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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Dialister-driven succinate accumulation is associated with disease activity and postoperative recurrence in Crohn’s disease
Albert Boronat-Toscano, Maria Isabel Queipo-Ortuño, Diandra Monfort-Ferré, Roger Suau, Irene Vañó-Segarra, Gemma Valldosera, Claudia Cepero, Brenno Astiarraga, Laura Clua-Ferré, Isaac Plaza-Andrade, Lucía Aranega-Martín, Lidia Cabrinety, Carme Abadia de Barbarà, Daniel Castellano-Castillo, Alicia Moliné, Aleidis Caro, Eugeni Domènech, Jose Francisco Sánchez-Herrero, Robert Benaiges-Fernandez, Sonia Fernández-Veledo, Joan Vendrell, Iris Ginés, Lauro Sumoy, Josep Manyé, Margarita Menacho, Carolina Serena
Albert Boronat-Toscano, Diandra Monfort-Ferré, Irene Vañó-Segarra, Gemma Valldosera, Claudia Cepero, Brenno Astiarraga, Laura Clua-Ferré, Lidia Cabrinety, Carme Abadia de Barbarà, Alicia Moliné, Aleidis Caro, Sonia Fernández-Veledo, Joan Vendrell, Iris Ginés, Margarita Menacho, Carolina Serena, Hospital Universitari Joan XXIII, Institut d’Investigació Sanitària Pere Virgili, Tarragona 43007, Catalonia, Spain
Maria Isabel Queipo-Ortuño, Isaac Plaza-Andrade, Lucía Aranega-Martín, Daniel Castellano-Castillo, Medical Oncology Clinical Management Unit, Virgen Victoria Hospital FIMABIS, Biomed Res Lab, Campus Teatinos S-N, Málaga 29010, Andalucia, Spain
Maria Isabel Queipo-Ortuño, Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga 29010, Spain
Roger Suau, Laura Clua-Ferré, Josep Manyé, Inflammatory Bowel Diseases Research Group, Institut de Recerca Germans Trias i Pujol, Badalona 08916, Catalonia, Spain
Eugeni Domènech, Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Badalona 08916, Spain
Eugeni Domènech, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
Eugeni Domènech, Josep Manyé, Carolina Serena, CIBER de Enfermedades hepaticas y digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid 08029, Spain
Jose Francisco Sánchez-Herrero, Robert Benaiges-Fernandez, Lauro Sumoy, Genòmica d’Alt Contingut i Bioinformàtica, Institut de Recerca Germans Trias i Pujol, Badalona 08916, Catalonia, Spain
Sonia Fernández-Veledo, Joan Vendrell, CIBER De Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto De Salud Carlos III, Madrid 08029, Spain
Iris Ginés, Carolina Serena, Departament of Biochemistry and Biotecnology, Universitat Rovira i Virgili, Tarragona 43007, Catalonia, Spain
Co-first authors: Albert Boronat-Toscano and Maria Isabel Queipo-Ortuño.
Author contributions: Boronat-Toscano A, Monfort-Ferré D, Suau R, Vañó-Segarra I, Clua-Ferré L, Astiarraga B, and Ginés I conducted the experiments; Valldosera G, Cepero C, Cabrinety L, Abadia de Barbarà C, Moliné A, Domènech E, Caro A, and Menacho M contributed to the selection of the study population and the processing of human samples; Queipo-Ortuño MI, Suau R, Plaza-Andrade I, Aranega-Martín L, Castellano-Castillo D, Benaiges-Fernandez R, Sánchez-Herrero JF, and Sumoy L performed microbiota experiments and data analysis; Queipo-Ortuño MI, Vañó-Segarra I, Benaiges-Fernandez R, Sánchez-Herrero JF, Sumoy L, and Serena C carried out the statistical analyses; Boronat-Toscano A, Monfort-Ferré D, Fernández-Veledo S, Vendrell J, Menacho M, and Serena C conceptualized the study, interpreted the data; Boronat-Toscano A and Serena C drafted the manuscript; Queipo-Ortuño MI, Sumoy L, Manyé J, and Serena C reviewed the manuscript; Serena C serves as the guarantor of this work.
Supported by the grant from I Clinical GETECCU_Galapagos (to Menacho M and Serena C); the grant from the Ministerio de Ciencia, Innovación y Universidades, PID2023-146315OB-I00 (to Manyé J and Serena C); the grant by the Instituto Salud Carlos III, PI20/00420 (to Manyé J) and PI22/01498 (to Domènech E and Sumoy L), co-funded by the European Union; and the grant, PI-AGAUR 2022-B00577 (to Boronat-Toscano A).
