2. Academic Validation
  3. Gut-microbiota-derived indole sulfate promotes heart failure in chronic kidney disease

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

  • Cell Host Microbe. 2025 Oct 8;33(10):1715-1730.e5. doi: 10.1016/j.chom.2025.08.014.
Yun Zhang 1,  Xuejie Han 2,  Tao Feng 1,  Zewen Li 1,  Hui Yu 2,  Ye Chen 3,  Yunlong Gao 2,  Qianhui Gao 2,  Linwei Zhang 2,  Shanshan Li 1,  Ling Shi 2,  Xiru Zhang 1,  Zhuang Li 4,  Yue Li 5,  Hongwei Zhou 6
Affiliations

Affiliations

  • 1 Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China.
  • 2 Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
  • 3 Department of Gastroenterology, Integrative Microecology Clinical Center, Shenzhen Key Laboratory of Gastrointestinal Microbiota and Disease, Shenzhen Clinical Research Center for Digestive Disease, Shenzhen Hospital, Southern Medical University, Shenzhen 518000, China; Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
  • 4 Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China. Electronic address: jiandandjx@smu.edu.cn.
  • 5 Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China. Electronic address: ly99ly@vip.163.com.
  • 6 Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China; Department of Cardiology, Shenzhen Hospital, Southern Medical University, Shenzhen 518000, China; State Key Laboratory of Organ Failure Research, Southern Medical University, Shenzhen Hospital, Shenzhen 518000, China; Shenzhen Key Laboratory of Gastrointestinal Microbiota and Disease, Southern Medical University, Shenzhen Hospital, Shenzhen 518000, China; State Key Laboratory of Multi-Organ Injury Prevention and Treatment, Southern Medical University, Shenzhen Hospital, Shenzhen 518107, China. Electronic address: biodegradation@gmail.com.
PMID: 40961933 DOI: 10.1016/j.chom.2025.08.014
Abstract

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.

Keywords

Escherichia coli; chronic kidney disease; heart failure; indoxyl sulfate.

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