Paneth Cell dysfunction links Alpha-1 Antitrypsin Deficiency to colitis susceptibility

ABSTRACT: Alpha-1 Antitrypsin (AAT) is a critical serine protease inhibitor that protects tissue by neutralizing neutrophil elastase and other proteases, particularly in the lungs. Mutations in the SERPINA1 gene lead to Alpha-1 Antitrypsin deficiency (AATD), characterized by low circulating AAT levels and increased risk of pulmonary emphysema, liver cirrhosis, and hepatocellular carcinoma. Beyond these well-characterized manifestations, AATD has been associated with several extrahepatic conditions, including panniculitis, rheumatoid arthritis, and glomerulonephritis. Emerging evidence has also hinted a link between AATD and inflammatory bowel disease (IBD), though experimental validation has been lacking. In this study, we demonstrate that AATD predisposes to intestinal inflammation using PiZ transgenic mice, which express the mutant, polymer-forming ATZ variant pf AAT. PiZ mice exhibited heightened susceptibility to dextran sodium sulfate (DSS)-induced colitis, driven by impaired Paneth cell function. Specifically, intracellular accumulation of polymeric ATZ in Paneth cells activated endoplasmic reticulum (ER) stress response, disrupted lysosomal clearance, enhanced secretory granule biogenesis, and led to excessive secretion of Lysozyme-1 (Lyz1). This cascade not only aggravated intestinal inflammation but also promoted hepatic injury and altered microbiota composition. Notably, pharmacologic inhibition of ER stress restored crypt homeostasis and normalized Lyz1 secretion. These findings were corroborated in human iPSC-derived intestinal organoids and biopsies from AATD patients. Our results unveil a previously underappreciated gut-liver axis dysfunction in AATD and identify ER stress as a potential therapeutic target for treating AATD-associated intestinal pathology.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Rossella De Cegli  

LAB HEAD: Nunzia Pastore

PROVIDER: PXD065749 | Pride | 2026-10-05

REPOSITORIES: Pride