Intestinal Inflammation Alters the Expression of Hepatic Bile Acid Receptors Causing Liver Impairment

Abstract

The gut-liver axis has been recently investigated in depth in relation to intestinal and hepatic diseases. Key actors are bile acid (BA) receptors, as farnesoid-X-receptor (FXR), pregnane-X-receptor (PXR) and G-protein-coupled-receptor (TGR5), that control a broad range of metabolic processes as well as inflammation and fibrosis.The present study aims to investigate the impact of intestinal inflammation on liver health with a focus on FXR, PXR and TGR5 expression. The strategy to improve liver health by reducing gut inflammation is also considered. Modulation of BA receptors in the inflamed colonic tissues of Inflammatory Bowel Disease (IBD) pediatric patients is analyzed. Methods: A dextran-sulphate (DSS) colitis animal model was built. Co-cultures with Caco2 and HepG2 cell lines were set up. Modulation of BA receptors in biopsies of IBD pediatric patients was assessed by Real-time-PCR and immunohistochemistry. Results: Histology showed inflammatory cell infiltration in the liver of DSS mice, where FXR and PXR were significantly decreased and oxidative stress was increased. Exposure of Caco2 to inflammatory stimuli resulted in the reduction of BA receptor expression in HepG2.Caco2 treatment with dipotassium glycyrrhizate (DPG) reduced these effects on liver cells.Inflamed colon of patients showed altered FXR, PXR and TGR5 expression.Conclusions: this study strongly suggests that gut inflammation affects hepatic cells by altering BA receptor levels as well as increasing the production of pro-inflammatory cytokines and oxidative stress. Hence, reducing gut inflammation is needed non only to improve the intestinal disease but also to protect the liver.

The Pathophysiology of Farnesoid X Receptor (FXR) in the GI Tract: Inflammation, Barrier Function and Innate Immunity

“…A similar decrease was also seen in FGF19 expression in adult patients with CD [57,63]. Interestingly, children with either UC or CD have significantly decreased expression of FXR in areas of active disease [64], which may explain why childhood IBD responds differently than in adults.…”

Role of nuclear receptor PXR in immune cells and inflammatory diseases

“…It was also revealed that the bile acid-activated receptor PXR modulated the communications between the intestinal immune system and intestinal microbiota (87). Moreover, additional studies reported the increased infiltration of inflammatory cells accompanied with the decreased expression of PXR in the liver of colitis mice treated with DSS (88). Collectively, these studies provided a preliminary hint that PXR may serve as a mediator in the "gut-liver" axis.…”

The Multi-Omics Analysis Revealed Microbiological Regulation of Rabbit Colon with Diarrhea Fed an Antibiotic-Free Diet

“…Metabolites enriched in the bile pathway were associated with regulating carbohydrate and lipid absorption and energy metabolism [ 49 ]. Bile acids (BA) could promote the absorption of vitamins in the intestine and improve the immune function of the body to maintain individual health [ 50 , 51 ]. Lithocholic acid and deoxycholic acid could regulate bile levels and hepatoenteric circulation by activating the Farnesoid X receptor (FXR).…”