Succinate signaling attenuates high-fat diet-induced metabolic disturbance and intestinal barrier dysfunction

Pharmacol Res. 2023 Aug:194:106865. doi: 10.1016/j.phrs.2023.106865. Epub 2023 Jul 22.

Abstract

Succinate is a vital signaling metabolite produced by the host and gut microbiota. Succinate has been shown to regulate host metabolic homeostasis and inhibit obesity-associated inflammation in macrophages by engaging its cognate receptor, SUCNR1. However, the contribution of the succinate-SUCNR1 axis to intestinal barrier dysfunction in obesity remains unclear. In the present study, we explored the effects of succinate-SUCNR1 signaling on high-fat diet (HFD)-induced intestinal barrier dysfunction. Using a SUCNR1-deficient mouse model under HFD feeding conditions, we identified the effects of succinate-SUCNR1 axis on obesity-associated intestinal barrier impairment. Our results showed that HFD administration decreased goblet cell numbers and mucus production, promoted intestinal pro-inflammatory responses, induced gut microbiota composition imbalance, increased intestinal permeability, and caused mucosal barrier dysfunction. Dietary succinate supplementation was sufficient to activate a type 2 immune response, trigger the differentiation of barrier-promoting goblet cells, suppress intestinal inflammation, restore HFD-induced mucosal barrier impairment and intestinal dysbiosis, and eventually exert anti-obesity effects. However, SUNNR1-deficient mice failed to improve the intestinal barrier function and metabolic phenotype in HFD mice. Our data indicate the protective role of the succinate-SUCNR1 axis in HFD-induced intestinal barrier dysfunction.

Keywords: Inflammation; Intestinal barrier; Microbiota; Obesity; SUCNR1; Succinate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diet, High-Fat / adverse effects
  • Gastrointestinal Diseases*
  • Inflammation / metabolism
  • Intestinal Diseases*
  • Mice
  • Mice, Inbred C57BL
  • Obesity / metabolism
  • Signal Transduction
  • Succinic Acid

Substances

  • Succinic Acid