L-kynurenine reshapes immune microenvironment to alleviate methamphetamine-induced chronic lung injury through gut-lung axis

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Long-term abuse of methamphetamine (MA) is strongly associated with severe lung injury. Microbiome metabolites are one way to understand the interactions between microbes and disease. Although gut microbes and their metabolites play a crucial role in the gut–lung axis, the microbial mechanism by which MA induces lung injury is unclear. The purpose of this work was to identify the omics characteristic factor associated with MA abuse and explore its immune regulatory mechanism by 16 s rDNA sequencing, LC–MS/MS non-targeted metabolomics analysis, hemodynamics, flow cytometry, and some methods of cellular and molecular biology and morphology. Based on the joint analysis of the gut microbiome and metabolomics, it was found that MA abuse disrupted the structure of the gut microbiome and drove the reprogramming of metabolites, leading to a reduction in Lactobacillus rhamnosus and its metabolite L-kynurenine (L-KYN). Activated Lactobacillus increased L-KYN level in MA-administrated mice. L-KYN, as a product of Lactobacillus, is a key omics signature factor for MA abuse, which has been further confirmed in vivo. L-KYN induced Treg cells differentiated from CD4 + T cells and reshaped the immune microenvironment. L-KYN induced the secretion of IL-10 by Treg cells, mediated the communication between Treg cells and alveolar epithelial cells (AEC) through IL-10, and alleviated MA-induced lung inflammation and alveolar barrier damage through the IL-10/JAK1/STAT3 pathway. From the perspective of intestinal microbiome–metabolite–immune network regulation, the omics characteristic factor L-KYN reshaped the immune microenvironment and alleviated methamphetamine-induced chronic lung injury through the gut–lung axis, providing a new theoretical and experimental basis for the prevention and treatment of MA-induced chronic lung injury. Video Abstract

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