Non-responsive Celiac disease symptoms associated with microbiome network structure and function

Non-responsive celiac disease (NRCD) poses a challenge for clinicians due to the persistence of symptoms despite maintaining a gluten-free diet (GFD). This study investigated the gut microbiome, mucosal integrity, and metabolomic profiles of 39 NRCD patients to gain insights into the underlying mechanisms contributing to symptom persistence. Two distinct clusters of patients were identified based on clinical and demographic variables not influenced by gluten consumption. Cluster 1, labelled “Low-grade symptoms,” displayed milder symptoms and lower inflammatory markers. In contrast, Cluster 2, named “High-grade symptoms,” exhibited more severe gastrointestinal and extraintestinal symptoms, along with elevated inflammatory markers and increased intestinal permeability. Despite similar mucosal damage in both clusters, network analysis of the gut microbiome revealed specific microbial taxa with potential functional implications. Cluster 1 displayed a microbiome associated with immune homeostasis and gut barrier integrity, potentially lowering inflammation and symptom severity. In contrast, Cluster 2 had a distinct microbiome linked to lactate production, Th17 activation, possibly contributing to heightened inflammation and gastrointestinal symptoms. Metabolomic analysis revealed differential metabolites between clusters, particularly in amino acid metabolism pathways. Metabolites associated with specific symptoms were identified, implicating their potential role in symptom manifestation. Notably, vitamin D deficiency was observed in both clusters, suggesting its relevance in the context of NRCD. The study highlights the importance of the gut microbiome, mucosal integrity, and metabolic pathways in symptom persistence among NRCD patients. The associations between microbial-derived metabolites and symptom severity provide valuable insights into potential therapeutic targets. Further research is needed to validate these findings and develop targeted interventions for improving clinical outcomes in NRCD patients. ### Competing Interest Statement The authors have declared no competing interest.