Clinical antibiotic therapy disrupts microbial bile acid metabolism and depletes secondary bile acids without altering pulmonary antibacterial defense

Abstract Antibiotic exposure is highly prevalent among hospitalized patients and is a major risk factor for subsequent hospital-acquired pneumonia (HAP) and other healthcare-associated infections. However, the mechanisms underlying antibiotic-associated infection susceptibility remain incompletely understood. We investigated secondary bile acids, microbiota-derived metabolites implicated in immune modulation. Clinical antibiotic therapy disrupted microbial bile acid metabolism, including depletion of the 7α-dehydroxylation-associated gene baiA1 . Secondary bile acids were reduced in stool and plasma of antibiotic-treated patients, whereas primary bile acids remained unchanged or increased. To assess the functional relevance of these changes for pulmonary antibacterial defense, we used complementary animal models. While microbiota depletion impaired resistance to MDR Klebsiella pneumoniae infection, targeted modulation of the secondary bile acid-TGR5 axis did not measurably affect antibacterial defense. Thus, clinical antibiotic therapy disrupts microbial secondary bile acid metabolism and causes systemic depletion of secondary bile acids, but this perturbation does not appear to mediate impaired pulmonary antibacterial defense.