Abstract: TH-PO0222
ST2 Signaling Drives Gut-Immune-Kidney Axis via Mitochondrial Reprogramming and Microbial Remodeling in Chronic Kidney Injury
Session Information
- CKD: Mechanisms of Injury and Fibrosis - 1
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Sabapathy, Vikram, University of Virginia, Charlottesville, Virginia, United States
- Pelletier, Oliver B., University of Virginia, Charlottesville, Virginia, United States
- Sharma, Rahul, University of Virginia, Charlottesville, Virginia, United States
Background
The IL-33 bearing hybrid cytokine IL233 promotes expansion of regulatory T cells (Tregs) and tissue repair, but the mechanisms linking ST2 activation to Treg metabolic fitness and sustained protection from chronic kidney injury are not fully understood. As Tregs rely on oxidative metabolism, and the gut microbiome can influence immune cell metabolism, we hypothesized that IL-233–mediated ST2 activation promotes kidney protection through the coordinated enhancement of Treg mitochondrial function and microbiome-derived metabolic support within a gut–immune–kidney axis.
Methods
Using a unilateral ischemia–reperfusion injury (uIRI) model of chronic kidney disease, mice received IL233 either prophylactically or therapeutically following injury. To identify the effect of IL233 on gut microbiome, a dose-escalation study (10, 30, 100 µg/kg) was performed. ST2+Tregs were quantified by flow cytometry, and Treg metabolism was assessed by transcriptional and functional analysis. Kidney injury was evaluated by plasma creatinine, BUN, and histopathology. Gut microbiome composition and pathways were analyzed using metagenomic profiling and genus–pathway network analysis.
Results
IL233 significantly attenuated chronic kidney injury when administered either pre- and post-uIRI, as evidenced by improved renal function and histology. There was a dose-dependent expansion of ST2+ Tregs and enhanced Treg mitochondrial metabolism and oxidative phosphorylation. Microbiome analysis revealed dose-dependent remodeling of microbial composition and function, with enrichment of pathways involved in carbohydrate metabolism, fermentation, amino acid biosynthesis, and redox processes, including quinone metabolism. Notably, Lactobacillus-associated pathways linked to glycolysis, fermentation, and biosynthesis were increased, indicating a microbial community capable of generating immunomodulatory metabolites.
Conclusion
Activation of the IL-33/ST2 axis promotes expansion of metabolically active ST2+ Tregs, leading to protection against chronic kidney injury. Concurrent remodeling of the gut microbiome that supports redox balance and metabolite production, potentially reinforcing Treg mitochondrial function. These findings define a novel gut–immune–kidney axis in which microbial metabolic programs and host immune signaling converge to regulate tissue protection and repair.
Funding
- NIDDK Support