Gut microbiota-derived indole-3-lactic acid attenuates renal ischemia-reperfusion injury through AhR-modulated oxidative stress

Abstract Susceptibility to renal ischemia-reperfusion injury (IRI) varies substantially among individuals, but the endogenous mechanisms underlying this heterogeneity remain incompletely defined. Here, using an extreme-phenotype screening strategy in mice, we identified the gut microbiota-derived tryptophan metabolite indole-3-lactic acid (ILA) as a critical correlate of renal IRI resistance. Injury-resistant mice exhibited an enrichment of Lactobacillus murinus and elevated systemic ILA. Fecal microbiota transfer from resistant donors, targeted L. murinus colonization, or prophylactic ILA supplementation elevated circulating ILA and attenuated renal dysfunction, oxidative stress, and tubular cell death after IRI. Mechanistically, ILA engaged aryl hydrocarbon receptor (AhR) signaling, an event associated with the transcriptional downregulation of Cybb (NOX2), reduced reactive oxygen species (ROS) accumulation, and the maintenance of the GPX4/SLC7A11 defense program. In microbiota-depleted mice and CYBB knockdown models, ILA attenuated NOX2-associated lipid peroxidation. Prophylactic dietary tryptophan administration engaged this microbiota–ILA–AhR axis to alleviate experimental IRI, whereas lower preoperative plasma ILA and fecal L. murinus abundance correlated with subsequent postoperative acute kidney injury (AKI) following partial nephrectomy. These findings delineate a nutritional-microbial-host network that influences intrinsic renal ischemic resilience and may inform perioperative strategies for AKI risk management.