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/ObHFD 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/ObHFD 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.