World journal of gastroenterology · 2025
Dialister-driven succinate accumulation is associated with disease activity and postoperative recurrence in Crohn's disease.
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Boronat-Toscano Albert, Queipo-Ortuño Maria Isabel, Monfort-Ferré Diandra, Suau Roger, Vañó-Segarra Irene, Valldosera Gemma, Cepero Claudia, Astiarraga Brenno, Clua-Ferré Laura, Plaza-Andrade Isaac, Aranega-Martín Lucía, Cabrinety Lidia, Abadia de Barbarà Carme, Castellano-Castillo Daniel, Moliné Alicia, Caro Aleidis, Domènech Eugeni, Sánchez-Herrero Jose Francisco, Benaiges-Fernandez Robert, Fernández-Veledo Sonia, Vendrell Joan, Ginés Iris, Sumoy Lauro, Manyé Josep, Menacho Margarita, Serena Carolina
Аннотация
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.
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.