Determinant microbiota and lauroylcarnitine mediated immune activation in checkpoint inhibitor pneumonitis

<bold>Background:</bold> Checkpoint inhibitor pneumonitis (CIP) is a potentially fatal adverse event in cancer patients undergoing immune checkpoint inhibitor therapy. <bold>Objective:</bold> To explore the relationship between the microbiota and host immunity in CIP. <bold>Methods:</bold> We recruited 13 patients with CIP, 11 with idiopathic pulmonary fibrosis (IPF), and 10 with non-small cell lung cancer. Bronchoalveolar lavage fluid (BALF) was collected for 16S rRNA sequencing. Lymphocyte percentages were determined using flow cytometry. The interactions between microbiota, metabolites, and lymphocytes were studied using cultured mouse splenocytes. <bold>Results:</bold> We characterized the microbial landscape in BALF of CIP patients, identifying 19 phyla and 276 genera. Proteobacteria was the most dominant phylum, particularly abundant in both CIP and IPF groups. Vibrio, Halomonas, Mangrovibacter, and Salinivibrio were marked as determinant genera due to their discriminative abundance patterns and significant correlations with lymphocytes, particularly Vibrio with lymphocytes (r=0.72, P=0.037). Specifically, Vibrio metschnikovii and Mangrovibacter plantisponsor displayed markedly higher abundances in the CIP group. Lauroylcarnitine was a key intermediary metabolite influenced by determinant genera, possessing potent activation effect on mouse T-cell cytokine secretion, notably IFN-γ and TNF-α from CD4 and CD8 cells in vitro assays. <bold>Conclusions:</bold> The study identified key microbes in CIP linked to immunity and metabolic alterations, highlighting lauroylcarnitine's role in pro-inflammation. This suggests targeting acylcarnitine metabolism dysregulation may offer a therapeutic approach for CIP.