Abstract Background Alpha-1 Antitrypsin (AAT) is a major serine protease inhibitor produced mainly by hepatocytes that protects tissues from proteolytic damage. The Z variant of the SERPINA1 gene causes Alpha-1 Antitrypsin Deficiency (AATD), characterized by reduced circulating AAT and hepatic accumulation of misfolded ATZ polymers resulting in increased risk of pulmonary and hepatic diseases. While AATD is primarily associated with liver and lung manifestations, emerging evidence suggests a possible association with inflammatory bowel diseases (IBDs). However, the mechanisms underlying intestinal susceptibility remain poorly defined. Methods We employed PiZ transgenic mice, mouse model used to study the liver disease associated with AATD, which express the polymer-forming ATZ variant of human AAT, to investigate intestinal homeostasis and susceptibility to dextran sodium sulfate (DSS)- induced colitis. We assessed intestinal morphology, Paneth cell function, accumulation of the polymeric ATZ, endoplasmic reticulum (ER) stress responses, autophagy and lysosomal pathways, microbiota composition, and liver injury. Complementary validation was performed in human iPSC-derived intestinal organoids and human intestinal epithelial cells expressing ATZ. Ileal biopsies from AATD patients with Crohn’s disease were also examined for ATZ polymer accumulation. Results PiZ mice exhibited increased susceptibility to DSS-induced colitis, associated with Paneth cell dysfunction, intracellular ATZ polymeric accumulation, and activation of the ER stress response. This resulted in impaired lysosomal clearance and enhanced secretory autophagy, leading to excessive lysozyme release and intestinal dysbiosis. These alterations correlated with aggravated mucosal inflammation and concurrent liver injury. Pharmacologic inhibition of ER stress restored crypt homeostasis and normalized lysozyme secretion. These findings were validated in human iPSC-derived intestinal organoids and epithelial cell models, as well as in ileal biopsies from AATD patients. Conclusion AATD predisposes to intestinal inflammation through ER stress–driven Paneth cell dysfunction and dysregulated secretory autophagy, resulting in excessive lysozyme secretion and microbiota imbalance. These findings uncover a previously unrecognized gut–liver axis mechanism in AATD and identify ER stress modulation as a potential therapeutic approach for AATD associated intestinal disease. References: 1.Silverman, E. K. & Sandhaus, R. A. Clinical practice. Alpha1-antitrypsin deficiency. The New England journal of medicine, 2009, 360, 2749-2757. doi.org/10.1056/NEJMcp0900449 2.Elzouki, A. N., Eriksson, S., Löfberg, R. The prevalence and clinical significance of alpha 1-antitrypsin deficiency (PiZ) and ANCA specificities (proteinase 3, BPI) in patients with ulcerative colitis. Inflammatory bowel diseases, 1999, 5, 246-252. doi.org/10.1097/00054725-199911000-0000210 3.Piitulainen, E. & Tanash, H. A. The Clinical Profile of Subjects Included in the Swedish National Register on Individuals with Severe Alpha 1-Antitrypsin deficiency. COPD 12 Suppl 1, 36-41 (2015). https://doi.org/10.3109/15412555.2015.102190912 4.Stone, H., Pye, A. & Stockley, R. A. Disease associations in alpha-1-antitrypsin deficiency. Respir Med, 2014, 108, 338-343. doi.org/10.1016/j.rmed.2013.10.006 Conflict of interest: Dr. Annunziata, Francesco: No conflict of interest Dos Santos Matos, Felipe: No conflict of interest Relvini, Irene: No conflict of interest Lu, Jing: No conflict of interest Schiano, Valentina: No conflict of interest D’Agostino, Claudia: No conflict of interest Maffia, Veronica: No conflict of interest Maria Custode, Bruno: No conflict of interest Raiola, Gaetano: No conflict of interest De Cegli, Rossella: No conflict of interest Del Prete, Eugenio: No conflict of interest Polishchuk, Elena: No conflict of interest Ambrosio, Carmen: No conflict of interest Compare, Debora: No conflict of interest Nardone, Gerardo: No conflict of interest Neri, Francesco: No conflict of interest Pastore, Nunzia: No conflict of interest
Annunziata et al. (Thu,) studied this question.