Dialister-driven succinate accumulation is associated with disease activity and postoperative recurrence in Crohn's disease

Identifier:  imarina:9470302

Handle: https://hdl.handle.net/20.500.11797/imarina9470302

Authors:  Boronat-Toscano A; Queipo-Ortuño MI; Monfort-Ferré D; Suau R; Vañó-Segarra I; Valldosera G; Cepero C; Astiarraga B; Clua-Ferré L; Plaza-Andrade I; Aranega-Martín L; Cabrinety L; de Barbarà CA; Castellano-Castillo D; Moliné A; Caro A; Domènech E; Sánchez-Herrero JF; Benaiges-Fernandez R; Fernández-Veledo S; Vendrell J; Ginés I; Sumoy L; Manyé J; Menacho M; Serena C

Abstract:
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.