The Role of Succinate in the Regulation of Intestinal Inflammation

Abstract

Succinate is a metabolic intermediate of the tricarboxylic acid (TCA) cycle within host cells. Succinate is also produced in large amounts during bacterial fermentation of dietary fiber. Elevated succinate levels within the gut lumen have been reported in association with microbiome disturbances (dysbiosis), as well as in patients with inflammatory bowel disease (IBD) and animal models of intestinal inflammation. Recent studies indicate that succinate can activate immune cells via its specific surface receptor, succinate receptor 1(SUCNR1), and enhance inflammation. However, the role of succinate in inflammatory processes within the gut mucosal immune system is unclear. This review includes current literature on the association of succinate with intestinal inflammation and the potential role of succinate⁻SUCNR1 signaling in gut immune functions.

Keywords: dysbiosis; inflammatory bowel disease; metabolic receptor; metabolite; microbiome.

Figure 1

Pathways for production of succinate by host cells and gut microbiota. (A) In the regular tricarboxylic acid (TCA) cycle within host mitochondria, succinate is produced as an intermediate metabolite formed from the conversion of succinyl-CoA, and is then oxidized by succinate dehydrogenase (SDH) to form fumarate. Succinate is also produced from succinic semialdehyde (SSA) via the γ-aminobutyric acid (GABA) shunt, and from isocitrate via the glyoxylate shunt. Under conditions of low oxygen, succinate can accumulate due to reversed action of SDH. (B) In microbial fermentation, succinate is commonly formed by the reversal of partial TCA cycle reactions. Pyruvate is carboxylated to form oxaloacetate, which is then reduced to malate, fumarate, and succinate. Succinate can then be decarboxylated to form propionate.