# Microbial Peptides: Key Players in Reducing Gluten Immunogenicity Through Peptide Degradation
## 6 Conclusions  
The application of enzymatic treatment for the degradation of immunogenic gluten peptides has been extensively investigated as a strategy to mitigate the effects of gluten-related disorders rather than to prevent their initial development. Various microbial, fungal, and plant-derived peptidases have demonstrated efficacy in hydrolyzing proline and glutamine-rich peptides, such as gliadins and glutenins, that resist digestion in the human gastrointestinal tract. These enzymes have been incorporated into different industrial processes, including food production, brewing, and dietary supplements, aiming to reduce gluten immunogenicity before consumption and thereby alleviate symptoms in affected individuals. Despite significant advancements, major challenges remain. A critical obstacle to the pharmacological application of glutenases is their rapid inactivation and structural instability under the acidic conditions of the stomach. These enzymes are susceptible to degradation by endogenous digestive proteases such as pepsin, trypsin, and chymotrypsin, often preventing them from remaining active until reaching the small intestine, where gluten-derived peptides trigger T-cell-mediated inflammatory responses. Protective pharmaceutical strategies like PEGylation and microencapsulation have been explored to improve enzyme stability and bioavailability; however, clinical success has been limited due to issues including immune reactions, altered enzymatic activity, inconsistent drug release, and manufacturing challenges. In addition, new enzyme variants with improved gastric stability, such as TAK-062 (zamagluttenase) and latiglutenase (ALV003), have demonstrated promising clinical results, showing both mucosal protection and symptom reduction in seropositive patients. An emerging area of interest is the interaction between glutenases and the host microbiota. Specifically, oral and intestinal microorganisms such as _Rothia_ and _Actinomyces_ have been shown to contribute to gluten degradation during digestion, and recent studies suggest that microbial composition may influence the activity and expression of these enzymes. These findings open avenues for microbiota-targeted therapies that could enhance enzyme-based treatments. Future research should also focus on standardizing evaluation protocols to compare enzyme efficacy across food processing and clinical settings. The development of personalized therapeutic approaches integrating enzyme cocktails, delivery systems, and microbiome modulation represents a promising direction for advancing non-dietary interventions in gluten-related disorders. Potential outcomes of enzymatic interventions include enhanced safety of gluten-containing foods for individuals with gluten sensitivity, improved therapeutic management of CeD symptoms, and the development of novel enzyme formulations with optimized performance. Future research should focus on enzyme engineering, innovative drug delivery systems, combination therapies, and rigorous clinical validation to advance the reliability and effectiveness of enzymatic treatments aimed at alleviating the impact of gluten exposure in affected patients. **Author Contributions:** A.S., M.S.-M., N.N., H.M.-B., M.A.F., L.B.R.-A. and A.C.-A. ; writing--original draft preparation: A.S., M.S.-M., N.N., H.M.-B., M.A.F., L.B.R.-A. and A.C.-A. ; writing--review and editing: M.S.-M., A.S. and A.C.-A. ; supervision: A.S., L.B.R.-A. and A.C.-A. All authors have read and agreed to the published version of the manuscript. **Funding:** The APC was funded by the University of Leon. We acknowledge the received support from the Spanish Ministerio de Ciencia e Innovacion, grant number PID2020-119044 GB-I00, and the Junta de Castilla y Leon, grant number LE01 SP20. **Institutional Review Board Statement:** Not applicable. **Informed Consent Statement:** Not applicable. **Data Availability Statement:** No new data have been created for this review article. **Acknowledgments:** We thank [PERSON] for providing technical assistance.