C15-10 The Pyy-selenbp1 Axis Attenuates Pulmonary Fibrosis via Gut-lung Crosstalk and Macrophage Metabolic Reprogramming

Rationale

Gut-lung crosstalk contributes to pulmonary fibrosis, but its molecular mediators remain poorly understood. Selenium-binding protein 1 (SELENBP1), highly expressed in colonic epithelium and pulmonary macrophages, regulates epithelial repair and immune homeostasis. We hypothesized that the gut hormone peptide YY (PYY) modulates this axis to influence fibrosis progression.

Methods

C57BL/6J mice and intestinal epithelial-specific Selenbp1 knockout mice were subjected to bleomycin-induced pulmonary fibrosis. Radiation-induced colitis models and human inflammatory bowel disease (IBD) patient-derived colonoids were used to assess epithelial injury and repair. Exogenous PYY was administered intraperitoneally or via mucosal delivery. Analyses included qPCR, Western blot, immunofluorescence, flow cytometry, and functional assays. Macrophage-fibroblast co-culture was used to evaluate fibroblast activation (alpha-smooth muscle actin) and collagen production.

Results

Bleomycin-induced pulmonary fibrosis was associated with reduced colonic SELENBP1 expression and intestinal inflammation. Intestinal epithelia-specific Selenbp1 deletion exacerbated lung injury, linked to increased pro-inflammatory polarization of peripheral macrophages and enhanced fibroblast-to-myofibroblast transition. Mechanistically, PYY directly bound the SELENBP1 promoter, driving its transcription in intestinal epithelial cells and macrophages. Consequently, exogenous PYY restored colonic SELENBP1, ameliorated intestinal inflammation, and significantly attenuated pulmonary fibrosis in the 21-day bleomycin model, as evidenced by lowered Ashcroft scores and decreased collagen deposition. In vitro, SELENBP1 knockdown in macrophages promoted a pro-inflammatory phenotype, whereas PYY enhanced oxidative phosphorylation and suppressed inflammatory responses. Critically, in human IBD-derived colonoids, SELENBP1 expression inversely correlated with disease severity, was upregulated by PYY, and served as a key indicator of epithelial reparative capacity, functionally linking gut mucosal homeostasis to distal attenuation of lung fibrosis.

Conclusions

We identify PYY as a direct transcriptional activator of SELENBP1 and define the PYY-SELENBP1 axis as a central regulator of gut-lung crosstalk. By restoring SELENBP1 expression, PYY mitigates intestinal inflammation and reprograms macrophage metabolism to suppress pro-fibrotic signaling, thereby alleviating pulmonary fibrosis. This axis represents a novel, therapeutically actionable pathway for treating fibrotic lung diseases.

This abstract is funded by: Nanjing Municipal Health Commission Research Fund (Grant No. CGB25035)