Succinate metabolism: underlying biological mechanisms and emerging therapeutic targets in inflammatory bowel disease Original paper

What was studied?

This review focused on the dual roles of succinate in the pathogenesis and modulation of inflammatory bowel disease (IBD), particularly its involvement in immune regulation and metabolism. Succinate, a key metabolite produced by both host cells and gut microbiota, plays an essential role in the inflammation process by influencing immune cell signaling and modulating intestinal barrier functions. The review examines the metabolic and immune interactions between succinate and inflammatory pathways in IBD, along with the microbial factors that influence succinate levels.

Who was studied?

The study reviewed data from both clinical and experimental models of IBD, focusing particularly on patients with Crohn’s disease (CD) and ulcerative colitis (UC). It highlights the dysregulation of succinate metabolism in these patients, noting increased succinate concentrations in the serum and feces, especially during active disease phases. It also explores the role of various gut microbiota, specifically those that produce succinate, and their influence on IBD severity.

Most important findings

The review identifies succinate as a central molecule linking metabolism, immune responses, and microbiota in IBD. Elevated succinate levels correlate with disease severity, particularly in IBD patients where microbial dysbiosis leads to increased succinate production. Succinate acts through the SUCNR1 receptor, initiating pro-inflammatory pathways, including NF-kB and MAPK signaling, which exacerbate intestinal inflammation. In contrast, at lower concentrations, succinate can promote tissue repair by enhancing epithelial cell function and supporting immune responses that repair intestinal barriers. The concentration-dependent effects of succinate, where low levels are protective and high levels induce inflammation, provide crucial insights into potential therapeutic strategies.

The review also emphasizes the importance of gut microbiota composition in regulating succinate levels. Specific bacteria such as Phascolarctobacterium and Dialister consume succinate, while Bacteroides and Prevotella contribute to its production, influencing the inflammatory environment in the gut. This dual role is further modulated by factors like diet, antibiotics, and microbial balance, underlining the complex relationship between microbiota and host metabolism in IBD.

Key implications

The findings suggest potential therapeutic strategies targeting succinate metabolism. By modulating microbial succinate production or altering the host’s succinate signaling pathways, it may be possible to attenuate the inflammatory responses in IBD. SUCNR1 antagonists, probiotics that consume succinate, or dietary interventions that optimize succinate production-consumption balance are promising approaches. Understanding the precise concentration thresholds for succinate’s protective and pathogenic roles could pave the way for more personalized and effective treatments, particularly in early-stage or flare-up IBD. Further research into the spatial dynamics of succinate signaling within the gut, coupled with microbiome-targeted therapies, offers new avenues for clinical interventions.