Dietary tryptophan mitigates lung ischemia-reperfusion injury in association with increased indole-3-propionate and aryl hydrocarbon receptor signaling

BACKGROUND: Lung ischemia-reperfusion (IR) injury drives early morbidity after lung transplantation and cardiothoracic surgery, yet targeted preventive therapies are lacking. The gut-lung axis and microbiota-derived tryptophan metabolites, including indole-3-propionate (IPA), may regulate pulmonary immunity and inflammation. We investigated whether a tryptophan-rich (Trp-Rich) diet attenuates sterile lung IR injury by increasing microbiota-derived indole metabolites and reprogramming alveolar macrophage (AM) inflammatory responses. METHODS: nutritional IR, LPS stimulation, and AhR stimulation and blockade using synthetic agonists and antagonists. RESULTS: nutritional IR injury, and its effects were attenuated by pharmacologic AhR blockade. CONCLUSIONS: A Trp-Rich diet attenuated sterile lung IR injury, coinciding with gut microbiota remodeling, increased systemic and pulmonary IPA, reduced inflammatory priming, and reprogrammed AM responses. These data support diet- or microbiome-directed strategies targeting IPA-AhR signaling to mitigate perioperative lung IR injury.