A study led by Nunzia Pastore at TIGEM shows that the mutated protein responsible for the disease also alters intestinal cells, opening new avenues for identifying at-risk patients and understanding the variability of the disease.
Alpha-1 antitrypsin deficiency is a rare genetic disorder best known for its effects on the liver and lungs. Now, a team of researchers at the Telethon Institute of Genetics and Medicine (TIGEM) in Pozzuoli has discovered that the same mutation responsible for the disease can also profoundly alter intestinal function, increasing susceptibility to intestinal inflammation and contributing to the worsening of liver damage through the so-called “gut-liver axis.”
The findings of the study, led by Nunzia Pastore and published in Signal Transduction and Targeted Therapy, a Nature portfolio journal, provide the first biological explanation for clinical observations long reported in several epidemiological studies. These studies have shown that individuals with the most severe forms of alpha-1 antitrypsin deficiency are at a higher risk of developing chronic inflammatory bowel diseases than the general population.
A new organ involved in the Disease
Alpha-1 antitrypsin deficiency is caused by mutations in the SERPINA1 gene, which encodes a protein produced primarily by the liver and essential for protecting tissues from the damaging effects of inflammatory enzymes. In the most severe form of the disease, the mutated protein, known as Z alpha-1 antitrypsin (ATZ), tends to accumulate inside cells, causing damage particularly to the liver while reducing the amount of functional protein available throughout the body, with consequences for the lungs as well.
To date, however, it has remained unclear whether the mutation could also have direct effects on the intestine. To address this question, TIGEM researchers used mouse models of the disease, intestinal organoids derived from patients’ pluripotent stem cells, and human tissue samples. The study revealed that the mutated protein also accumulates in Paneth cells, specialized cells located in the intestinal crypts that play a critical role in maintaining microbiota homeostasis and supporting the mucosal immune response.
The accumulation of the mutant protein impairs the normal function of these cells and alters the secretion of lysozyme, an antimicrobial protein involved in maintaining intestinal homeostasis. In the models studied, these alterations were associated with changes in gut microbiota composition, increased susceptibility to intestinal inflammation, and exacerbation of liver pathology.
Validation in human models
Of particular significance, the findings obtained in experimental models were also confirmed in human systems. In intestinal organoids generated from patient-derived cells, researchers observed the same accumulation of the mutant protein together with molecular alterations consistent with those identified in animal models. Furthermore, protein aggregates were detected in an intestinal biopsy from a patient with alpha-1 antitrypsin deficiency and intestinal disease, providing the first evidence in humans supporting the mechanism identified by the research team.
The mechanism proposed by the authors shows that the intestine may play an active role in disease progression. “For years, a possible link between alpha-1 antitrypsin deficiency and inflammatory bowel diseases had been observed in clinical and epidemiological studies, but a biological explanation was lacking,” explains Nunzia Pastore, head of the TIGEM Laboratory of Mechanisms of Liver Diseases and coordinator of the study. “We discovered that the mutant protein accumulates not only in the liver but also in Paneth cells in the intestine, impairing their function. This finding helps us better understand aspects of the disease that have remained unclear until now.”
Potential diagnostic implications
Another important aspect of the discovery concerns its potential diagnostic implications. Alpha-1 antitrypsin deficiency is characterized by considerable clinical variability: some patients primarily develop lung disease, others predominantly experience liver complications, while still others present with much milder symptoms. The involvement of the intestine may help explain, at least in part, these differences.
«Our findings suggest that the intestine may represent an important modifier of disease severity», concludes Pastore. «Looking ahead, this could help identify subgroups of patients at higher risk of developing specific complications and support a more comprehensive and personalized diagnostic approach. In addition, our data suggest that screening for SERPINA1 gene alterations in patients with inflammatory bowel diseases may be beneficial, potentially helping to identify cases that currently remain undiagnosed».
A new perspective on the Gut-Liver axis
The discovery may also have important implications for chronic inflammatory bowel diseases. While further studies in larger patient cohorts are needed to validate these findings, the results suggest that SERPINA1 gene alterations may contribute to the development or progression of ulcerative colitis and Crohn’s disease in some patients, providing new insights into the biological mechanisms underlying these conditions.
Overall, the study broadens our understanding of the mechanisms underlying alpha-1 antitrypsin deficiency and identifies the intestine as a previously unrecognized organ involved in the disease. The findings pave the way for future research aimed at improving diagnosis, refining patient stratification, and shedding light on the factors that shape the disease’s clinical progression.
