Integrated Role of Microbial, Fungal, and Plant-Derived Interventions in the Management of Celiac Disease: A Narrative Review

Celiac disease (CeD) is a chronic autoimmune enteropathy triggered by gluten ingestion in genetically susceptible individuals carrying human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 haplotypes. While a strict gluten-free diet (GFD) remains the primary treatment, many patients experience persistent symptoms and incomplete mucosal recovery, often due to accidental exposure. This narrative review evaluates complementary biological strategies that enhance gluten management beyond dietary avoidance. We discuss enzymatic approaches using bacterial and fungal prolyl endopeptidases (PEPs) and engineered enzyme combinations, such as latiglutenase, to degrade immunogenic peptides in the gastrointestinal tract. Furthermore, we examine the restoration of intestinal barrier integrity through zonulin antagonists such as larazotide acetate. The role of gut microbiota modulation with probiotics, such as Lactobacillus and Bifidobacterium strains, is analyzed for its potential to reduce inflammation and support gliadin degradation. Additionally, plant-derived cysteine proteases from sprouting cereals are presented as promising agents for gluten detoxification. Finally, the application of enzymatic degradation in food processing is considered to improve the safety and affordability of gluten-free products. Together, these strategies offer a multidimensional framework for enhancing clinical outcomes and quality of life for individuals with CeD.