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

Methamphetamine abuse disrupted gut microbiome structure and led to a reduction in Lactobacillus rhamnosus and its metabolite L-kynurenine.

• Joint analysis of gut microbiome and metabolomics was used to identify the relationship between MA abuse and microbial changes.
• 16S rDNA sequencing was employed to characterize gut microbiome structure in MA-administered mice.
• LC-MS/MS non-targeted metabolomics analysis was used to profile metabolite reprogramming driven by MA abuse.
• MA abuse drove reprogramming of metabolites alongside disruption of gut microbiome structure.

L-kynurenine (L-KYN) was identified as a key omics signature factor associated with methamphetamine abuse.

• L-KYN was identified as a product of Lactobacillus rhamnosus activity.
• The role of L-KYN as a key omics characteristic factor for MA abuse was confirmed in vivo.
• Activated Lactobacillus increased L-KYN levels in MA-administered mice.
• L-KYN was identified through joint analysis of gut microbiome and metabolomics data.

L-KYN induced differentiation of Treg cells from CD4+ T cells and reshaped the immune microenvironment.

• Flow cytometry was used to assess Treg cell differentiation.
• L-KYN treatment induced CD4+ T cells to differentiate into Treg cells.
• Treg cell induction by L-KYN contributed to reshaping of the immune microenvironment in the context of MA-induced lung injury.
• Methods of cellular and molecular biology were used to characterize this immune regulatory mechanism.

L-KYN induced IL-10 secretion by Treg cells and mediated communication between Treg cells and alveolar epithelial cells through IL-10.

• Treg cells stimulated by L-KYN secreted IL-10.
• IL-10 served as a mediator of communication between Treg cells and alveolar epithelial cells (AEC).
• This Treg-AEC communication was identified as a mechanism by which L-KYN alleviates lung inflammation and alveolar barrier damage.
• The signaling pathway involved was identified as IL-10/JAK1/STAT3.

L-KYN alleviated MA-induced lung inflammation and alveolar barrier damage through the IL-10/JAK1/STAT3 pathway.

• Hemodynamics, morphological methods, and molecular biology techniques were used to assess lung injury outcomes.
• MA abuse was associated with lung inflammation and alveolar barrier damage.
• L-KYN treatment reduced these pathological changes via the IL-10/JAK1/STAT3 signaling axis.
• The findings were demonstrated in vivo in MA-administered mice.

Long-term methamphetamine abuse is strongly associated with severe lung injury.

• This association motivated investigation into the microbial mechanisms underlying MA-induced lung injury.
• The study used a chronic MA administration model to examine lung injury.
• Morphological and hemodynamic assessments were used to characterize the extent of lung injury.
• The gut-lung axis was identified as a relevant mechanistic framework for understanding MA-induced pulmonary pathology.