Microbiota-derived bile acid ameliorates lung inflammation through metabolic rewiring of alveolar macrophages

Using mouse models of airway inflammation, we identified a causal link between the microbiota-dependent bile acid isolithocholic acid and protection against lung immunopathology. We further found that this protection involves Sphingosine-1-phosphate receptor 2–dependent metabolic rewiring of alveolar macrophages as a key mechanism. Collectively, our findings demonstrate that isolithocholic acid, a microbiota-derived bile acid, can ameliorate lung inflammation through previously unrecognized pathways, highlighting its therapeutic potential—and that of its derivatives—in lung disease. Overall design: Acute lung injury was induced in six wild-type C57BL/6J mice by intranasal instillation of LPS. Following induction, half of the mice were treated with isolithocholic acid for three days, while the other half received vehicle. A control group of mice that did not receive LPS underwent the same treatment regimen. After four days, lungs were collected, dissociated into single-cell suspensions, and analyzed using scRNA-seq.