Microbial dysbiosis sculpts a systemic ILC3/IL-17 axis governing lung inflammatory responses and central hematopoiesis

Ahmed K Kabil; Leo T Liu; Chengxi Xu; Natalia Nayyar; Laura González; Sameeksha Chopra; Julyanne Brassard; Marie-Josée Beaulieu; Yicong Li; Ayaz Damji; Peter W Zandstra; Marie-Renée Blanchet; Michael R Hughes; Kelly M McNagny

doi:10.1016/j.mucimm.2025.07.002

Microbial dysbiosis sculpts a systemic ILC3/IL-17 axis governing lung inflammatory responses and central hematopoiesis

Mucosal Immunol. 2025 Oct;18(5):1139-1158. doi: 10.1016/j.mucimm.2025.07.002. Epub 2025 Jul 20.

Affiliations

¹ School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.
² Department of Chemistry, University of British Columbia, Vancouver, BC, Canada.
³ Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, Canada.
⁴ School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, Canada.
⁵ School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, Canada. Electronic address: mhughes@brc.ubc.ca.
⁶ School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; Center for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada. Electronic address: kelly@brc.ubc.ca.

PMID: 40695364
DOI: 10.1016/j.mucimm.2025.07.002

Abstract

Advancements in vaccination and sanitation have significantly reduced the prevalence and burden of infectious diseases; however, these benefits have coincided with a marked rise in autoimmune and allergic disorders. Recent studies have investigated these linked trends through the lens of host-microbiome alterations, proposing these shifts as a potential explanatory mechanism. Previously, we demonstrated that vancomycin-induced depletion of short-chain fatty acid (SCFA) producing bacteria results in hyperactivation of ILC2s and exacerbated allergic responses. Here we investigate the effects of low-dose streptomycin on innate and adaptive immune cell populations and their activation states. Although streptomycin-treated mice exhibit normal allergic responses, they display heightened susceptibility to Th1/Th17-mediated disease, specifically hypersensitivity pneumonitis (HP). This is characterized by a two-fold increase in ILC3s and Th17 cells in the lungs, alongside activation of antigen-presenting cells (APCs) at steady state, an effect that is further amplified upon exposure to HP-inducing agents. Shotgun metagenomic analysis revealed that streptomycin-induced dysbiosis reduces microbial diversity, depletes bile acid-metabolizing bacteria, and enriches for metabolic pathways involved in branched-chain amino acid biosynthesis, including leucine, a known activator of mTORC1. Strikingly, administration of the secondary bile acid metabolite isolithocholic acid (an inverse agonist of RORγt), or an IL-23 neutralizing antibody, reverses the enhanced susceptibility to HP. Inhibition of mTORC1 also significantly reduced Th17/ILC3 responses and histopathology. Our findings underscore microbial equilibrium as a key determinant of susceptibility to HP and uncover a positive feedback loop between IL-23-producing APCs and ILC3/Th17 cells that mechanistically links dysbiosis to sustained type 3 inflammation; and we identify a simple, actionable means of intervention.

Keywords: Innate lymphoid cells; Interstitial lung disease; chronic inflammation; microbiome-driven hematopoiesis and immune development.

MeSH terms

Animals
Disease Models, Animal
Dysbiosis* / immunology
Hematopoiesis*
Immunity, Innate
Interleukin-17* / metabolism
Lung* / immunology
Mice
Mice, Inbred C57BL
Microbiota
Streptomycin
Th17 Cells* / immunology

Substances

Interleukin-17
Streptomycin