Abstract TAC234: Gut Metabolite Urolithin A attenuates Pyroptosis and Kidney Injury in a Swine Model of Fecal Peritonitis

Fecal peritonitis (FP) is a severe, life-threatening condition that often precipitates sepsis. Sepsis-induced acute kidney injury (AKI) remains a leading cause of morbidity and mortality in critically ill patients, yet effective treatments are lacking. Pyroptosis—a proinflammatory form of programmed cell death driven by NLRP3 inflammasome activation—has emerged as a key contributor to septic kidney dysfunction. Urolithin A (UA), a gut microbiota-derived metabolite of ellagitannins and ellagic acid, exhibits anti-inflammatory and cytoprotective properties in various disease models; however, its efficacy in septic AKI is unknown. This study evaluated the therapeutic potential of UA in a clinically relevant swine model of FP-induced sepsis and examined its effects on pyroptosis. Six- to eight-week-old pigs were randomized to receive vehicle or UA following sepsis induction via intraperitoneal instillation of autologous fecal slurry under general anesthesia. After 24 hours of recovery, animals were re-anesthetized and mechanically ventilated for an assessment of systemic and renal function, including mean arterial pressure (MAP), cardiac output (CO), renal blood flow, renal vascular resistance, and transdermal glomerular filtration rate (GFR). Biochemical markers of kidney injury were analyzed, and kidney tissues were harvested post-mortem. In parallel, in vitro experiments using primary porcine proximal tubule epithelial cells assessed UA’s effects on lipopolysaccharide (LPS)-induced caspase-1 activation. FP significantly elevated plasma procalcitonin, impaired systemic and renal hemodynamics, increased renal vascular resistance, reduced GFR and worsened renal injury markers. UA treatment significantly ameliorated these effects by preserving MAP, CO, and GFR and lowering plasma creatinine, BUN, cystatin C, and urinary NGAL. UA also suppressed NLRP3 inflammasome activation and downstream pyroptosis mediators, including gasdermin D and interleukin-18, and reduced renal oxidative stress. In vitro, UA inhibited LPS-induced caspase-1 activation. In conclusion, UA confers robust renoprotective effects in septic AKI by improving renal hemodynamics, reducing oxidative stress, and inhibiting pyroptosis. These findings support the translational potential of UA as a novel therapeutic strategy for sepsis-associated AKI.