A transepithelial pathway delivers succinate to macrophages, thus perpetuating their pro-inflammatory metabolic state

Moran Fremder, Seung Won Kim, Ahlam Khamaysi, Liana Shimshilashvili, Hadar Eini-Rider, I. Seul Park, Uzi Hadad, Jae Hee Cheon, Ehud Ohana

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number109521
JournalCell Reports
Volume36
Issue number6
DOIs
StatePublished - 10 Aug 2021

Keywords

  • citrate
  • epithelia
  • inflammation
  • ion transport
  • macrophages
  • metabolism
  • microbiota
  • succinate

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