한빛사논문
Moran Fremder1,6, Seung Won Kim2,3,4,6, Ahlam Khamaysi1, Liana Shimshilashvili1, Hadar Eini-Rider1, I Seul Park2,3, Uzi Hadad5, Jae Hee Cheon2,3,4,7,*, Ehud Ohana1,7,8,*
1Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
2Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
3Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
4Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
5The Ilse Katz Institute for Nanoscale Science and Technology Ben-Gurion University of the Negev, Beer-Sheva, Israel
*Corresponding author.
Abstract
The gut metabolite composition determined by the microbiota has paramount impact on gastrointestinal physiology. However, the role that bacterial metabolites play in communicating with host cells during inflammatory diseases is poorly understood. Here, we aim to identify the microbiota-determined output of the pro-inflammatory metabolite, succinate, and to elucidate the pathways that control transepithelial succinate absorption and subsequent succinate delivery to macrophages. We show a significant increase of succinate uptake into pro-inflammatory macrophages, which is controlled by Na+-dependent succinate transporters in macrophages and epithelial cells. Furthermore, we find that fecal and serum succinate concentrations were markedly augmented in inflammatory bowel diseases (IBDs) and corresponded to changes in succinate-metabolizing gut bacteria. Together, our results describe a succinate production and transport pathway that controls the absorption of succinate generated by distinct gut bacteria and its delivery into macrophages. In IBD, this mechanism fails to protect against the succinate surge, which may result in chronic inflammation.
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