Bile acid metabolites enhance expression of cathelicidin antimicrobial peptide in airway epithelium through activation of the TGR5-ERK1/2 pathway

• Published in: Scientific reports Vol. 14; no. 1; p. 6750
• Main Authors: Myszor, Iwona T., Lapka, Kornelia, Hermannsson, Kristjan, Rekha, Rokeya Sultana, Bergman, Peter, Gudmundsson, Gudmundur Hrafn
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.03.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/2499; 631/250/262; Acids; Antimicrobial peptides; Bile; Dopamine D3 receptors; Epithelial cells; Epithelium; Extracellular signal-regulated kinase; Homeostasis; Humanities and Social Sciences; Immune response; Immunomodulation; Innate immunity; Kinases; Medicin och hälsovetenskap; Metabolites; Microbiota; multidisciplinary; Nuclear receptors; Peptides; Respiratory tract; Science; Science (multidisciplinary); Vitamin D3
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-57251-3

Signals for the maintenance of epithelial homeostasis are provided in part by commensal bacteria metabolites, that promote tissue homeostasis in the gut and remote organs as microbiota metabolites enter the bloodstream. In our study, we investigated the effects of bile acid metabolites, 3-oxolithocholic acid (3-oxoLCA), alloisolithocholic acid (AILCA) and isolithocholic acid (ILCA) produced from lithocholic acid (LCA) by microbiota, on the regulation of innate immune responses connected to the expression of host defense peptide cathelicidin in lung epithelial cells. The bile acid metabolites enhanced expression of cathelicidin at low concentrations in human bronchial epithelial cell line BCi-NS1.1 and primary bronchial/tracheal cells (HBEpC), indicating physiological relevance for modulation of innate immunity in airway epithelium by bile acid metabolites. Our study concentrated on deciphering signaling pathways regulating expression of human cathelicidin, revealing that LCA and 3-oxoLCA activate the surface G protein-coupled bile acid receptor 1 (TGR5, Takeda-G-protein-receptor-5)—extracellular signal-regulated kinase (ERK1/2) cascade, rather than the nuclear receptors, aryl hydrocarbon receptor, farnesoid X receptor and vitamin D3 receptor in bronchial epithelium. Overall, our study provides new insights into the modulation of innate immune responses by microbiota bile acid metabolites in the gut-lung axis, highlighting the differences in epithelial responses between different tissues.