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Name of Journal: World Journal of Gastroenterology Manuscript Type: LETTER TO THE EDITOR Dialister-Associated Succinate Dysregulation in Crohn’s Disease: Clinical and Therapeutic Implications 1Fotios S. Fousekis, 1Konstantinos H. Katsanos, 2Konstantinos Vlachos, 2Georgios D. Lianos 1Department of Gastroenterology, University Hospital of Ioannina, University of Ioannina Ioannina, Greece 2Department of Surgery, University Hospital of Ioannina, University of Ioannina, Greece Corresponding author: Fotios S. Fousekis, MD, PhD, Department of Gastroenterology, University Hospital of Ioannina, University of Ioannina Ioannina, Greece, email: fotisfous@gmail.com Abstract Growing evidence suggests that altered gut microbiota–derived succinate metabolism plays an important role in Crohn’s disease activity and postoperative recurrence. Particular emphasis is placed on Dialister, a gut bacterial genus that consumes succinate inefficiently, potentially leading to its accumulation and increased intestinal inflammation. Elevated succinate may impair immune regulation and enhance inflammatory signaling through SUCNR1 activation and hypoxia-inducible factor-1α stabilization. Recent findings identifying specific Dialister strains associated with postoperative recurrence provide new insight into disease monitoring and risk stratification. Although the study offers an integrative view linking microbial composition, metabolism, and inflammation, further validation using direct metabolomic and shotgun metagenomic approaches is needed. Overall, succinate appears to be a promising biomarker and therapeutic target, supporting future microbiota- and metabolism-based strategies for the management of inflammatory bowel disease. Key words: Crohn’s disease; Inflammatory bowel disease; Gut microbiota; Succinate; Dialister; Postoperative recurrence Core tip Accumulation of the microbial metabolite succinate is increasingly recognized as a key driver of inflammation in Crohn’s disease. Recent evidence links Dialister enrichment to impaired succinate clearance, disease activity, and postoperative recurrence, highlighting succinate as a promising biomarker and therapeutic target in inflammatory bowel disease. To the editor Dialister, an anaerobic Gram-negative genus of the human gut microbiome, has gained clinical interest due to its role in succinate metabolism. While capable of utilizing succinate as a substrate for propionate production, Dialister exhibits relatively slow consumption rates compared with efficient succinate consumers such as Phascolarctobacterium. This inefficiency may result in elevated luminal succinate levels, particularly in the context of inflammatory bowel disease (IBD) (1). Succinate accumulation may disrupt regulatory T cell (Treg) function by promoting FOXP3 degradation, thereby reducing immune tolerance and further amplifying inflammation (2). Furthermore, elevated succinate stabilizes hypoxia-inducible factor-1α (HIF-1α) by inhibiting prolyl hydroxylase activity, which prevents HIF-1α degradation and leads to enhanced inflammatory gene expression and perpetuation of tissue injury, particularly in IBD (3). We read with great interest the recently published article by Boronat-Toscano and colleagues on Dialister-driven succinate accumulation and its association with disease activity and postoperative recurrence in Crohn’s disease (4). This study offers valuable insights into a rapidly growing field of research that links gut microbiota, host metabolism, and inflammation. It positions succinate not just as a metabolic by-product but also as a functional biomarker and potential therapeutic target. One of the major strengths of this work is its integrative, multi-level approach, which combines clinical and biochemical measures of disease activity, such as the Harvey–Bradshaw Index, C-reactive protein, and fecal calprotectin, with gut microbiome profiling using 16S rRNA sequencing and host molecular markers related to succinate signaling, specifically the expression of the succinate receptor SUCNR1 (4). Notably, this study highlights specific Dialister operational taxonomic units (OTUs) in the intestinal mucosa that correlate with the risk and severity of postoperative recurrence. This goes beyond existing knowledge by identifying strain-level microbial signatures with potential predictive value, suggesting that variability within Dialister is vital for patient stratification and disease progression after surgery. The authors also propose a mechanism for succinate accumulation in Crohn's disease, involving the downregulation of NADH dehydrogenase and the upregulation of fumarate reductase and succinate transporters. This metabolic shift enhances succinate production and export by the gut microbiota (4). Despite these strengths, we would like to highlight several issues that merit further discussion. The functional analysis of the gut microbiome is based on predictive approaches (PICRUSt2) rather than on direct measurements of metabolic fluxes or shotgun metagenomic sequencing. Validation of these predictions is essential for robust conclusions. Targeted metabolomic analyses, using mass spectrometry or nuclear magnetic resonance, allow for direct quantification of metabolites as succinate and can confirm the functional activity of predicted pathways (5). In addition shotgun metagenomic sequencing may provide a more comprehensive and direct assessment of the genetic potential for metabolic pathways, including those involved in succinate production and consumption, by sequencing all microbial DNA present in a sample (6). These findings also open important avenues for future research and therapeutic development in inflammatory bowel disease. Given the central role of succinate in promoting intestinal inflammation through SUCNR1 activation and HIF-1α stabilization, strategies aimed at reducing succinate accumulation or blocking its downstream signaling pathways warrant further investigation. Microbiota-targeted interventions, including dietary fiber enrichment, prebiotics, and probiotics designed to enhance the abundance of efficient succinate-consuming bacteria such as Phascolarctobacterium, represent a particularly promising approach, as preclinical studies have demonstrated their ability to lower succinate levels, attenuate inflammatory signaling, and restore epithelial barrier integrity (7). Avoiding supplementation of the diet with refined inulin may be considered, as evidence from mouse models suggests that it can induce abnormal succinate accumulation in the intestinal lumen, thereby contributing to colonic inflammation (8). In parallel, pharmacological inhibition of SUCNR1 using small-molecule antagonists, as well as interventions targeting HIF-1α stabilization, may offer complementary strategies to suppress succinate-driven inflammation (9, 10). Huo et al. demonstrated that the SUCNR1 inhibitor NF-56-EJ40 may suppress glycolysis in intestinal epithelial cells and attenuates Th17-mediated inflammation in a dextran sodium sulfate–induced mouse model of ulcerative colitis. Treatment reduced pro-inflammatory cytokine production, improved epithelial barrier integrity, and alleviated colonic injury, supporting SUCNR1 antagonism as a therapeutic strategy targeting both metabolic and immune pathways (7). Consistently, genetic deletion of SUCNR1 in mice protected against both acute colitis and intestinal fibrosis, while in human fibroblasts derived from Crohn’s disease patients, succinate increased SUCNR1 expression and promoted inflammatory and fibrotic markers that were effectively reversed by SUCNR1 blockade (11). While these approaches are supported by growing mechanistic and translational evidence, well-designed clinical trials will be essential to determine their efficacy and safety in patients with IBD. Conclusion The study conducted by Boronat-Toscano et al. enhances the understanding of how microbiota-driven metabolic dysregulation relates to Crohn’s disease by identifing succinate and Dialister-associated microbial signatures associated as important factors that influence disease activity and the likelihood of postoperative recurrence. These findings support the use of succinate-related biomarkers in future risk assessment and postoperative monitoring strategies. Additionally, they provide a strong biological basis for therapeutic interventions that target succinate metabolism or SUCNR1-mediated signaling. Overall, this study marks a crucial step towards developing metabolically informed, microbiome-based precision medicine for IBD. 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