A transepithelial pathway delivers succinate to macrophages, thus perpetuating their proinflammatory metabolic state

In the last decade, the TCA-cycle intermediate, succinate, has been gaining attention as a signaling and regulatory molecule that promotes numerous physiological effects, including inflammatory diseases such as arthritis and inflammatory bowel diseases (IBD). The physiological role of endogenous succinate in re-programming cellular metabolism towards a pro-inflammatory state is the focus of many recent studies in the field of immuno-metabolism and associated diseases, most notably, IBD. However, how exogenous succinate affects intracellular metabolism and bioenergetics is unknown. Therefore, we have delineated the mechanisms that govern succinate delivery from the intestinal lumen into macrophages. We showed a significant increase of succinate uptake into pro-inflammatory macrophages, controlled by Na⁺-dependent succinate transporters in macrophages and epithelial cells. Our results indicate that succinate transporters of the SLC13 family control intestinal absorption of succinate, which is metabolized by gut bacteria. Furthermore, we found that fecal and serum succinate concentrations were markedly augmented in IBD and corresponded to changes in succinate-metabolizing gut bacteria. Finally, we demonstrated that elevated extracellular succinate concentrations perpetuate the pro-inflammatory response of macrophages and, hence, may result in chronic inflammation which is a hallmark of IBD. Together, our results suggest that succinate production and transport pathways determine succinate homeostasis and drive the inflammatory state of macrophages. When impaired, this may lead to chronic inflammation. Therefore, succinate transport pathways may be utilized as potential therapeutic targets to treat succinate-related pathologies including chronic inflammation, hypertension, and renal diseases and cancer.