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.