Intestinal Stem Cells Damaged by Deoxycholic Acid via AHR Pathway Contributes to Mucosal Barrier Dysfunction in High-Fat Feeding Mice

Abstract

High-fat exposure leads to impaired intestinal barrier function by disrupting the function of intestinal stem cells (ISCs); however, the exact mechanism of this phenomenon is still not known. We hypothesize that high concentrations of deoxycholic acid (DCA) in response to a high-fat diet (HFD) affect aryl hydrocarbon receptor (AHR) signalling in ISCs and the intestinal barrier. For this purpose, C57BL/6J mice feeding on a low-fat diet (LFD), an HFD, an HFD with the bile acid binder cholestyramine, and a LFD with the DCA were studied. We found that high-fat feeding induced an increase in faecal DCA concentrations. An HFD or DCA diet disrupted the differentiation function of ISCs by downregulating AHR signalling, which resulted in decreased goblet cells (GCs) and MUC2, and these changes were reversed by cholestyramine. In vitro experiments showed that DCA downregulated the differentiation function of ISCs, which was reversed by the AHR agonist 6-formylindolo [3,2-b]carbazole (FICZ). Mechanistically, DCA caused a reduction in indoleamine 2,3-dioxygenase 1 (IDO1) in Paneth cells, resulting in paracrine deficiency of the AHR ligand kynurenine in crypts. We demonstrated for the first time that DCA disrupts intestinal mucosal barrier function by interfering with AHR signalling in ISCs. Supplementation with AHR ligands may be a new therapeutic target for HFD-related impaired intestinal barrier function.

Different Diet Energy Levels Alter Body Condition, Glucolipid Metabolism, Fecal Microbiota and Metabolites in Adult Beagle Dogs

“…The bile acids, such as DCA mentioned above, are precisely secondary bile acids, which suggests that the digestion and utilization process of high-fat diets altered the metabolic activity of intestinal microbiota, reflected by similar results in humans [87,88]. A study in mice demonstrated that high-fat diets induced an increase in fecal DCA content and low-fat diets decreased the total BA content [89]. They also found that DCA disrupts intestinal mucosal barrier function by interfering with aryl hydrocarbon receptor (AHR) signaling in intestinal stem cells.…”

Anthocyanin attenuates disturbance of intestinal barrier in high-fat/high-cholesterol diet-challenged mice through regulating the response of T-helper 17 cells

“…It has been reported that reduced numbers of some intestinal epithelial cell types, such as goblet cells, Paneth cells (PCs) and intestinal stem cells (ISCs), may lead to disruption of the intestinal barrier function and damage epithelium homeostasis [22,23] . We next investigated the status of the goblet cells and the expression of MUC2 in SI.…”