# Microbial Peptides: Key Players in Reducing Gluten Immunogenicity Through Peptide Degradation
## 3 Treatment for Gluten Elimination: Pros and Cons  
Gluten-related disorders, particularly celiac disease (CeD) and non-celiac gluten sensitivity (NCGS), represent a significant clinical challenge due to the persistent exposure to gluten peptides that provoke immune activation in susceptible individuals [42; 43]. Al  
Figure 1: Gluten intake and peptide processing after partial digestion in the stomach. The peptides derived from gliadins and glutenins are rich in proline and glutamine residues, making them highly resistant to gastrointestinal enzymatic digestion. When they cross the gut epithelium, increasing the membrane permeability, they are recognized by tissular TG2, leading to the formation of deamidated gluten peptides that interact with APC carrying HLA-DQ2/DQ8 receptors, triggering a cascade of gluten-specific immune response characterized by a release of certain cytokines, with the overexpression of IL-15 in epithelium and lamina propria responsible of chronic inflammation and even epithelial damage [40]. IEC means intestinal epithelial cells and IEL, intraepithelial lymphocytes. Figure prepared in Biorender.com. though the cornerstone of treatment remains a strict gluten-free diet (GFD), adherence is challenging due to the ubiquity of gluten in many food products and the risk of crosscontamination [44]. Therefore, alternative and complementary treatment approaches aimed at reducing gluten immunogenicity have been actively researched, including enzymatic therapies, fermentation strategies, and digestive supplements. Enzymatic degradation of gluten peptides, as discussed, offers a promising adjunct to dietary management. These enzymes are designed to cleave resistant proline-rich sequences that human digestive enzymes cannot process [45]. However, despite encouraging in vitro and early clinical results, enzymatic treatments have limitations that must be carefully considered [46]. One major challenge lies in ensuring sufficient enzyme activity throughout the gastrointestinal tract, which presents a highly variable environment. The acidic pH of the stomach, presence of endogenous proteases, and changing pH gradients in the small intestine can reduce enzyme stability and effectiveness [47; 41]. Formulation strategies such as microencapsulation or use of enzyme cocktails combining different peptidases are under investigation to overcome these barriers and enhance therapeutic efficacy [47]. Clinically, enzymatic therapies have shown variable success. While they may reduce the immunogenic gluten load and mitigate symptoms caused by accidental gluten exposure, they have not been demonstrated to fully prevent mucosal damage in patients with active celiac disease [21; 48]. This is particularly relevant for individuals with severe intestinal lesions or refractory celiac disease, where enzyme supplementation alone is insufficient. Furthermore, enzymatic treatments are generally unable to reverse existing tissue damage, emphasizing their role as supportive rather than curative [49]. The development and commercialization of enzymatic supplements such as taglithe-nase and Tolerance G have expanded treatment options for patients. However, the high costs associated with production, quality control, and regulatory compliance can limit their accessibility, particularly in resource limited settings [50; 51]. Regulatory frameworks for enzyme-based therapeutics also vary globally, complicating widespread adoption and standardization [52]. These challenges highlight the importance of continued investment in research, manufacturing innovation, and policy harmonization. In addition to enzymatic approaches, advancements in fermentation processes offer promising routes to reduce gluten content in food products. Sourdough fermentation using specific lactic acid bacteria strains has been shown to partially hydrolyze gluten proteins, improving digestibility and reducing immunogenicity [9; 45; 53].