Institutional review board statement: This study was approved by the Ethics Committee of the Hospital Universitari Joan XXIII (Approval No. PI21/00011).
Conflict-of-interest statement: Fernández-Veledo S, Vendrell J, and Serena C are co-inventors of a patent (WO2019141780A1) licensed to SUCCIPRO S.L. In addition, Fernández-Veledo S and Vendrell J are co-founders of this company. The authors declare that these relationships have neither influenced nor biased the design, execution, or interpretation of the present work. All authors further declare that they have no other financial or personal relationships that could be perceived as potential conflicts of interest.
Data sharing statement: The 16S rRNA gene sequencing data generated in this study have been deposited in the NCBI Sequence Read Archive. Data from the HJ23 cohort are available under BioProject accession number PRJNA1250964 (
http://www.ncbi.nlm.nih.gov/bioproject/1250964) and PRJNA1241201 (
http://www.ncbi.nlm.nih.gov/bioproject/1241201) for the validation cohort at IGTP. These datasets will be made publicly available upon publication. Functional profiling results presented in the manuscript were obtained through computational analysis (PICRUSt2) of the HJ23 cohort 16S rRNA data and are therefore fully reproducible using the deposited sequences. Quantitative PCR data from PBMCs and circulating succinate levels from the HJ23 cohort are provided in
Supplementary Table 3.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Carolina Serena, PhD, Head, Principal Investigator, Hospital Universitari Joan XXIII, Institut d’Investigació Sanitària Pere Virgili, C/Escorxador s/n, Tarragona 43007, Catalonia, Spain.
carolina.serena@iispv.cat
Received: August 1, 2025
Revised: August 29, 2025
Accepted: October 17, 2025
Published online: December 7, 2025
Processing time: 124 Days and 20.8 Hours
BACKGROUND
Succinate, a metabolite produced by both the gut microbiota and the host, has emerged as a key player in chronic inflammation. In patients with Crohn’s disease (CD), increased succinate in the intestinal lumen correlates with both dysbiosis and greater disease activity.
AIM
To investigate circulating succinate as a biomarker of CD activity and its associations with gut microbiota, immune, and clinical features.
METHODS
This study with the prospective inclusion of patients with CD in remission, active CD, and non-inflammatory bowel disease controls matched by age, sex, and body mass index. Remission was defined as Harvey-Bradshaw index < 6, C-reactive protein < 0.4 mg/dL, fecal calprotectin < 250 μg/g, and endoscopic activity index Simple Endoscopic Score for CD < 6. Faecal microbiota profiling was performed using 16S rRNA gene sequencing, and demographic, clinical, and treatment variables were recorded along with blood samples (C-reactive protein and succinate) and stool samples.
RESULTS
Succinate levels were significantly elevated in active CD patients compared to inactive patients and non-inflammatory bowel disease controls. These increases were associated with higher Harvey-Bradshaw Index scores, increased expression of the succinate receptor 1 in immune cells, and enrichment of the succinate-producing genus Prevotella and the pro-inflammatory phylum Proteobacteria. Conversely, succinate levels negatively correlated with Odoribacter, a known succinate consumer. Interestingly, Dialister, a slow succinate consumer, was enriched in both active and inactive CD patients and was associated with impaired circulating succinate clearance and increased disease activity as well as postoperative recurrence in a validation cohort. Functional microbial analyses revealed upregulation of fumarate reductase and succinate transporters, alongside reduced NADH dehydrogenase expression, indicating disrupted succinate metabolism.
CONCLUSION
These findings highlight succinate as a promising biomarker for CD activity and progression, suggesting that targeting succinate metabolism or key microbial taxa may offer novel therapeutic opportunities.
Core Tip: The study reported that circulating succinate, a microbial and host metabolite, are markedly elevated in patients with Crohn’s disease. Interestingly, we found that succinate strongly correlates with inflammatory activity and is linked to changes in the gut microbiota, including an increased abundance of the slow succinate consumer genera Dialister. Importantly, the presence of the Dialister in intestinal tissue was also associated with post-operative recurrence in these patients. These findings highlight succinate as a promising biomarker for disease activity and progression in Crohn’s disease and suggest that targeting succinate metabolism or modulating specific microbial taxa could open new therapeutic opportunities.
