Abstract: TH-PO1148
Integrative Metabolomic and Microbiota Analyses Reveal Indole-3-Propionic Acid Worsens Cisplatin-Induced CKD via AHR/NF-κB Pathway
Session Information
- CKD: Mechanisms, AKI, and Beyond - 1
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Wang, Qian, State Key Laboratory of Multi-organ Injury Prevention and Treatment, National Clinical Research Center of Kidney Disease, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Chen, Jie, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Zhou, Hong, State Key Laboratory of Multi-organ Injury Prevention and Treatment, National Clinical Research Center of Kidney Disease, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Fu, Haiyan, State Key Laboratory of Multi-organ Injury Prevention and Treatment, National Clinical Research Center of Kidney Disease, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
Background
Cisplatin is a commonly used chemotherapy agent for treating various solid tumors, but its clinical use is limited by nephrotoxicity. From a novel perspective, this study aimed to investigate the association between the gut microbiome and metabolomic profiles of repeated doses of cisplatin caused CKD and evaluate the role of microbiota-derived metabolite indole-3-propionic acid (IPA) in cisplatin-induced CKD and the underlying molecular mechanism.
Methods
Gut microbiota alteration and tryptophan metabolism production were analyzed through 16S rRNA sequencing, metabolomics/tryptophan targeted metabolomic, Raman spectroscopy and DESI-MSI. The datasets were integrated for combined analysis using various bioinformatics approaches, and the gene and protein expression in renal tissues and colon were detected by qRT-PCR, western blot, and immunohistochemical staining.
Results
In this study, we demonstrated that cisplatin-induced CKD is associated with renal dysfunction, inflammation, and intestinal barrier dysfunction. 16S rRNA sequencing and metabolomics revealed that cisplatin-induced gut dysbiosis and elevated tryptophan metabolites. Notably, oral administration of the microbiota-derived metabolite IPA reproduced and worsen CKD phenotypes in mice. Integrated microbiota, metabolomics analysis, Raman spectroscopy and DESI-MSI showed that IPA supplementation promotes uremic toxins production linked to tryptophan metabolism and pathogenic bacteria growth. Mechanistically, IPA suppresses aryl hydrocarbon receptor (AHR) expression, activates the NF-κB signaling pathway, and increases macrophage infiltration and cytokine release, amplifying inflammation in cisplatin-induced CKD.
Conclusion
Taken together, this study reveals that IPA exacerbates renal inflammation and fibrosis by regulating of AHR/NF-κB signaling pathways, gut microbiota composition, and tryptophan metabolism, highlighting the potential risks of unregulated use of IPA supplementation in CKD.
Funding
- Other NIH Support