P0119 Elevated Circulating Succinate in Crohn's Disease Correlates with Gut Microbiota Alterations and Inflammatory Activity
Authors: Boronat-Toscano A , Menacho M , Monfort-Ferré D , Valldosera G , Clua-Ferré L , Plaza-Andrade I , Arángena-Martín L , Astiarraga B , Abadia C , Cabrinety L , Moliné A , Vañó I , Caro A , Castellano-Castillo D , Suau R , Fernández-Veledo S , Vendrell J , Manyé J , Queipo-Ortuño M , Serena C 
Published: January 2025

Abstract

Background
Circulating succinate, a metabolite produced by both the intestinal microbiota and the host, is elevated in several diseases characterized by chronic inflammation (1). In Crohn's disease (CD), an association has been observed between increased succinate levels in the intestinal lumen, disease activity, and dysbiosis (2,3). The objective is to evaluate circulating succinate levels as a biomarker of activity in patients with active and inactive CD and to relate these levels to fecal microbiota, as well as to demographic, clinical, and treatment variables.

Methods
This is a cross-sectional observational study with the prospective inclusion of patients with CD in remission, active CD, and healthy controls matched by age, sex, and body mass index (BMI). Remission criteria include: Harvey-Bradshaw index &lt;6, CRP &lt;0.4 mg/dL, fecal calprotectin (FC) &lt;250 μg/g, and endoscopic activity index SES-CD &lt;6. A fecal microbiota analysis was performed using 16S-RNA sequencing, and demographic, clinical, and treatment variables were recorded along with blood samples (CRP and succinate) and stool samples.

Results
Eighteen CD patients (10 active and 8 in remission) and 13 healthy controls were included. Circulating succinate levels were significantly higher in patients with active CD (148 µM) and inactive CD (115 µM) compared to controls (45 µM; p&lt;0.01). Significant differences were also observed between active and inactive patients (p=0.009). Furthermore, a positive correlation was found between circulating succinate levels and CRP (R²=0.57, p=0.01), the proinflammatory phylum Proteobacteria (R²=0.48, p&lt;0.001), its receptor SUCNR1 (R²=0.52, p=0.007), and the succinate-producing genus Prevotella (R²=0.55, p=0.01) (Fig1A). A highly significant increase in the abundance of Fusobacterium nucleatum, Escherichia coli, and Prevotella buccae species was also recorded in active patients (Fig1B). Microbial metabolite analysis revealed significant changes in 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylate synthase, the tricarboxylic acid cycle (TCA), and Na+-transporting NADH oxidoreductase, all linked to succinate metabolism.

Conclusion
CD patients exhibit elevated succinate levels, which are associated with alterations in the intestinal microbiota and disease activity, suggesting a link between succinate, microbiota metabolites, and CD pathogenesis.

References
1.Serena C et al. Elevated circulating levels of succinate in human obesity are linked to specific gut microbiota. ISME J 2018 Jun;12(7):1642-1657
2.Connors J et al. The Role of Succinate in the Regulation of Intestinal Inflammation. Nutrients 2019 Jan 11(1): 256.
3.Macias-Ceja DC et al. Succinate receptor mediates intestinal inflammation and fibrosis. Mucosal Immunol 2019. Jan;12(1):178-187.