Microbial metabolite oxindole curbs acute lung injury by suppressing CXCL13.

Tryptophan metabolism was significantly dysregulated in ARDS patients compared to healthy controls.

• Untargeted metabolomics of plasma was used to compare ARDS patients and healthy controls.
• The dysregulation of tryptophan metabolism was identified as a key feature distinguishing ARDS patients from controls.
• Oxindole and CXCL13 levels correlated with ARDS severity in patients, suggesting clinical relevance.

High dietary tryptophan intake alleviated ALI severity in mice, while tryptophan deficiency exacerbated injury, and this protection was gut microbiota dependent.

• Murine dietary interventions demonstrated that high tryptophan intake alleviated ALI severity.
• Tryptophan deficiency exacerbated injury in the murine model.
• The protective effect of tryptophan was shown to be gut microbiota dependent.
• These findings were established through dietary intervention experiments in mouse models of ALI.

Lactobacillus johnsonii was markedly depleted during ALI, and its supplementation attenuated ALI in a dietary tryptophan-dependent manner.

• 16S rRNA gene sequencing revealed marked depletion of Lactobacillus johnsonii, described as a 'functionally central bacterium,' during ALI.
• Supplementation with L. johnsonii or its encapsulated form attenuated ALI.
• The protective effect of L. johnsonii supplementation required dietary tryptophan sufficiency.
• L. johnsonii was identified as the mechanistic link between dietary tryptophan and pulmonary protection.

Lactobacillus johnsonii converts tryptophan into oxindole, which enters pulmonary macrophages and promotes aryl hydrocarbon receptor-RelA binding.

• The mechanistic pathway was identified as: L. johnsonii converts tryptophan into oxindole.
• Oxindole enters pulmonary macrophages.
• Within pulmonary macrophages, oxindole promotes the binding of aryl hydrocarbon receptor (AhR) to RelA.
• This AhR-RelA interaction suppresses RelA-mediated transcriptional activation of CXCL13.

Both genetic ablation and pharmacological inhibition of CXCL13 ameliorated ALI symptoms.

• Genetic ablation of CXCL13 was used as one approach to test its role in ALI.
• Pharmacological inhibition of CXCL13 was used as a complementary approach.
• Both approaches resulted in amelioration of ALI symptoms.
• CXCL13 (C-X-C motif chemokine 13) was identified as a downstream effector of the oxindole-AhR-RelA pathway.

Plasma oxindole levels and CXCL13 levels correlated with ARDS severity in patients.

• Oxindole levels in patients correlated with ARDS severity.
• CXCL13 levels in patients correlated with ARDS severity.
• These correlations suggest the clinical relevance of the identified gut-lung axis pathway.
• The findings support oxindole and CXCL13 as potential clinical biomarkers or therapeutic targets in ARDS.

The gut-lung axis in ALI/ARDS is mediated by dietary tryptophan-derived oxindole acting through CXCL13 suppression.

• The findings define 'a protective microbiota-dependent gut-lung axis in ALI/ARDS.'
• The axis is mediated by dietary tryptophan-derived oxindole.
• Oxindole acts 'at least partially through CXCL13 suppression.'
• The authors describe this as underscoring 'targetable diet-microbe-metabolite therapeutic paradigms.'