RT Journal Article
T1 Microbiome gut community structure and functionality are associated with symptom severity in non-responsive celiac disease patients undergoing a gluten-free diet
A1 Loria Kohen, Viviana Constanza
A1 Marcos-Zambrano, Laura Judith
A1 Lacruz-Pleguezuelos, Blanca
A1 Aguilar-Aguilar, Elena
A1 Marcos-Pasero, Helena
A1 Valdés, Alberto
A1 Cifuentes, Alejandro
A1 Ramírez de Molina, Ana
A1 Díaz-Ruiz, Alberto
A1 Pancaldi, Vera
A1 Carrillo de Santa Pau, Enrique
AB Non-responsive celiac disease (NRCD) challenges clinicians due to persistent symptoms despite a gluten-free diet (GFD). We present a cross-sectional pilot study including 39 NRCD patients to describe the underlying mechanisms contributing to symptom persistence by integrating different levels of data (fecal shotgun metagenomics, mucosal integrity markers, and metabolomic profiles) and using microbial networks to unravel the community structure of the patient's microbiome. Two distinct clusters of patients were identified based on clinical and demographic variables not influenced by gluten consumption. Cluster 1, labeled "Low-grade symptoms," displayed milder symptoms and lower inflammatory markers and a fragmented microbial network characterized by high modularity and a reliance on localized hubs, suggesting a microbial community under stress but capable of maintaining limited functionality. Cluster 2, named "High-grade symptoms," exhibited more severe symptoms, elevated inflammatory markers, and a more connected but antagonistic microbial network with a greater number of keystone taxa, including taxa associated with Th17 activation and inflammation. In contrast, the control network, representing asymptomatic treated celiac disease (tCD) patients, was highly interconnected, resilient, and cooperative, with a robust structure maintained even under simulated disruptions. Metabolomic analysis revealed differential metabolites between clusters, particularly those involved in amino acid metabolism pathways and microbial-derived metabolites such as indolelactic acid and mannitol, which were associated with symptom severity. This study identifies NRCD subgroups based on the gut microbiome and metabolic signatures associated with clinical manifestations, highlighting variations in microbial network stability and metabolite profiles as contributors to symptom persistence and potential therapeutic targets.Importance: Celiac disease (CD) is a chronic immune-mediated systemic disorder caused by consuming gluten in genetically susceptible individuals. There is currently no cure for CD, and the most effective treatment is maintaining a strict, lifelong gluten-free diet (GFD). This nutritional therapy aims to prevent the immune reaction triggered by gluten and promote the healing of the intestinal lining, resolving the clinical, serological, and histological abnormalities within 6-12 months. However, up to 30% of patients may continue to experience symptoms or exhibit laboratory abnormalities or intestinal inflammation suggestive of active CD, despite following a GFD. This challenge, which encompasses various diagnoses, is known as nonresponsive celiac disease (NRCD). In this study, we explored the role of intestinal microbiota in causing NRCD, finding an association between the persistence of symptoms and changes in mucosal integrity biomarkers, with different gut microbiome structures among NRCD patients, indicating a significant role of the microbiome in NRCD.
PB American Society for Microbiology
YR 2025
FD 2025
LK https://hdl.handle.net/20.500.14352/121189
UL https://hdl.handle.net/20.500.14352/121189
LA eng
NO Marcos-Zambrano, L. J., Lacruz-Pleguezuelos, B., Aguilar-Aguilar, E., Marcos-Pasero, H., Valdés, A., Loria-Kohen, V., Cifuentes, A., Ramirez de Molina, A., Diaz-Ruiz, A., Pancaldi, V., & Carrillo de Santa Pau, E. (2025). Microbiome gut community structure and functionality are associated with symptom severity in non-responsive celiac disease patients undergoing a gluten-free diet. mSystems, e0014325. Advance online publication. https://doi.org/10.1128/msystems.00143-25
NO This study has been funded by CD3DTech-CM (TEC-2024/BIO-167), a Research Grant 2020 of the European Society of Clinical Microbiology, Infectious Diseases (ESCMID) to L.J.M.-Z; Project PID2023-150146OA-I00 founded by MICIU/AEI /10.13039/501100011033 and FEDER, UE; Institute of Health Carlos III (project IMPaCT-Data, exp. IMP/00019), co-funded by the European Union, European Regional Development Fund (‘A way to make Europe’); AI4FOOD-CM (Y2020/TCS-6654), RED2022-134934-T funded by MICIU/AEI/10.13039/501100011033. B.L.P is funded by Formación del ProfesoradoUniversitario grant (FPU22/04053) from the Spanish State Ministerio de Universidades.
NO European Society of Clinical Microbiology, Infectious Diseases (ESCMID)
NO Agencia Estatal de Investigación (España)
NO European Commission
NO Instituto de Salud Carlos III
NO Comunidad de Madrid
NO Ministerio de Universidades (España)
DS Docta Complutense
RD 17 dic 2025