Novel Bile Acid Suppresses Neutrophilic Airway Inflammation in Non-Type 2 Asthma

Ahmed Kabil – Ph.D. Candidate, School of Biomedical Engineering, University of British Columbia; Samuel Shin – School of Biomedical Engineering – University of British Columbia; Maggie Chopra – MD/PhD Student, Faculty of Medicine, University of British Columbia; Michael Hughes, Ph.D. – University of British Columbia; Kelly McNagny, Ph.D. – Professor, School of Biomedical Engineering, University of British Columbia

Abstract Text: Asthma affects more than 300 million individuals worldwide. Broadly, asthma can be characterized by eosinophilic T2 and neutrophilic non-T2 endotypes. Patients with non-T2 asthma show severe symptoms, lung neutrophilia, and poor responsiveness to the current gold-standard treatment for asthma including corticosteroids. The key pathogenic cells are group 3 innate lymphoid cells (ILC3) and T helper 17 (Th17) cells that express the transcription factor RORγt and play crucial roles in mediating neutrophilic inflammation. Isolithocholic acid (isoLCA) - a microbiome-derived secondary bile acid - is a reversible inhibitor of RORγt and shows efficacy in modulating Th17-driven intestinal inflammatory diseases. Here, we investigate the potential of isoLCA to inhibit RORγt in pathogenic ILC3 and Th17 cells in a murine model of non-type 2 asthma. High-dimensional spectral flow cytometry and immunohistochemistry reveal that oral administration of isoLCA significantly reduces airway neutrophilia. Mechanistically, isoLCA inhibits RORγt expression in the lungs, leading to reduced pathogenic ILC3 and Th17 cell populations, and lowers IL-17A levels in lung CD4 T cells and ILCs. Our results show that isoLCA attenuates neutrophilic airway inflammation in non-type 2 asthma by specifically inhibiting RORγt-driven pathways. These findings suggest that isoLCA has therapeutic potential as a novel agent suppressing RORγt to treat non-type 2 asthma, especially in cases unresponsive to corticosteroids.