Human umbilical cord MSC-derived exosomes attenuate radiation-induced pulmonary fibrosis via remodeling the gut-lung axis in mice.

hUC-MSC-Exos significantly reduced pulmonary collagen deposition and restored fibrosis marker expression in a mouse model of radiation-induced pulmonary fibrosis.

• Therapeutic efficacy was evaluated using histopathology and western blot analysis of fibrosis markers including α-SMA, Vimentin, and E-cadherin.
• The study used a mouse model of RIPF (radiation-induced pulmonary fibrosis).
• hUC-MSC-Exos were derived from human umbilical cord mesenchymal stem cells.
• Collagen deposition in lung tissue was significantly reduced following hUC-MSC-Exos treatment.

hUC-MSC-Exos enhanced gut barrier function and attenuated intestinal inflammation in irradiated mice.

• Gut barrier integrity was assessed by measuring tight junction proteins ZO-1 and Occludin using immunohistochemistry.
• Intestinal inflammation markers IL-6 and IL-1β were examined using RT-qPCR and ELISA.
• hUC-MSC-Exos treatment resulted in concomitant improvement in both gut barrier integrity and reduction in intestinal inflammatory markers.
• Methods included immunohistochemistry, RT-qPCR, and ELISA for gut assessments.

Multi-omics analysis revealed that hUC-MSC-Exos restored gut microbiota homeostasis and induced metabolic reprogramming, with the alanine, aspartate, and glutamate pathway being notably co-regulated.

• Gut microbial composition was characterized via metagenomics sequencing.
• Metabolic profiles were characterized via untargeted metabolomics.
• Integrated bioinformatics analyses were used to identify key pathways and metabolites.
• The alanine, aspartate, and glutamate metabolic pathway was identified as notably co-regulated between microbiome and metabolome data.

L-Glutamic acid was the most significantly altered metabolite and correlated significantly positively with the severity of pulmonary fibrosis and gut dysfunction.

• L-Glutamic acid was identified through untargeted metabolomics as the most significantly changed metabolite.
• A significant positive correlation was found between L-Glutamic acid levels and pulmonary fibrosis severity.
• A significant positive correlation was also found between L-Glutamic acid levels and gut dysfunction.
• L-Glutamic acid is a key metabolite in the alanine, aspartate, and glutamate pathway identified as co-regulated.

Specific gut microbiota associated with L-Glutamic acid, including Duncaniella and Ruminococcus, were significantly restructured following hUC-MSC-Exos treatment.

• Microbial composition was assessed using metagenomics analysis.
• Duncaniella and Ruminococcus were identified as L-Glutamic acid-associated microbiota that were significantly altered.
• Restructuring of these microbial taxa was associated with hUC-MSC-Exos treatment in the RIPF mouse model.
• These microbiota were identified through integrated bioinformatics analyses linking microbiome and metabolomics data.