Succinate receptor mediates intestinal inflammation and fibrosis

Abstract

Succinate, an intermediate of the tricarboxylic acid cycle, is accumulated in inflamed areas and its signaling through succinate receptor (SUCNR1) regulates immune function. We analyze SUCNR1 expression in the intestine of Crohn's disease patients and its role in murine intestinal inflammation and fibrosis. We show that both serum and intestinal succinate levels and SUCNR1 expression in intestinal surgical resections were higher in CD patients than in controls. SUCNR1 co-localized with CD86, CD206, and α-SMA+ cells in human intestine and we found a positive and significant correlation between SUCNR1 and α-SMA expression. In human isolated fibroblasts from CD patients SUCNR1 expression was higher than in those from controls and treatment with succinate increased SUCNR1 expression, fibrotic markers and inflammatory cytokines through SUCNR1. This receptor modulated the expression of pro-inflammatory cytokines in resting murine macrophages, macrophage polarization and fibroblast activation and Sucnr1 −/− mice were protected against both acute TNBS-colitis and intestinal fibrosis induced by the heterotopic transplant of colonic tissue. We demonstrate increased succinate levels in serum and SUCNR1 expression in intestinal tissue of CD patients and show a role for SUCNR1 in murine intestinal inflammation and fibrosis.

Gut microbiota-derived succinate: Friend or foe in human metabolic diseases?

“…This might be particularly relevant in pathological conditions associated with alterations in intestinal barrier function (leaky gut). Indeed, an increase in both serum and intestinal succinate levels has been reported in patients with Crohn's disease when compared with healthy subjects [66]. Similarly, higher succinate levels have been reported in breast milk from mothers with IBD as compared with healthy peers [74].…”

“…In the context of disease, several studies have revealed a clear association between gut microbiota disturbances, linked for example to antibiotic-induced dysbiosis [63,64], motility disturbances [65] and specially IBD [34,66,67], and succinate accumulation in the gut lumen. More specifically, there is a wealth of evidence, both in mice and humans, demonstrating that IBD causes an increase in fecal succinate, which has been related to disease activity [68][69][70][71].…”

“…Colonization with other succinate producers such as Parabacteroides distasonis has also proven effective for improving metabolic dysfunctions associated with obesity [20]. Interestingly, the abundance of this commensal bacterium has been negatively correlated with IBD, which has been widely demonstrated to be linked to elevations in cecal succinate levels [34,66,67]. Nonetheless, secondary bile acids have also been identified as a potential mechanism involved in the metabolic beneficial effects of P. distasonis [20].…”

Diminished Vitamin D Receptor Protein Levels in Crohn’s Disease Fibroblasts: Effects of Vitamin D

“…Primary fibroblasts and epithelial cells were isolated from human intestinal resections of control and CD patients, as previously reported [20,21]. The tissue was cut in small pieces and incubated in agitation with HBSS-EDTA 30 min at 37 • C. After this step, the supernatant was collected and centrifuged to obtain the epithelial cells.…”

“…The in vivo model of intestinal fibrosis was induced in C57BL/6 mice using a heterotopic intestinal transplant as previously described [21,24]. In this protocol, small pieces of colon were subcutaneously transplanted into the dorsal neck region of recipient mice.…”