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

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OBJECTIVE: To investigate whether human umbilical cord mesenchymal stem cell-derived exosomes (hUC-MSC-Exos) attenuate radiation-induced pulmonary fibrosis (RIPF) through modulation of the gut-lung axis. METHODS: The therapeutic efficacy of hUC-MSC-Exos was evaluated in a mouse model of RIPF through histopathology and western blot analysis of fibrosis markers (α-SMA, Vimentin, and E-cadherin). Gut barrier integrity (ZO-1, Occludin) and intestinal inflammation (IL-6, IL-1β) were examined using immunohistochemistry, RT-qPCR, and ELISA. Gut microbial composition and metabolic profiles were characterized via metagenomics and untargeted metabolomics, followed by integrated bioinformatics analyses to identify key pathways and metabolites. RESULTS: hUC-MSC-Exos significantly reduced pulmonary collagen deposition and restored fibrosis markers expression, concomitant with enhanced gut barrier function and attenuated intestinal inflammation. Multi-omics analysis revealed restoration of gut microbiota homeostasis and metabolic reprogramming, with the alanine, aspartate, and glutamate pathway being notably co-regulated. L-Glutamic acid was the most significantly altered metabolite and correlated significantly positively with the severity of pulmonary fibrosis and gut dysfunction. Gut microbiota associated with L-Glutamic acid (e.g., Duncaniella, Ruminococcus) were also significantly restructured. CONCLUSIONS: hUC-MSC-Exos attenuate RIPF through a comprehensive remodeling of the gut-lung axis, in which L-Glutamic acid and its associated microbiota serve as potential mediators. These findings highlight the gut-lung axis as a promising therapeutic target for RIPF.

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