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©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet
Juan Pablo Stefanolo, Verónica Segura, Martina Grizzuti, Abel Heredia, Isabel Comino, Ana Florencia Costa, Roberto Puebla, María Paz Temprano, Sonia Isabel Niveloni, Gabriel de Diego, María E Oregui, Edgardo Gustavo Smecuol, Mauricio C de Marzi, Elena F Verdú, Carolina Sousa, Julio César Bai
Juan Pablo Stefanolo, Roberto Puebla, María Paz Temprano, Sonia Isabel Niveloni, Edgardo Gustavo Smecuol, Small Bowel Section, Department of Medicine, Gastroenterology Hospital of Buenos Aires “Dr. C. Bonorino Udaondo”, Buenos Aires 1264, Argentina
Verónica Segura, Abel Heredia, Isabel Comino, Carolina Sousa, Department of Microbiology and Parasitology, Faculty of Pharmacy, University of Seville, Seville 41080, Spain
Martina Grizzuti, Ana Florencia Costa, María E Oregui, Julio César Bai, Department of Medicine, Dr. C. Bonorino Udaondo Gastroenterology Hospital, Buenos Aires 1264, Argentina
Gabriel de Diego, Mauricio C de Marzi, Basic and Applied Research Group in Immunology and Bioactives (GIBAIB), Institute of Ecology and Sustainable Development (INEDES), National University of Lujan, Luján 6700, Buenos Aires, Argentina
Elena F Verdú, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton L8S 4L8, Ontario, Canada
Julio César Bai, Facultad de Medicina, Universidad del Salvador, Buenos Aires C1051ABB, Argentina
Author contributions: Stefanolo JP contributed to the study’s design, collected the patients, performed statistical analysis of the data and critical review of the manuscript; Segura V, Heredia A, and Comino I performed the gluten immunogenic peptides stool tests; Grizutti M, Costa AF, and Oregui ME collected the patients and performed data acquisition; Temprano MP performed the dietary assessment; Puebla R, de Diego G, and de Marzi MC produced the biochemical determinations and performed the serology; Niveloni SI and Smecuol EG contributed to the data acquisition; Bai JC planned the study; Bai JC, Verdú EF, and Sousa C contributed to the study design, data analysis, and writing of the manuscript; All authors read and approved the final manuscript.
Supported by the Asociación de Celíacos y Sensibles al Gluten de Madrid, No. ACM2020); and Research Committee Argentine Society of Gastroenterology, No. 2020.
Institutional review board statement: The study was reviewed and approved by Dr. C. Bonorino Udaondo Gastroenterology Hospital’s institutional ethical committee (CEI) and the local research committee (CODEI).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Clinical trial registration statement: The study was registered at ClinicalTrials.gov. The registration identification number is NCT04788797.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: No additional data are available.
CONSORT 2010 statement: The authors have read the CONSORT 2010 statement, and the manuscript was prepared and revised according to the CONSORT 2010 statement.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Julio César Bai, MD, Emeritus Professor of Medicine, Facultad de Medicina, Universidad del Salvador, 640 Rodriguez Peña, Buenos Aires C1051ABB, Argentina.
jbai@intramed.net
Received: December 8, 2023
Peer-review started: December 8, 2023
First decision: December 21, 2023
Revised: December 31, 2023
Accepted: February 18, 2024
Article in press: February 18, 2024
Published online: March 21, 2024
Processing time: 104 Days and 10.1 Hours
BACKGROUND
The gluten-free diet (GFD) has limitations, and there is intense research in the development of adjuvant therapies.
AIM
To examine the effects of orally administered Aspergillus niger prolyl endopeptidase protease (AN-PEP) on inadvertent gluten exposure and symptom prevention in adult celiac disease (CeD) patients following their usual GFD.
METHODS
This was an exploratory, double-blind, randomized, placebo-controlled trial that enrolled CeD patients on a long-term GFD. After a 4-wk run-in period, patients were randomized to 4 wk of two AN-PEP capsules (GliadinX; AVI Research, LLC, United States) at each of three meals per day or placebo. Outcome endpoints were: (1) Average weekly stool gluten immunogenic peptides (GIP) between the run-in and end of treatments and between AN-PEP and placebo; (2) celiac symptom index (CSI); (3) CeD-specific serology; and (4) quality of life. Stool samples were collected for GIP testing by ELISA every Tuesday and Friday during run-ins and treatments.
RESULTS
Forty patients were randomized for the intention-to-treat analysis, and three were excluded from the per-protocol assessment. Overall, 628/640 (98.1%) stool samples were collected. GIP was undetectable (< 0.08 μg/g) in 65.6% of samples, and no differences between treatment arms were detected. Only 0.5% of samples had GIP concentrations sufficiently high (> 0.32 μg/g) to potentially cause mucosal damage. Median GIP concentration in the AN-PEP arm was 44.7% lower than in the run-in period. One-third of patients exhibiting GIP > 0.08 μg/g during run-in had lower or undetectable GIP after AN-PEP treatment. Compared with the run- in period, the proportion of symptomatic patients (CSI > 38) in the AN-PEP arm was significantly lower (P < 0.03). AN-PEP did not result in changes in specific serologies.
CONCLUSION
This exploratory study conducted in a real-life setting revealed high adherence to the GFD. The AN-PEP treatment did not significantly reduce the overall GIP stool concentration. However, given the observation of a significantly lower prevalence of patients with severe symptoms in the AN-PEP arm, further clinical research is warranted.
Core Tip: In treated celiac disease (CeD) patients, exposure to gluten due to both voluntary and involuntary dietary lapses is prevalent and often leads to persistent symptoms despite adherence to a gluten-free diet. The potential of oral administration of Aspergillus niger prolyl endopeptidase (AN-PEP) in preventing the effects of inadvertent gluten exposure, as confirmed by gluten immunogenic peptide (GIP) stool excretion, and reducing CeD-specific symptoms in adults remains uncertain. Our study findings indicate that while AN-PEP did not significantly reduce overall GIP stool excretion, it notably lowered the prevalence of severe symptoms compared to the placebo arm.
