TGR5 activation impairs lung natural killer cell function and promotes bile acid–mediated injury in metabolic liver disease

Introduction and aim Bile acids (BAs) contribute to acute lung injury (ALI), yet their effects on pulmonary immune cells remain unclear. This study investigated whether elevated hepatic BA levels in metabolic dysfunction–associated steatohepatitis (MASH) promote lung injury by suppressing natural killer (NK) cell function through the bile acid receptor TGR5. Methods Leptin-deficient ( Ob/Ob ) mice were fed a high-fat diet (HFD) for 16 weeks to induce MASH, while wild-type mice served as controls. Lung fibrosis was assessed histologically. NK cell activation (CD107a, NKp46) and TGR5 expression were analyzed by flow cytometry. Lung injury markers (SP-D and sRAGE) and BA concentrations in bronchoalveolar lavage fluid (BALF) were quantified. Ex-vivo assays evaluated the effects of taurocholic acid (TCA) and TGR5 blockade on NK cell activation. Results Ob/Ob HFD mice developed MASH accompanied by lung injury and fibrotic remodeling. Lung weight increased by ∼1.5 g compared with controls. SP-D and sRAGE levels increased 2.5-fold and 2.0-fold, respectively (P < 0.01). BALF BA concentrations rose from 0.2 µM in controls to 1.2–1.9 µM in Ob/Ob HFD mice, indicating hepatic–pulmonary BA trafficking. NK cell activity was markedly suppressed, with a 3.5-fold reduction in activation, decreased CD107a expression, and a 1.75-fold reduction in NKp46 levels. TGR5 expression on lung NK cells increased ∼3.5-fold. TCA exposure impaired NK activation, whereas TGR5 blockade restored CD107a and NKp46 expression. Conclusion BA–TGR5 signaling suppresses pulmonary NK cell function and contributes to lung injury in MASH, suggesting TGR5 as a potential therapeutic target for BA-driven immune dysfunction.