# Microbial Peptides: Key Players in Reducing Gluten Immunogenicity Through Peptide Degradation
## 5 Future Perspectives on the Application of Enzymes for Celiac Disease Treatment
Using the same enzyme cocktail, other researchers have also evaluated the expression of gluten-specific antibodies and T cells [91; 92]. However, a larger multicenter phase 2b study in patients strictly adhering to a gluten-free diet failed to show significant histological improvement over placebo, likely due to enhanced dietary compliance under clinical supervision [93]. Nonetheless, recent trials involving controlled gluten challenges confirmed that Latiglutenase (IMGX003) reduced both mucosal injury and symptom severity in seropositive patients, reinforcing its potential as a personalized adjuvant therapy [94]. ALV003, administered daily for up to 42 days to seronegative patients undergoing a daily oral gluten challenge while on a strict gluten-free diet, was well tolerated. Discontinuations were mainly due to moderate to severe nausea, vomiting, and abdominal pain, largely attributed to gluten exposure. The study reported no serious adverse events and no clinically significant changes in vital signs, safety laboratory tests, or electrocardiogram results. An additional promising development is TAK-062 (zamaglutenase), a recombinant enzyme engineered for high activity and stability in gastric conditions. In a recent phase 1 clinical study, TAK-062 exhibited robust gluten-degrading capacity, high oral bioavailability, and favorable safety and tolerability profiles, suggesting strong therapeutic potential for future clinical application [95]. In clinical evaluations, TAK-062 demonstrated a favorable safety profile. The highest dose administered (900 mg, liquid formulation) was well tolerated, with no treatment emergent adverse events exceeding Grade 1 severity. Critically, no adverse events were attributed to the study drug, nor were any serious adverse events or fatalities observed throughout the trial. Furthermore, routine safety assessments, including clinical laboratory parameters, vital signs, physical examinations, electrocardiograms, and antidrug antibody levels, revealed no clinically significant trends. Moreover, enzyme combinations involving _Aspergillus niger_, derived aspergill in (ASP), _Aspergillus oryzae_, and derived dipeptidyl peptidase IV (DPP-IV) have shown limited but notable synergistic effects in degrading immunogenic peptides in vitro [96]. Although such combinations have not yet demonstrated consistent in vivo efficacy, they continue to serve as valuable models for evaluating enzymatic synergy and formulation. These strategies are summarized in Figure 3, which illustrates the current and emerging biotechnological approaches aimed at enhancing the stability, specificity, and delivery of glutenases for therapeutic and industrial use. Recent evidence has highlighted the potential role of the human microbiota in modulating the activity of glutenase. Specifically, microbial communities in the oral cavity, such as _Rothia_ and _Actinomyces_ spp., have been shown to produce subtilisin-like proteases capable of initiating gluten degradation during mastication [62; 74]. Moreover, metaproteomic and microbiome analyses suggest that the composition and metabolic activity of the oral and intestinal microbiota may influence both the expression and efficiency of microbial glutenases [74; 75]. These findings point to a dynamic interplay between microbial populations and enzymatic function, potentially opening new avenues for probiotic or microbiota-targeted therapeutic strategies. Figure 3: Peptides from microorganisms or plants (individually or in combination) might show significant capacity for gluten degradation. They can be used in the food industry, brewing, or as dietary supplements. New biotechnological strategies consist in modifications of enzymes to improve their resistance to gastric conditions, degrading gluten before remaining peptides reach the gut epithelium. Microencapsulation of peptidases is another effective strategy to protect them from degradation, enabling their intact delivery to the intestine.