UCSF

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

C57BL/6 mice receiving isocaloric tryptophan-standard (Trp-Std) or tryptophan-rich (Trp-Rich) diets underwent lung IR injury. Oxygen saturation, lung cytokines, and aryl hydrocarbon receptor (AhR) signaling readouts were evaluated. Gut microbiota was profiled by 16S rRNA sequencing, and targeted metabolomics quantified tryptophan metabolites in feces, portal vein (PV) plasma, and lung tissue. To further assess inflammatory priming in vivo, mice were additionally challenged with intratracheal lipopolysaccharide (LPS). Mechanistic studies compared IPA with related indoles in cell lines and primary human AMs, including ex vivo nutritional IR, LPS stimulation, and AhR stimulation and blockade using synthetic agonists and antagonists.

Results

Trp-Rich feeding improved post-IR oxygenation, reduced lung IL-1β, and increased pulmonary AhR-downstream gene expression. Trp-Rich diet remodeled gut microbiota, enriching for Bifidobacterium and Lactobacillus, and increasing IPA levels across feces, PV plasma, and lung tissue. In the LPS intratracheal challenge, Trp-Rich feeding reduced IL-6 levels in lung tissue and systemic plasma. Primary AMs isolated from Trp-Rich mice also showed reduced IL-1β and IL-6 release in an ex vivo nutritional IR model. Among the tested indole metabolites, IPA showed the strongest dose-dependent suppression of LPS-induced cytokines and chemokines, suppressed ex vivo 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.