mechanisms remain unclear, complicating diagnosis and treatment. In this study, we identify indoxyl sulfate (IS), produced by E. coli through the tryptophanase (TnaA) pathway, as a key metabolite involved in CKD-related HF. Mechanistically, IS disrupts cardiac mitochondrial function and induces myocardial apoptosis via the AHR-CYP1B1 axis, driving HF progression. To target this gut-microbiota-IS axis for clinical improvement of CKD-related HF, we applied probiotics to reduce E. coli abundance and IS levels, resulting in improved cardiac outcomes in rats and CKD patients. This study was registered at the Chinese Clinical Trial Register ( https://www.chictr.org.cn : ChiCTR2500098366 and ChiCTR2500100588). Furthermore, E. coli abundance shows diagnostic potential for early prediction of HF onset within 6 months in a prospective CKD cohort study. These findings underscore the critical role of gut microbiota in CKD-related HF and suggest a microbiota-targeted therapeutic and diagnostic strategy for clinical intervention. • CKD patients with heart failure have elevated E. coli and E. coli -derived indoxyl sulfate • Indoxyl sulfate causes cardiac mitochondrial dysfunction via AHR-CYP1B1 axis • Probiotic DM02 reduces indoxyl sulfate and improves cardiac function in rats and patients • Gut microbiota profiles can predict the future risk of heart failure in CKD Heart failure (HF) is highly prevalent among patients with chronic kidney disease (CKD), yet the exact mechanisms remain unclear. Zhang et al. demonstrate that E. coli -derived indoxyl sulfate promotes heart failure progression in CKD via AHR-CYP1B1 signaling. Targeting the microbiota-indoxyl sulfate pathway offers diagnostic and therapeutic potential for CKD-related HF.